History of physical treatments
The classification of drugs used in psychiatry
Other physical treatments
This chapter is concerned with the use of drugs and other physical treatments, such as electroconvulsive therapy and neurosurgical procedures. Psychological treatments are the subject of Chapter 20. This separation, although convenient when treatments are described, does not imply that the two kinds of therapy are to be thought of as exclusive alternatives when an individual patient is considered; on the contrary, many patients require both. In this book, the ways of combining treatments are considered in other chapters where the treatment of individual syndromes is discussed. It is important to keep this point in mind when reading this chapter and the next.
Our concern is with clinical therapeutics rather than basic psychopharmacology, which the reader is assumed to have studied already. An adequate knowledge of the mechanisms of drug action is essential if drugs are to be used in a rational way, but a word of caution is appropriate. The clinician should not assume that the therapeutic effects of psychotropic drugs are necessarily explained by the pharmacological actions that have been discovered so far. In addition, there is relatively little knowledge about the neuropsychological mechanisms through which pharmacological manipulation can ameliorate psychological symptomatology.
This caution does not imply that a knowledge of pharmacological mechanisms has no bearing on psychiatric therapeutics. On the contrary, there have been substantial advances in pharmacological knowledge since the first psychotropic drugs were introduced in the 1950s, and it is increasingly important for the clinician to relate this knowledge to their use of drugs. As noted in Chapter 6, evidence-based clinical guidelines are increasingly used to assist practitioners in their use of medication, and it is important to be aware of these. However, in specialist psychiatric practice there is often rather little high-quality evidence to guide prescribing, and a knowledge of pharmacology will help to ensure that safe and reasonable prescribing practices are followed.
History of physical treatments
Physical treatments have been applied to patients with psychiatric disorders since antiquity, although, in retrospect, the most that could be claimed for the best of these interventions is that they were relatively harmless. Of course, the same holds for the management of patients with general medical disorders, for which similar treatments, such as bleeding and purging, were often used regardless of diagnosis. It is wise not to be too censorious about the treatment of disorders of which the aetiology is still largely unknown, but to bear in mind that ‘it may well be that in a hundred years current therapies, psychotherapies as well as physical therapies, will be looked upon as similarly uncouth and improbable’ (Kiloh et al., 1988).
Historically, physical treatments can be divided into two main classes:
• those that were aimed at producing a direct change in a pathophysiological process, usually by some alteration in brain function
• those that were aimed at producing symptomatic improvement through a dramatic psychological impact.
The latter interventions were often based on philosophical theories about the moral basis of madness. For example, many physicians appear to have followed the proposal of Heinroth (1773–1843) that insanity was the product of evil and personal wrongdoing. Accordingly, restraint with chains and corporal punishment were seen as appropriate remedies. Other physical treatments, such as the spinning chair introduced by Erasmus Darwin (1731–1802), seemed to be designed to produce a general ‘shock to the system’, and perhaps thereby to interrupt the morbid preoccupations of the patient. A less arduous regimen was the use of continuous warm baths, often given in combination with cold packs. This treatment was recommended by clinicians as distinguished as John Connolly (1794–1866) and Emil Kraepelin (1856–1926), and was still in use at the Bethlem Hospital in the 1950s.
Drugs that produce changes in the function of the central nervous system, such as opiates and anticholinergic agents, have been used in the treatment of mental disorders for hundreds of years. Although some of these drugs may sometimes have had calming effects, they were of no specific value in the treatment of psychiatric disorders. Often a physical treatment was used not because of its proven efficacy, but because it was recommended by an eminent and vigorous physician. Also, the assessment of efficacy depended almost entirely on uncontrolled clinical observation.
In 1933, about 10 years after the isolation of insulin by Frederick Banting and Charles Best, Manfred Sakel introduced insulin coma treatment for psychosis (Sakel, 1938). A suitable dose of insulin was used to produce a coma, which was terminated by either tube feeding or intravenous glucose. A course of treatment could include up to 60 comas. Not surprisingly, serious side-effects were common, and a mortality of at least 1% could be expected, depending on the standard of the clinic and the physical state of the patient. Insulin coma treatment was rapidly taken up throughout Europe, and many specialized treatment units were built. There was a great improvement in the morale of patients and staff because of the belief that this dramatic treatment could cure symptoms of some of the most serious psychiatric disorders.
There were always some practitioners who doubted the efficacy of insulin coma treatment. Their doubts were reinforced by a controlled trial by Ackner and Oldham (1962), who found that, in patients with schizophrenia, insulin coma was no more effective than a similar period of unconsciousness induced by barbiturates. This study was published about the time when chlorpromazine was introduced, and both factors led to a rapid decline in the use of insulin coma treatment. It should be noted that the controlled studies did not exclude the efficacy of insulin treatment in some circumstances, and a number of workers continued to maintain that it was effective. Therefore it is interesting that recent experimental studies have shown that insulin administration causes striking changes in the release of monoamine neurotransmitters in the brain. Perhaps the main lesson to be learned from insulin coma treatment is that the introduction of a new medical treatment should be preceded by adequate controlled trials to determine whether it is therapeutically more effective or safer than current therapies (see Chapter 6). This lesson is particularly important in psychiatry, because the aetiology of most disorders is obscure and outcome may vary widely, even among patients with the same clinical syndrome.
Electroconvulsive therapy (ECT) was introduced about the same time as insulin coma treatment. Unlike the latter, ECT has retained a place in current clinical practice. The rationale for convulsive therapy was a postulated antagonism between schizophrenia and convulsions such that the one would exclude the other. This view is erroneous in so far as schizophrenia-like illnesses are actually more common in patients with temporal lobe epilepsy than would be expected by chance (see p. 339). Astute clinical observation, in combination with controlled trials, has shown that ECT is effective in the acute treatment of severe mood disorders. Thus, even though the rationale for the introduction of ECT was incorrect and its mode of action remains unclear, controlled trials have confirmed that, in carefully defined clinical situations, ECT is a safe and effective treatment (see p. 557).
The action of lithium in reducing mania was a chance finding by Cade (1949), who had been investigating the effects of urates in animals and had decided to use the lithium salt because of its solubility. Lithium is a toxic agent, so Cade’s important observations did not have a significant impact on clinical practice until the following decade, when controlled trials showed that lithium was effective in both the acute treatment of mania and the prophylaxis of recurrent mood disorders.
Box 19.1 Introduction of some physical treatments in psychiatry
1934 Insulin coma treatment (Sakel)
1936 Frontal leucotomy (Moniz)
1936 Metrazole convulsive therapy (Meduna)
1938 Electroconvulsive therapy (Cerletti and Bini)
1949 Lithium (Cade)
1952 Chlorpromazine (Delay and Deniker)
1954 Benzodiazepines (Sternbach)
1957 Iproniazid (Crane and Kline)
1957 Imipramine (Kuhn)
1966 Valpromide (valproate) in bipolar disorder (Lambert et al.)
1967 Clomipramine in obsessive–compulsive disorder (Fernandez and Lopez-Ibor)
1971 Carbamazepine in bipolar disorder (Takezaki and Hanaoka)
1988 Clozapine in treatment-resistant schizophrenia (Kane et al.)
1999 Lamotrigine in bipolar depression (Calabrese et al.)
Other agents that revolutionized psychopharmacology were introduced about this time (see Box 19.1). Their efficacy and their indications were first recognized through clinical observation, and were subsequently confirmed by controlled clinical trials. None of these agents was introduced on the basis of an aetiological hypothesis. Indeed, such aetiological hypotheses as there are in biological psychiatry have been largely derived from knowledge of the mode of action of effective drugs. Thus the dopamine-receptor-antagonist properties of antipsychotic drugs have given rise to the dopamine hypothesis of schizophrenia, while the action of tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) in facilitating the effects of noradrenaline and 5-hydroxytryptamine (5-HT) has led to the various monoamine hypotheses of mood disorders.
The last 30 years have brought a period of consolidation in psychopharmacology. Clinical trials have been widely used to refine the indications of particular drug treatments and to maximize their risk/benefit ratios. New compounds have become available, but because most of them have been derived from previously described agents, their range of activity is not strikingly different from that of their predecessors. In general, however, the newer agents are better tolerated and sometimes safer—developments which are important for clinical practice.
There may now be grounds for more optimism about the prospects for advances in psychopharmacology. For example, there is rapidly increasing knowledge about chemical signalling in the brain. Numerous neurotransmitters and neuromodulators interact with specific families of receptors, many of which exist in a number of different subtypes. Most of these receptors have been cloned, and selective ligands for them are becoming available. There is increasing knowledge as to how these chemical messengers may modify behaviour through their interactions with specific brain regions and distributed neuronal circuits.
Future compounds that are developed as consequence of these scientific advances are likely to differ from current drugs in their range of behavioural effects, and could lead to important new developments in psychopharmacology. Given the complex causes of psychiatric disorders, it seems likely that detailed knowledge of aetiology and pathophysiology may lag behind advances in therapeutics. Of course, this disparity is not uncommon in general medicine. It serves to reinforce the importance of randomized clinical trials in the assessment of new psychopharmacological treatments.
The pharmacokinetics of psychotropic drugs
Before psychotropic drugs can produce their therapeutic effects, they must reach the brain in adequate amounts. The extent to which they do so depends on their absorption, metabolism, excretion, and passage across the blood–brain barrier. A short review of these processes is given here. The reader who has not studied them before is referred to the chapter on pharmacokinetics in Grahame-Smith and Aronson (2002). The following processes are important:
In general, psychotropic drugs are easily absorbed from the gut because most of them are lipophilic and are not highly ionized at physiological pH values. Like other drugs, they are absorbed faster from an empty stomach, and in reduced amounts by patients suffering from intestinal hurry or malabsorption syndrome.
Psychotropic drugs are distributed in the plasma, where most of them are largely bound to proteins—for example, diazepam and amitriptyline are about 95% bound. They pass easily from the plasma to the brain because they are highly lipophilic. For the same reason, they enter fat stores, from which they are released slowly long after the patient has ceased to take the drug. This means that psychotropic drugs tend to have large volumes of distribution.
Most psychotropic drugs are metabolized in the liver. This process begins as the drugs pass through the liver in the portal circulation on their way from the gut. This ‘first-pass’ metabolism reduces the amount of available drug, and is one of the reasons why larger doses are needed when a drug such as chlorpromazine is given by mouth than when it is given intramuscularly. The extent of this liver metabolism differs from one person to another. It is altered by certain other drugs which, if taken at the same time, induce liver enzymes (e.g. carbamazepine) or inhibit them (e.g. selective serotonin reuptake inhibitors [SSRIs]).
Some drugs, such as carbamazepine, induce their own metabolism, especially after being taken for a long time. Not all drug metabolites are inactive—for example, fluoxetine is metabolized to a hydroxy derivative, norfluoxetine, which is also a potent 5-HT reuptake inhibitor. Where drugs give rise to active metabolites, measurements of plasma concentrations of the parent drug alone are a poor guide to therapeutic activity.
Psychotropic drugs and their metabolites are excreted mainly through the kidney. When kidney function is impaired, excretion is reduced and a lower dose of drug should be given. Lithium is filtered passively and then partly reabsorbed by the same mechanism that absorbs sodium. The two ions compete for this mechanism; hence reabsorption of lithium increases when that of sodium is reduced (e.g. by thiazide diuretics). Certain fractions of lipophilic drugs such as chlorpromazine are partly excreted in the bile, enter the intestine for the second time, and are then partly reabsorbed (i.e. a proportion of the drug is recycled between intestine and liver).
Measurement of circulating drug concentrations
As a result of individual variations in the mechanisms described above, plasma concentrations after standard doses of psychotropic drugs vary substantially from one patient to another. For example, tenfold differences have been observed with the antidepressant drug nortriptyline. Therefore it might be expected that measurements of the plasma concentration of circulating drugs would help the clinician. However, with a few exceptions (e.g. lithium and clozapine), this practice is rarely helpful because the plasma drug levels that predict therapeutic response or toxicity within individuals vary so much. Clearly for any drug to work it must be present in plasma above a certain minimum concentration, and for some medications ‘target’ levels have been suggested. However, it is still not unusual for some individuals to show a therapeutic response when plasma levels are lower than recommended.
As an alternative to these assays, it may be possible to measure the pharmacological property which is thought to be responsible for the therapeutic effect of a particular drug. For example, positron emission tomography can be used to measure directly the degree of brain dopamine-receptor blockade produced by antipsychotic drugs during treatment. Such information has proved valuable in designing appropriate dosage regimens of antipsychotic drugs (see Table 19.6). However, these pharmacodynamic measures have not yet been able to identify why some patients do not respond to medication. For example, the degree of dopamine-receptor blockade is the same in patients who respond to antipsychotic drugs as in those who do not. Pharmacogenetic approaches to prediction of treatment response (see Box 19.2) are a topic of current interest, although most of the findings remain controversial and yet to have an impact on routine clinical practice. For a review, see Zandi and Judy (2010).
Plasma concentrations of drugs vary throughout the day, rising immediately after the dose and falling at a rate that differs between individual drugs and individual people. The rate at which a drug level declines after a single dose ranges from hours for lithium carbonate to weeks for slow-release preparations of injectable antipsychotic agents. Knowledge of these differences allows more rational decisions to be made about appropriate intervals between doses.
Box 19.2 Pharmacogenetics in psychiatry
Polymorphic (allelic) variation in DNA may affect the expression (and therefore the function) of genes involved in the actions, or metabolism, of psychotropic drugs. That is, they may modify the likelihood of therapeutic response or the development of adverse effects. Examples are listed below.
• Genetic variation in CYP-metabolizing enzymes can affect blood levels of drugs and thereby brain exposure. Mutations in the gene for CYP2D6 may be associated with antipsychotic drug-induced tardive dyskinesia.
• Alleles associated with decreased expression of 5-HT transporter may be associated with poorer response to SSRIs.
• Therapeutic response to clozapine may be associated with specific alleles of the 5-HT2A receptor.
• Weight gain with antipsychotic drugs is associated with an allele of the 5-HT2C receptor.
The concept of plasma half-life is useful here. The half-life of a drug in plasma is the time taken for its concentration to fall by a half, once dosing has ceased. For most psychotropic drugs, the amount eliminated over time is proportional to the plasma concentration, and in this case it will take approximately five times the half-life for the drug to be eliminated from plasma. Equally, when dosing with a drug begins, it will take five times the half-life for the concentration in plasma to reach steady state. This can be important when planning treatment. For example, MAOIs should not be given with SSRIs. Therefore if a patient is taking sertraline, which has an elimination half-life of about 26 hours, it will be important to leave at least five times the half-life (a week is recommended) before starting MAOI treatment. When sertra-line treatment begins, the plasma concentrations will continue to rise for about a week before reaching a steady state.
When two psychotropic drugs are given together, one may interfere with or enhance the actions of the other. Interference may arise through alterations in absorption, binding, metabolism, or excretion (pharmacokinetic interactions), or by interaction between the pharmacological mechanisms of action (pharmacodynamic interactions).
Interactions that affect drug absorption are seldom important for psychotropic drugs, although it is worth noting that absorption of chlorpromazine is reduced by antacids. Interactions due to protein bindingare also uncommon, even though many psychotropic drugs are highly protein bound. Interactions that affect drug metabolism are of considerable importance. Examples include the inhibition of the metabolism of antipsychotic drugs by SSRIs, and the stimulation of the metabolism of many psychotropic drugs by carbamazepine, which induces the relevant cytochrome P450 enzymes (see below). Interactions that affect renal excretion are mainly important for lithium, the elimination of which is decreased by thiazide diuretics.
Cytochrome P450 enzymes. There have been significant developments in the understanding of the microsomal cytochrome P450 enzyme system. These enzymes are located mainly in the liver but also in other tissues, including the gut wall and brain. Their role is to detoxify exogenous substances such as drugs, and their activity can be increased or decreased by concomitant drug administration. This can give rise to clinically important drug interactions (Grahame-Smith and Aronson, 2002). Importantly, several new antidepressants, particularly selective SSRIs, potently inhibit P450 enzymes (see Table 19.11).
Pharmacodynamic interactions are exemplified by the serotonin syndrome, in which drugs that potentiate brain 5-HT function by different mechanisms (e.g. SSRIs and MAOIs) can combine to produce dangerous 5-HT toxicity (see p. 541).
As a rule, a single drug can be used to produce all of the effects required of a combination—for example, many antidepressant drugs have useful anti-anxiety effects. It is desirable to avoid combinations of psychotropic drugs whenever possible, and if a combination is to be used, it is essential to know about possible interactions. The British National Formulary provides a useful guide.
Many psychotropic drugs do not achieve useful therapeutic effects for several days or even weeks. After the drugs have been stopped, there is often a comparable delay before their effects are lost. Psychotropic and indeed many other classes of drugs produce neuroadaptive changes during repeated administration. Tissues therefore have to readjust when drug treatment is stopped; this readjustment may appear clinically as a withdrawal or abstinence syndrome. Characteristic abstinence syndromes have been described for antidepressants, antipsychotics, and anxiolytics, while sudden discontinuation of lithium can provoke a ‘rebound’ mania. It is important to be able to distinguish withdrawal syndromes from relapse of the disorder that is being treated. In addition, the risk of abstinence symptoms makes it prudent to withdraw psychotropic drugs slowly wherever possible.
General advice about prescribing
Use well-tried drugs
It is good practice to use well-tried drugs with therapeutic actions and side-effects that are thoroughly understood. The clinician should become familiar with a small number of drugs from each of the main classes. In this way he can become used to adjusting the dosage and recognizing side-effects. Well-tried drugs are usually less expensive than new preparations.
Give an adequate dose
Having chosen a suitable drug, the doctor should prescribe it in adequate doses. He should not change the drug or add others without a good reason. In general, if there is no therapeutic response to one established drug, there is no likelihood of a better response to another that has very similar pharmacological properties (provided that the first drug has been taken in adequate amounts). However, since the main obstacle to adequate dosage is usually side-effects, it may be appropriate to change to a drug with a different pattern of side-effects—for example, from a tricyclic antidepressant to an SSRI, or vice versa.
Use drug combinations cautiously
Occasionally, combinations of psychotropic drugs are given deliberately in the hope of producing interactions that will be more potent than the effects of either drug taken alone in full dosage (e.g. a tricyclic antidepressant with a MAOI). This practice, if it is to be used, is best carried out by experienced psychiatrists (or under their guidance), because the adverse effects of combinations are less easy to predict than those of single drugs.
Dosing and treatment duration
When a drug is prescribed, it is necessary to determine the dose, the interval between doses, and the likely duration of treatment. The dose ranges for commonly used drugs are indicated later in this chapter. Ranges for others can be found in the manufacturers’ literature, the British National Formulary, or a comparable work of reference. Within the therapeutic range, the correct dose for an individual patient should be decided after considering the severity of symptoms, the patient’s age and weight, and any factors that may affect drug metabolism (e.g. other drugs that are being taken, or renal disease).
Next, the interval between doses must be decided. Psychotropic drugs have often been given three times a day, even though their duration of action is such that most can be taken once or twice a day without any undesirable fall in plasma concentrations between doses. Less frequent administration has the advantage that outpatients are more likely to be reliable in taking drugs. In hospital, less frequent drug rounds mean that nurses have more time for psychological aspects of treatment. Some drugs, such as anxiolytics, are required for immediate effect rather than continuous action; they should not be given at regular intervals, but shortly before occasions on which symptoms are expected to be at their worst. The duration of treatment depends on the disorder under treatment; it is considered in the chapter that deals with the relevant clinical syndrome.
What patients want to know
Psychotropic drugs have the aim of changing what people think and feel; not surprisingly, many patients have misgivings about taking them. It is therefore important to make it clear what the drug is being used for, what therapeutic effects are expected, and when they should start to appear. Other key questions that must be dealt with include the following:
• What effects will I experience on first taking the drug?
• What side-effects can I expect?
• What serious side-effects should I report immediately?
• For how long should I take the drug?
• Is the drug addictive?
• What will I notice when I stop the drug?
Compliance, concordance, and collaboration
Many patients do not take the drugs that are prescribed for them. Of course this problem is not restricted to psychiatric practice, but the use of psychotropic drugs raises additional issues in terms of societal stigma and the nature of the adverse effects. Problems with compliance are mainly manifested when treating outpatients, but also occur in hospital, where some patients find ways of avoiding taking the drugs administered by nurses.
If patients are to take medication reliably, they must be convinced of the need to take it, be free from unfounded fears about its dangers, and be aware of how to take it. Each of these requirements presents particular problems when the patient has a psychiatric disorder. Thus patients with schizophrenia or seriously depressed patients may not be convinced that they are ill, or they may not wish to recover. Deluded patients may distrust clinical staff, and hypochondriacal patients may fear dangerous side-effects. Anxious patients often forget the prescribed dosage and frequency of their drugs. Therefore it is not surprising that many psychiatric patients do not take their drugs in the prescribed way. It is important for the clinician to pay attention to this problem. Time spent discussing the patient’s concerns is time well spent, for it often increases compliance with treatment. Written instructions can be a valuable adjunct, and are now often included with drug packaging.
The successful and safe use of medication requires an essentially collaborative relationship between patient and doctor. Some have proposed that the terms concordance or adherence should therefore be preferred to compliance, which carries the implicit assumption that the patient’s job is to obey instructions. Whatever the term used, it is clearly important to recognize that the use of drug treatment, particularly in psychiatry, requires a thorough understanding of the patient’s attitude to both their illness and its treatment (Chaplin et al., 2007; National Institute for Health and Clinical Excellence, 2009a; Britten et al., 2010).
Ethical aspects of drug prescription
The ethical issues in this complex area have been reviewed by Kader and Pantelis (2009).
1. The basis of ethical prescribing is the practitioner’s comprehensive knowledge of the risks and benefits of drug therapies. This will be derived from evidence-based approaches where possible.
2. The doctor–patient relationship is the appropriate framework through which this knowledge is communicated to the patient.
3. The therapeutic partnership between patient and doctor must lead to true informed consent, which includes the right of competent patients to refuse treatment.
Difficulties arise when the evidence base for treatment is lacking and when there is uncertainty about what approach to pursue. Here the clinician has the responsibility to advise treatments that would be supported by peer opinion and to use clinical guidelines. The clinician should also support the right of patients to genuinely effective treatment where this is being hindered by cost constraint and other economic factors. Another difficult problem concerns refusal of treatment when capacity is impaired and the health and safety of the patient or others are at risk. In fact, empirical research suggests that refusal of treatment in these circumstances is often transient and due to current clinical factors. Indeed most patients whose refusal of treatment is clinically overridden apparently conclude eventually that the decision to treat them was justified (Kader and Pantelis, 2009). It is, of course, important to elucidate and document the reasons for treatment refusal, and to respect the right of competent patients to refuse treatment.
Prescribing for special groups
Children and the elderly
Psychotropic drugs usually lack specific licences for use in young people, and relevant controlled trials are sparse. However, advice from the UK Committee on Safety of Medicines is that the efficacy of some SSRIs and venlafaxine treatment in depressed adolescents does not outweigh their disadvantages in terms of agitation and suicidal behaviour (see also Whittington et al., 2004). Practitioners need to make themselves aware of local guidelines concerning the use of psychotropic medication in young people, and should seek specialist advice when in doubt.
Clinical trials of most psychotropic medications often exclude older patients, even though conditions such as depression are more common in the elderly. Elderly patients are often sensitive to side-effects of medication, and may have impaired renal or hepatic function; for these reasons it is important to start treatment with low doses.
There are special problems with regard to prescribing psychotropic drugs in pregnancy, because of the risk of teratogenesis. Information about the teratogenic risk of individual drugs can be obtained from the relevant manufacturer and from the British National Formulary, although the available evidence is often sparse or difficult to interpret. The practitioner and patient have the difficult task of weighing this information against the risk of managing the illness without medication. In addition, a substantial number of pregnancies are unplanned. For this reason, it is prudent where possible to advise women of childbearing age who require psychotropic drugs specifically to avoid pregnancy until the need for the drug treatment is over. For reviews of the use of psychotropic drugs in pregnancy, see National Institute for Health and Clinical Excellence (2007e) and Paton (2008).
Anxiolytics and antidepressants
Anxiolytic drugs are seldom essential in early pregnancy, and psychological treatments can usually be used. If medication is needed, benzodiazepines have in general not been shown to be teratogenic, although one meta-analysis has shown an increased risk of oral clefts after first-trimester exposure. If an antidepressant drug is required, it is probably better to use long-established preparations such as imipramine or amitriptyline for which there is no consistent evidence of a teratogenic effect after many years of use. There is also reasonable experience with fluoxetine, which does not appear to be associated with an increased risk of major malformations. However, paroxetine treatment in the first trimester may result in increased cardiac defects, and SSRIs taken after 20 weeks’ gestation may result in an increased risk of pulmonary hypertension in the newborn.
Antipsychotic drugs and mood stabilizers
It is seldom necessary to start antipsychotic drugs in early pregnancy. There is little evidence that high-potency agents such as haloperidol carry an increased teratogenic risk. However, there may be a higher rate of congenital malformations in babies who are exposed to lower-potency agents such as chlorpromazine. There is little information on the teratogenic risk of newer antipsychotic agents.
Lithium treatment early in pregnancy has been associated with cardiac abnormalities in the fetus, particularly Ebstein’s anomaly. Therefore women who are considering pregnancy have been recommended to discontinue lithium before conceiving. Similarly, women who become pregnant while taking lithium have usually been advised to stop the treatment. However, recent epidemiological studies have suggested that although the relative risk of Ebstein’s anomaly is increased at least tenfold in infants who are exposed to lithium in the first trimester, the absolute risk is still fairly low, at 0.05–0.1%. Withdrawal of lithium carries a high risk of relapse in patients with bipolar illness, and the balance of risk to mother and baby may therefore suggest continuation of lithium treatment during pregnancy in some cases.
Anticonvulsant drugs such as carbamazepine and valproate are increasingly used as mood stabilizers. However, both of these agents are clearly associated with an increased risk of neural-tube defects as well as other fetal abnormalities. The neural-tube defects associated with anti-convulsant use may be associated with changes in folate metabolism. However, a role for folate treatment in their prevention has not been established.
Exposure to psychotropic drugs in the later stages of pregnancy can give rise to neonatal toxicity either through the presence of the drug or through a withdrawal syndrome. For example, it has been reported that among babies born to mothers who have been receiving tricyclic antidepressants there may be withdrawal reactions that include tremulousness, vomiting, poor feeding, and seizures. Direct anticholinergic effects such as gastrointestinal stasis and bladder distension have also been reported. These reactions, although clearly problematic, appear to settle quickly without causing lasting sequelae.
There are also reports that late exposure to SSRIs may be associated with an increased risk of neonatal complications, including jitteriness, hypoglycaemia, poor muscle tone, and respiratory difficulties. The perinatal toxicity associated with lithium use includes ‘floppy baby syndrome’, with cyanosis and hypotonicity, whereas benzodiazepine treatment can result in impaired temperature regulation together with breathing and feeding difficulties.
Animal studies suggest that fetal exposure to psychotropic medication can cause longer-term abnormalities in brain development and behaviour, and it is possible that similar effects might occur in humans (see, for example, Pederson et al., 2010). However, disentangling such effects from those of depression is difficult (Grote et al., 2010).
Psychotropic drugs should be prescribed cautiously to women who are breastfeeding. Diazepam and other benzodiazepines pass readily into breast milk, and may cause sedation and hypotonicity in the infant. Antipsychotic drugs and antidepressants also enter breast milk, although rather less readily than diazepam. However, sulpiride is excreted in significant amounts and should be avoided. Fluoxetine and citalopram could also accumulate, but imipramine, nortriptyline, and sertraline are present in small amounts and breastfeeding can be permitted while the baby is observed for sedation or feeding difficulties. It is usually advised that mothers should express and discard breast milk that has been exposed to peak plasma levels of the drug concerned.
Lithium salts enter the milk freely, and serum concentrations in the infant can approach those of the mother, so breastfeeding requires great caution. However, the amounts of carbamazepine and valproate in breast milk are considered too low to be harmful. A general problem is that, even when the concentration of a particular drug in breast milk is low and no detectable clinical effect on the infant can be discerned, it is nevertheless possible that subtle longer-term effects on brain development and behaviour could occur. For this reason, some authorities recommend that women who are receiving psychotropic medication should not breastfeed at all. A more pragmatic view is provided by the British National Formulary (see also National Institute for Health and Clinical Excellence, 2007e; Moretti, 2009).
What to do if there is no therapeutic response
1. Is the drug being taken as recommended? The first step is to find out whether the patient has been taking the drug in the correct dose. They may not have understood the original instructions, or may be worried that a full dose will produce unpleasant side-effects. Some patients fear that they will become dependent if they take the drug regularly. Other patients may have little wish to take drugs for the reasons discussed above.
2. Is the patient is taking any other drug which could affect the metabolism or pharmacological action of the psychotropic agent? Misuse of legal or illegal substances might interfere with the therapeutic actions of psychotropic drugs.
3. Is the diagnosis correct? Review the diagnosis to make sure that the treatment is appropriate before deciding whether to increase the dose.
Failure to respond adequately to psychotropic medication is a common reason for psychiatric referral. Specific pharmacological approaches for individual disorders are discussed in the relevant chapters.
The classification of drugs used in psychiatry
Drugs that have effects mainly on mental symptoms are referred to as psychotropic. Psychiatrists also use the term antiparkinsonian agents, which refers to drugs that are employed to control the side-effects of some psychotropic drugs. Anticonvulsant drugs have a growing role in the treatment of mood disorders.
Psychotropic drugs are conventionally divided into different classes, as shown in Table 19.1, but the therapeutic actions of particular compounds are not confined to one diagnostic category. For example, SSRIs are classified as antidepressants and are effective in the treatment of major depression, but they also produce useful therapeutic effects in anxiety states, obsessive–compulsive disorders, and some eating disorders. Of course, this breadth of effect does not mean that the latter syndromes are forms of depression. It merely highlights the fact that the neuropsychological consequences of facilitating brain 5-HT function may provide beneficial effects in a variety of psychiatric disorders.
Although there is considerable understanding of the pharmacological actions of psychotropic drugs, little is known about the neuropsychological consequences of these pharmacological actions and about the ways in which neuropsychological changes are translated into clinical benefit in different diagnostic syndromes. At present, therefore, the best plan is to classify drugs according to their major therapeutic use, but to bear in mind that the therapeutic effects of different classes of drugs may overlap considerably.
Each of the main groups of drugs will now be reviewed in turn. For each group, an account will be given of therapeutic effects, pharmacology, the principal compounds available, pharmacokinetics, unwanted effects (both those appearing with ordinary doses and the toxic effects of unduly high doses), and contraindications. General advice will also be given about the use of each group in everyday clinical practice, but specific applications to the treatment of individual disorders will be found in the chapters that deal with those conditions. Drugs that have a limited use in the treatment of a single disorder—for example, disulfiram for alcohol problems, or cholinesterase inhibitors for dementia—are discussed in the chapters that deal with the relevant clinical syndromes.
Anxiolytic drugs, such as benzodiazepines, have been prescribed widely and often inappropriately. Before prescribing anxiolytic drugs it is always important to seek the causes of anxiety and to try to modify them. It is also essential to recognize that a degree of anxiety can motivate patients to take steps to reduce the problems that are causing it. Therefore removing all anxiety in the short term is not always beneficial to the patient in the long run. Anxiolytics such as benzodiazepines are most useful when given for a short time, either to tide the patient over a crisis or to help them to tackle a specific problem.
Tolerance is a particular problem with barbiturates and benzodiazepine-like anxiolytic drugs, and drug dependence can develop. Because the benzodiazepines are still widely used anxiolytics, they will be considered first. Anti-depressants are increasingly used to treat specific anxiety syndromes, but their therapeutic actions differ in important ways from benzodiazepine-like drugs. Their indications in the treatment of anxiety disorders will be considered here, but their detailed pharmacology is discussed in the section on antidepressant drugs (see p. 531). When reading this section, it is important to bear in mind that psychological treatments are effective in the management of anxiety disorders and have certain advantages over drug treatment, including more sustained efficacy after treatment cessation, as well as fewer adverse effects.
Table 19.1 Classification of clinical psychotropic drugs
Benzodiazepines have several actions:
• sedative and hypnotic
• muscle relaxant
Their pharmacological actions are mediated through specific receptor sites located in a supramolecular complex with gamma-aminobutyric acid (GABAA) receptors. Benzodiazepines enhance GABA neurotransmission, thereby indirectly altering the activity of other neurotransmitter systems, such as those involving noradrenaline and 5-HT.
Many different benzodiazepines are available. They differ both in the potency with which they interact with benzodiazepine receptors and in their plasma half-life (see Box 19.3). In general, high-potency benzodiazepines and those with short half-lives are more likely to be associated with dependence and withdrawal. Benzodiazepines with short half-lives (less than 12 hours) include lorazepam, temazepam, and lormetazepam.
Because of problems with dependence, long-acting benzodiazepines are preferable for the management of anxiety, even if such treatment is to be given intermittently on an ‘as-required’ basis. Long-acting benzodiazepines include drugs such as diazepam, chlordiazepoxide, alprazolam, and clonazepam. Diazepam is rapidly absorbed and can be used both for the continuous treatment of anxiety and for treatment ‘as required.’ Alprazolam, a high-potency benzodiazepine, is effective in the treatment of panic disorder. This therapeutic efficacy is not confined to alprazolam, because equivalent doses of other high-potency agents such as clonazepam are also effective.
Flumazenil is a benzodiazepine-receptor antagonist that produces little pharmacological effect by itself, but blocks the actions of other benzodiazepines. Therefore it may be useful in reversing acute toxicity produced by benzodiazepines, but carries a risk of provoking acute benzodiazepine withdrawal. Flumazenil is available only for intravenous use.
Box 19.3 Half-lives of some drugs that act at the GABA–benzodiazepine-receptor complex
Benzodiazepines are rapidly absorbed. They are strongly bound to plasma proteins but, because they are lipophilic, pass readily into the brain. They are metabolized to a large number of compounds, many of which have therapeutic effects of their own; temazepam and oxazepam are among the metabolic products of diazepam. Excretion is mainly as conjugates in the urine.
Benzodiazepines with short half-lives, such as temazepam and lorazepam, have a 3-hydroxyl grouping, which allows a one-step metabolism to inactive glucuronides. Other benzodiazepines, such as diazepam and clorazepate, are metabolized to long-acting derivatives, such as desmethyldiazepam, which are themselves therapeutically active.
It is now common practice to give benzodiazepines (often in combination with low-dose antipsychotic drugs) to produce a rapid calming effect in psychosis. In this situation, benzodiazepines may be given parenterally, and it is worth noting that the absorption of diazepam following intramuscular injection is poor, and lorazepam should be preferred if this route of administration is used.
Benzodiazepines are well tolerated. When they are given as anxiolytics, their main side-effects are due to the sedative properties of large doses, which can lead to ataxia and drowsiness (especially in the elderly), and occasionally to confused thinking and amnesia. Minor degrees of drowsiness and of impaired coordination and judgement can affect driving skills and the operation of potentially dangerous machinery; moreover, people who are affected in this way are not always aware of it. For this reason, when benzodiazepines are prescribed, especially those with a longer action, patients should be advised about these dangers and about the potentiating effects of alcohol. The prescriber should remember that these effects are more common among elderly patients and those with impaired renal or liver function.
Although in some circumstances benzodiazepines reduce tension and aggression, they can also rarely lead to a release of aggression by reducing inhibitions in people with a tendency to aggressive behaviour. In this they resemble alcohol. This possible effect should be remembered when prescribing for those judged to be at risk of child abuse, or for any person with a previous history of impulsive aggressive behaviour.
Benzodiazepines have few toxic effects. Patients usually recover from large overdoses because these drugs do not depress respiration and blood pressure as barbiturates do. Even so, fatal overdoses of benzodiazepines have occasionally been reported.
Benzodiazepines, like other sedative anxiolytics, potentiate the effects of alcohol and of drugs that depress the central nervous system. Significant respiratory depression has been reported in some patients receiving combined treatment with benzodiazepines and clozapine.
Dependence and withdrawal
It is now generally agreed that dependence develops after prolonged use of benzodiazepines. The frequency depends on the drug and the dosage, and has been estimated to be up to 50% of patients who are long-term users. Benzodiazepines are associated with a withdrawal syndrome and tolerance. Although drug-seeking behaviour is less common, it certainly can occur, and benzodiazepines are not uncommonly involved in polydrug misuse and dependence (Ashton, 2004).
The withdrawal syndrome associated with benzodiazepines is characterized by several different kinds of symptoms:
• apprehension, anxiety, and insomnia
• heightened sensitivity to perceptual stimuli and perceptual disturbances
• depression and suicidal thinking
• epileptic seizures (rarely).
Since many of these symptoms resemble those of anxiety disorder, it can sometimes be difficult to decide whether the patient is experiencing a benzodiazepine withdrawal syndrome or a recrudescence of the anxiety disorder for which the drug was originally prescribed. Perceptual disturbances are more likely to indicate benzodiazepine withdrawal.
Withdrawal symptoms generally begin within 2 to 3 days of stopping a short-acting benzodiazepine, and within 7 days of stopping a long-acting one. The symptoms generally last for 3 to 10 days. Withdrawal symptoms seem to be more frequent after taking drugs with a short half-life than after taking those with a long one. If benzodiazepines have been taken for a long time, it is best to withdraw them gradually over a period of several weeks. If this is done, withdrawal symptoms can be minimized or avoided (see p. 475). Benzodiazepines do have the advantage of becoming quickly effective. Therefore current advice is that they should be administered on a short-term basis only (not more than 4 weeks) to help a patient to cope with functionally disabling anxiety while other treatment measures are instituted.
Indications and pharmacology
The only drug in the azapirone class that is currently marketed for the treatment of anxiety is buspirone. It is effective in the treatment of generalized anxiety disorder but is not helpful in the treatment of panic disorder. Unlike the benzodiazepines, the anxiolytic effects of buspirone take several days to develop. It is also important to note that buspirone cannot be used to treat benzodiazepine withdrawal.
Pharmacologically, buspirone has no affinity for benzodiazepine receptors, but stimulates a subtype of 5-HT receptor called the 5-HT1A receptor. This receptor is found in high concentration in the raphe nuclei in the brainstem, where it regulates the firing of 5-HT cell bodies. Administration of buspirone lowers the firing rate of 5-HT neurons and thereby decreases 5-HT neurotransmission in certain brain regions. This action may be the basis of its anxiolytic effect.
Pharmacokinetics and adverse effect
Buspirone has poor systemic availability because it has an extensive first-pass metabolism. The side-effect profile differs from that of benzodiazepines. For example, buspirone treatment does not cause sedation, but instead is often associated with lightheadedness, nervousness, and headache early in treatment. There is little evidence that tolerance and dependence occur during buspirone use, although such a judgement must always be made with circumspection.
Buspirone is relatively free from significant drug interactions, but combination with MAOIs has been reported to cause raised blood pressure.
Antidepressant drugs used for anxiety
Antidepressant drugs usually ameliorate the anxiety that accompanies depressive disorders. Tricyclic antidepressants have also been shown to be effective in the management of generalized anxiety disorder, panic disorder, and post-traumatic disorder whether or not significant depressive symptoms are present. Similarly, SSRIs are effective in a broad range of anxiety disorders, including obsessive–compulsive disorder (Baldwin et al., 2005).
The therapeutic profile of antidepressant drugs in the treatment of anxiety differs significantly from that of benzodiazepines. The time of onset of effect is much slower with antidepressants and, particularly in panic disorder, there may be an exacerbation of symptoms early in treatment. However, the ultimate therapeutic effect of antidepressants is as least as great as that of benzodiazepines, and they are less likely to produce cognitive impairment (Baldwin et al., 2005). In addition, the use of antidepressants is not associated with tolerance and dependence although, as noted above, sudden cessation of treatment can cause abstinence symptoms.
Antipsychotic drugs used for anxiety
Conventional antipsychotic drugs have sometimes been prescribed in low doses for their anxiolytic effects, particularly in patients with persistent anxiety who have become dependent on other drugs, and those with aggressive personalities who respond badly to the disinhibiting effects of benzodiazepines. However, even low-dose antipsychotic treatment, if maintained, is not free from the risk of tardive dyskinesia. Newer antipsychotic drugs, such as quetiapine, may also possess anxiolytic effects when given either as a sole treatment or as augmentation treatment in patients who are non-responsive to more standard drug therapies (Davidson et al., 2010). However, the adverse-effect profile of antipsychotic drugs suggests that such an indication should be restricted to specialist use.
Beta-adrenoceptor antagonists that are used for anxiety
These drugs relieve some of the autonomic symptoms of anxiety, such as tachycardia, almost certainly by a peripheral effect. They are best reserved for anxious patients whose main symptom is palpitation or tremor, particularly in social situations. An appropriate drug is propranolol in a dose of 20–40 mg three times a day. Contraindications are heart block, systolic blood pressure below 90 mmHg, or a pulse rate of less than 60 beats/minute, and a history of bronchospasm. Beta-adrenoceptor antagonists precipitate heart failure in a few patients, and should not be given to those with atrioventricular node block, as they decrease conduction in the atrioventricular node and bundle of His. They can exacerbate Raynaud’s phenomenon and hypoglycaemia in diabetics.
Indications and pharmacology
Pregabalin is a derivative of the anticonvulsant drug, gabapentin. Like gabapentin, pregabalin has anticonvulsant and analgesic properties. It is licensed for the treatment of generalized anxiety disorder but not other anxiety disorders. Both gabapentin and pregabalin are analogues of GABA; however, neither compound is active at GABA or benzodiazepine receptors. It is believed that their therapeutic effects are mediated through interaction with the α2-δ subunit of voltage-gated calcium channels and a consequent modification of neurotransmitter release.
Controlled trials have shown that in doses of 150–600 mg, pregabalin is effective in the treatment of generalized anxiety disorder and is equivalent in efficacy to benzodiazepines such as lorazepam (Drug and Therapeutics Bulletin, 2010).
Pharmacokinetics and adverse effect
Pregabalin is rapidly absorbed, with peak plasma concentrations occurring within about 1 hour. Its half-life is about 6 hours, and it is eliminated unchanged primarily through renal excretion. Dose adjustment is therefore required in patients with impaired renal function. Because of its pattern of elimination, pregabalin treatment is not expected to cause pharmacokinetic interactions with other drugs, but the effects of central sedatives (e.g. benzodiazepines and alcohol) may be potentiated.
In clinical trials of patients with generalized anxiety disorder, discontinuation due to adverse events with pregabalin was about 12%, compared with 5% with placebo. The most common adverse effects are somnolence and dizziness. Other common unwanted effects of pregabalin include increased appetite, mood changes, confusion, ataxia, tremor, and memory impairment. The most potentially serious reactions are visual disturbances, including vision loss, blurred vision, and other changes of visual acuity. These symptoms mostly improve when pregabalin is discontinued. It also seems likely that withdrawal of pregabalin is associated with discontinuation symptoms such as insomnia, headache, nausea, diarrhoea, anxiety, sweating, and dizziness (Drug and Therapeutics Bulletin, 2010).
Advice on management
Before an anxiolytic drug is prescribed, the cause of the anxiety should always be sought. In addition, it is helpful to classify the nature of the anxiety disorder, as this can have implications for drug treatment. It is worth remembering that although medication is undoubtedly helpful in the treatment of anxiety syndromes, psychological treatments are as effective and are often preferred by patients. In practice, medication tends to be used when psychological treatments are not readily available or have not been successful.
For most patients with anxiety symptoms, attention to life problems, an opportunity to talk about their feelings, and reassurance from the doctor are enough to reduce anxiety to tolerable levels. If an anxiolytic is needed, a benzodiazepine should be given for a short time—not more than 3 weeks—and withdrawn gradually. It is important to remember that dependency is particularly likely to develop among people with alcohol-related problems. If the drug has been taken for several weeks, the patient should be warned that they may feel tense for a few days when it is stopped.
A compound such as diazepam is suitable for both the intermittent treatment of anxiety and continuous treatment throughout the day. The use of diazepam on an ‘as-needed’ basis usually means that lower total doses are consumed and the risk of tolerance and dependence is diminished. For longer-term treatment of severe generalized anxiety disorder, antidepressant medication is more appropriate (see Chapter 9).
Antidepressants are often helpful in the treatment of panic disorder, although the risk of early symptomatic worsening must be remembered and explained to the patient. The use of small doses early in treatment (e.g. 10 mg imipramine, 5 mg citalopram) can be helpful. High-potency benzodiazepines such as alprazolam and clonazepam are effective in panic disorder, but can cause cognitive impairment and withdrawal problems. However, they may be helpful in patients who do not respond to other treatments. MAOI treatment can also be used in treatment-resistant patients (Baldwin et al., 2005).
Hypnotics are drugs that are used to improve sleep. Many anxiolytic drugs also act as hypnotics, and they have been reviewed in the previous section. Hypnotic drugs are prescribed widely and are often continued for too long. This reflects the frequency of insomnia as a symptom (Ohayon and Lemoine, 2004). Insomnia is reported more often by women and by the elderly. Effective psychological treatments are available for the management of insomnia, and they appear to have a more sustained duration of action than hypnotics (Espie and Kyle, 2009).
The ideal hypnotic would increase the length and quality of sleep without residual effects the next morning. It would do so without altering the pattern of sleep and without any withdrawal effects when the patient ceased to take it. Unfortunately, no drug meets these exacting criteria. It is not easy to produce drugs that affect the whole night’s sleep and yet are sufficiently eliminated by morning for there to be no residual sedative effects.
Most prescribed hypnotics enhance the action of GABA through interaction with either the benzodiazepine receptor or other adjacent sites located on the GABA macro-molecular complex. Antihistamines and low doses of sedating antidepressants such as amitriptyline and trazodone are also used to facilitate sleep. The pineal hormone, melatonin, is involved in organizing circadian rhythms and is sometimes used for the treatment of primary insomnia.
The most commonly used hypnotics are benzodiazepines or non-benzodiazepine ligands which act at or close to the benzodiazepine-receptor site. The latter include zopi-clone, zolpidem, and zaleplon (‘the Z drugs’). The actions of these drugs can be reversed by the benzodiazepine-receptor antagonist, flumazenil. Other available hypnotic agents include chloral hydrate (or its derivatives), chlormethiazole, and sedating antihistamines (the latter are often present in ‘over-the-counter’ preparations). A sustained-release form of melatonin is also licensed for the short-term treatment of insomnia in the middle-aged and elderly (Wade and Downie, 2008).
Of the benzodiazepines, the shorter-acting compounds such as temazepam and lormetazepam are appropriate as hypnotics because of their relative lack of hangover effects (see Box 19.3). Other benzodiazepines that were previously marketed as hypnotics, such as flurazepam and nitrazepam, have a long duration of action and produce significant impairments in tests of cognitive function on the day following treatment.
Zopiclone is a cyclopyrrolone. It produces fewer changes in sleep architecture than benzodiazepine hypnotics. The most common side-effect is a bitter aftertaste following ingestion, but behavioural disturbances including confusion, amnesia, and depressed mood have been reported. Zolpidem and zaleplon are similar agents with shorter half-lives. Zaleplon has the shortest duration of action of all currently marketed hypnotics (about 1 hour). It has been recommended for ‘as-needed’ use in patients who wake in the middle of the night and cannot fall asleep again.
Other hypnotic drugs that facilitate GABA include chloral hydrate, which is sometimes prescribed for children and elderly people. It is a gastric irritant and should therefore be diluted adequately. Chloral is also available in tablet form. Clomethiazole edisylate is a hypnotic drug with anticonvulsant properties. It has often been used to prevent withdrawal symptoms in patients who are dependent on alcohol. For this reason, it is sometimes mistakenly believed to be a suitable hypnotic for alcoholic patients. This belief is erroneous because the drug is as likely as any other hypnotic drug to cause dependency, and can cause respiratory depression when combined with alcohol. It retains a place in the treatment of insomnia in the elderly because of its short duration of action. Unwanted effects include sneezing, conjunctival irritation, and nausea.
As well as the specific side-effects of individual compounds noted above, there are a number of general problems associated with the use of all hypnotics. One of the most important is the presence of residual effects, which are experienced by the patient on the next day as feelings of being slow and drowsy. These are accompanied by deficits in daytime performance. Such effects are less apparent with the shorter-acting compounds noted above. Other problems include the development of tolerance, whereby the original dose of the drug has progressively less efficacy, and ‘rebound’ insomnia on withdrawal, which makes preparations difficult to stop. Tolerance is less of a problem with sedating antidepressants, but such drugs have long half-lives accompanied by residual psychomotor effects the next day.
The most important interaction of hypnotic drugs is with alcohol, where a potentiated effect can be seen. The interaction between clomethiazole and alcohol is particularly dangerous, and can result in death from respiratory failure. For this reason there must be adequate supervision if the drug is used during withdrawal of alcohol. It should not be prescribed for alcoholics who continue to drink. Hypnotics will also potentiate the effect of other drugs with sedating actions, such as some antidepressant and antipsychotic agents.
Advice on management
Before prescribing hypnotic drugs, it is important to find out whether the patient is really sleeping badly and, if so, why. Many people have unrealistic ideas about the number of hours for which they should sleep. For example, they may not know that duration of sleep often becomes shorter in middle and late life. Others take ‘cat naps’ in the daytime, perhaps through boredom, and still expect to sleep as long at night. Some people ask for sleeping tablets in anticipation of poor sleep for one or two nights (e.g. when travelling). Such temporary loss of sleep is soon compensated for by increased sleep on subsequent nights, and any supposed advantage in terms of alertness after a full night’s sleep is likely to be offset by the residual effects of the drugs.
The common causes of disturbed sleep include excessive caffeine or alcohol, pain, cough, pruritus, dyspnoea, and anxiety and depression. When any primary cause is present, this should be treated, not the insomnia. Often simple ‘sleep hygiene’ measures may be helpful (see p. 362). If, after careful enquiry, a hypnotic appears to be essential, it should be prescribed for a few days only. The clinician should explain this to the patient, and should warn them that a few nights of restless sleep may occur when the drugs are stopped, but that this restlessness will not be a reason for prolonging the prescription.
The prescription of hypnotics for children is not justified, except for the occasional treatment of night terrors and somnambulism. Hypnotics should also be prescribed with particular care for the elderly, who may become confused and get out of bed in the night, and perhaps injure themselves. Many patients are started on long periods of dependency on hypnotics by the prescribing of ‘routine night sedation’ in hospital. Prescription of these drugs should not be routine, but should only be a response to a real need, and should be stopped before the patient goes home.
Guidance from the National Institute for Clinical Excellence (2004c) reinforced advice to use hypnotic medicines only for short periods in disabling insomnia. In addition, the use of zopiclone, zolpidem, and zaleplon was not recommended because of the lack of evidence for their superiority over benzodiazepine medications, and their higher cost.
This term is applied to drugs that reduce psychomotor excitement and control symptoms of psychosis. Alternative terms for these agents are neuroleptics and major tranquillizers. None of these names is wholly satisfactory. ‘Neuroleptic’ refers to the side-effects rather than to the therapeutic effects of the drugs, and ‘major tranquillizer’ does not refer to the most important clinical action. The term ‘antipsychotic’ is used here because it appears in the British National Formulary.
The main therapeutic uses of antipsychotic drugs are to reduce hallucinations, delusions, agitation, and psycho-motor excitement in schizophrenia, mania, or psychosis secondary to a medical condition. The drugs are also used prophylactically to prevent relapses of schizophrenia and other psychoses. The introduction of chlorpromazine in 1952 led to substantial improvements in the treatment of schizophrenia, and paved the way to the discovery of the many psychotropic drugs that are now available.
Table 19.2 A list of antipsychotic drugs
Antipsychotic drugs (see Table 19.2) share the property of blocking dopamine receptors. This may account for their therapeutic action, a suggestion that is supported by the close relationship between their potency in blocking dopaminergic receptors in vitro, and their therapeutic strength. Recent imaging studies suggest that acute psychosis is associated with increased dopamine release in striatal regions, and that the extent of this increase correlates with the therapeutic effect of antipsychotic drugs (see p. 278). A persuasive formulation of antipsychotic drug action suggests that these agents block the ability of increased dopamine release to attribute abnormal salience to irrelevant stimuli (Kapur, 2003).
Dopamine receptors are of several subtypes. It is the D2 receptor which is critical for antipsychotic action, and all licensed drugs in the category are antagonists at this receptor, with varying affinities for the D2 subtype. Positron emission tomography (PET) studies suggest that an antipsychotic effect is obtained when D2-receptor occupancy lies in the range 60–70%. Higher levels are associated with extrapyramidal movement disorders and hyperprolactinaemia, but not with greater efficacy (Kapur et al., 1999). Other side-effects are attributable to binding to a variety of other receptors (see below).
Distinction between typical and atypical antipsychotic drugs
The term atypical antipsychotic agent was introduced to distinguish the newer antipsychotic drugs from conventional typical agents, such as chlorpromazine and haloperidol. An alternative term is second generation. Although the definition of the term ‘atypical’ varies in the literature, a fundamental property of an atypical antipsychotic is its ability to produce an antipsychotic effect without causing extrapyramidal side-effects. This definition is problematic, not least as antipsychotics do not fall clearly into two classes in this respect, but lie along a spectrum. For example, low-potency conventional antipsychotic drugs such as chlorpromazine have a relatively low risk of producing extrapyramidal symptoms when prescribed at modest dosages; conversely, extrapyramidal side-effects can also occur with the atypical antipsychotic risperidone. However, it is true to say that atypical antipsychotic agents have a lower likelihood of causing extrapyramidal side-effects within their usual therapeutic range. In addition, the risk of tardive dyskinesia appears to be lower with the newer antipsychotic drugs (Naber and Lambert, 2009).
Another property that is sometimes attributed to atypical antipsychotic drugs is improved efficacy relative to typical agents. Although this is true in terms of positive psychotic symptoms for the prototypic atypical antipsychotic, clozapine, it is not clear how far more recently developed compounds meet this exacting criterion. The evidence in this respect is stronger for amisulpiride, olanzapine, and risperidone (Leucht et al., 2009a). However, pragmatic trials have so far failed to demonstrate important therapeutic differences between conventional and newer antipsychotic drugs, and even clozapine does not have proven efficacy against negative or cognitive symptoms (see p. 287). For these and other reasons, most authorities now believe that the terms ‘atypical’ and ‘typical’ antipsychotic are not useful, and that attention is better directed towards the pharmacological properties of individual drugs and their associated therapeutic profile (Cunningham Owens, 2008) (see Table 19.3).
Pharmacology of typical (conventional) antipsychotics
All of these drugs are effective dopamine-receptor antagonists, but many possess additional pharmacological properties which influence their adverse-effect profile.
Phenothiazines fall into three groups:
1. Aminoalkyl compounds such as chlorpromazine antagonize α1-adrenoceptors, histamine H1-receptors, and mus carinic cholinergic receptors. Blockade of α1-adrenoceptors and histamine H1-receptors gives chlorpromazine a sedating profile, whileα1-adrenoceptor blockade also causes hypotension. The anticholinergic activity may cause dry mouth, urinary difficulties, and constipation, while on the other hand offsetting the liability to cause extrapyramidal side-effects.
2. Piperidine compounds such as thioridazine and pipothiazine are similar to chlorpromazine but are very potent muscarinic antagonists with a correspondingly low incidence of movement disorders.
3. Piperazine compounds such as trifluoperazine and fluphenazine are the most selective dopamine-receptor antagonists, the least sedating, and the most likely to cause extrapyramidal effects.
Thioxanthenes and butyrophenones
Thioxanthenes such as flupenthixol and clopenthixol are similar in structure to the phenothiazines. The therapeutic effects are similar to those of the piperazine group. Butyrophenones such as haloperidol have a different structure but are clinically similar to the thioxanthenes. They are potent dopamine-receptor antagonists with few effects at other neurotransmitter receptors. They are not sedating, but have a high propensity to cause extrapyramidal side-effects.
Pharmacology of atypical antipsychotic drugs (see Table 19.3)
Selective D2 -receptor antagonists. Atypical antipsychotic drugs have a diverse pharmacology, but currently two main groupings can be discerned. On the one hand are substituted benzamides such as sulpirideand amisulpride. These drugs are highly selective D2-receptor antagonists which, for reasons that are not well understood, seem less likely to produce extrapyramidal movement disorders. They also lack sedative and anticholinergic properties. However, they do cause a substantial increase in plasma prolactin.
Table 19.3 Atypical antipsychotics
5-HT2-D2 -receptor antagonists. The other major group of atypical antipsychotic drugs possess 5-HT2-receptor-antagonist properties. In other aspects—for example, potency of dopamine D2-receptor blockade, these drugs differ significantly from one another (Meltzer, 2004). Risperidone is a potent antagonist at both 5-HT2 receptors and dopamine D2 receptors. It also possesses1-adrenoceptor-blocking properties, which can cause mild sedation and hypotension. Zotepine has a similar pharmacological profile to risperidone, but has a somewhat low selectivity for 5-HT2 over D2 receptors. It is also a stronger antihista-mine, making it more likely to cause weight gain.
Olanzapine is a slightly weaker D2-receptor antagonist than risperidone, but has anticholinergic and histamine H1-receptor-blocking activity. This gives it strong sedating effects. Quetiapine has modest 5-HT2-receptor-antagonist effects, with even weaker D2-receptor-antagonist effects. It has a very low propensity to cause movement disorders.
Sertindole is a potent 5-HT2-receptor antagonist with weak D2-receptor-antagonist effects. It causes clinically significant effects on the QT interval in the electrocardiogram, and its use is currently suspended. Ziprasidone is another 5-HT2 and D2-receptor antagonist which differs from the other 5-HT2/D2-receptor antagonists described here, because it also binds to 5-HT1Areceptors and is a noradrenaline reuptake inhibitor. Somnolence and dizziness are common side-effects of ziprasidone, and it causes relatively little weight gain. It has a tendency to increase the QTc interval, and has not been licensed in the UK. Aripiprazole is a partial dopamine agonist that also has 5-HT2-receptor-blocking and 5-HT1A-agonist properties. It has an activating profile and dopaminergic side-effects such as insomnia, nausea, and vomiting. It is less likely to cause weight gain or significant extrapyramidal side-effects.
To some extent these latter drugs were designed to reproduce the pharmacological profile of clozapine, which was the first antipsychotic agent to show definite benefit in the treatment of patients whose psychotic symptoms had failed to respond to conventional agents. In addition, clozapine has a low liability to cause movement disorders, and is therefore usually regarded as the prototypic atypical antipsychotic drug (Kane et al., 1988). Clozapine is a weak dopamine D2 -receptor antagonist but has a high affinity for 5-HT2receptors. It also binds to a variety of other neurotransmitter receptors, including histamine H1, 5-HT2, α1-adrenergic and muscarinic cholinergic receptors (Meltzer, 2004). Various studies have attempted to define a therapeutic plasma range for clozapine, with inconsistent results. A reasonable compromise is 350–500 µg/l.
The pharmacological basis for the increased efficacy of clozapine is not well understood. However, it is clear that the use of clozapine is associated with a significant risk of leucopenia, which restricts its use to patients who do not respond to or who are intolerant of other antipsychotic drugs. The haematological monitoring of clozapine treatment is discussed below.
Depot antipsychotic drugs
Slow-release preparations are used for patients who need to take antipsychotic medication to prevent relapse but cannot be relied upon to take it regularly. Their use differs considerably between countries. These ‘depot’ preparations include the esters fluphenazine decanoate, flupenthixol decanoate, zuclopenthixol decanoate, haloperidol decanoate, and pipothiazine palmitate. All are given intramuscularly in an oily medium. Zuclopenthixol acetate reaches peak plasma levels within 1–2 days and has a shorter duration of action than other depots. It is used for the immediate control of acute psychosis, but its superiority to ordinary intramuscular injections is not established. Slow-release injections of risperidone and olanzapine are also now available.
Antipsychotic drugs are well absorbed, mainly from the jejunum. When they are taken by mouth, part of their hepatic metabolism is completed as they pass through the portal system on their way to the systemic circulation (first-pass metabolism). Antipsychotic drugs are highly protein bound.
With the exception of sulpiride and amisulpride, which are excreted unchanged by the kidney, antipsychotic drugs are extensively metabolized by the liver to produce a range of active and inactive metabolites. For example, following administration of chlorpromazine, about 75 metabolites have been detected in the blood or urine. This complex metabolism has made it difficult to interpret the clinical significance of plasma concentrations of most antipsychotics; for this reason the plasma measures are seldom used in everyday clinical work. The half-life of most antipsychotic drugs (around 20 hours) is sufficient to allow once-daily dosing. However, quetiapine has a half-life of about 7 hours, and twice-daily dosing is recommended, although a modified-release preparation permits once-daily dosing.
The pharmacokinetic profile of depot preparations differs substantially from that of standard preparations. For all compounds except zuclopenthixol acetate, it takes several weeks for steady-state drug levels to be reached in the plasma (see Table 19.4). This means that relapse after treatment discontinuation is likely to be similarly delayed.
Antipsychotic drugs potentiate the effects of other central sedatives. They may delay the hepatic metabolism of tri-cyclic antidepressants and anti-epileptic drugs, leading to increased plasma levels of the latter agents. The hypotensive properties of chlorpromazine may enhance the effects of antihypertensive drugs, including ACE inhibitors.
Table 19.4 Some pharmacokinetic properties of depot antipsychotic drugs
Antipsychotic drugs, particularly pimozide and thioridazine, can increase the QT interval and should not be given with other drugs that are likely to potentiate this effect, such as anti-arrhythmics, astemizole and terfena-dine, cisapride, and tricyclic antidepressants. There are also reports of an increased risk of cardiac arrhythmias when pimozide has been combined with clarithromycin and erthyromycin. Clozapineshould not be given with any agent that is likely to potentiate its depressant effect on white cell count, such as carbamazepine, co-trimoxazole, and penicillamine. Some SSRIs slow the hepatic metabolism and increase blood levels of several antipsychotic drugs, including haloperidol, risperidone, aripiprazole, and clozapine.
The many different antipsychotic drugs share a broad pattern of unwanted effects that are mainly related to their antidopaminergic, anti-adrenergic, and anticholinergic properties (see Table 19.5). Details of the effects of individual drugs can be found in the British National Formulary or a similar work of reference. Here we give an account of the general pattern, with examples of the side-effects associated with a few commonly used drugs.
Table 19.5 Some unwanted effects of antipsychotic drugs
Antidopaminergic movement effects
Inhibition of ejaculation
Urinary hesitancy and retention
Precipitation of glaucoma
Weight gain and diabetes
These are related to the antidopaminergic action of the drugs on the basal ganglia. As already noted, the therapeutic effects may also derive from the antidopaminergic action, although at mesolimbic and mesocortical sites. The effects on the extrapyramidal system fall into four groups (Barnes and Spence 2000), which are summarized below.
This occurs soon after treatment begins, especially in young men. It is most often observed with butyrophenones and with the piperazine group of phenothiazines. The main features are torticollis, tongue protrusion, grimacing, and opisthotonos, an odd clinical picture which can easily be mistaken for histrionic behaviour. It can be controlled by an anticholinergic agent given carefully by intramuscular injection.
This is an unpleasant feeling of physical restlessness and a need to move, leading to an inability to keep still. Agitation with suicidal ideation can also occur. Akathisia may wrongly be mistaken for a worsening of psychosis, and more antipsychotic medication may then be inappropriately prescribed. It usually occurs during the first 2 weeks of treatment with antipsychotic drugs, but may begin only after several months. Akathisia is not reliably controlled by antiparkinsonian drugs. Beta-adrenoceptor antagonists and short-term treatment with benzodiazepines may be helpful. The best strategy is to reduce the dose of antipsychotic drug, if possible.
Antipsychotic-induced Parkinsonism is characterized by akinesia, an expressionless face, and lack of associated movements when walking, together with rigidity, coarse tremor, stooped posture, and, in severe cases, a festinant gait. This syndrome often does not appear until a few months after the drug has been taken, and then sometimes diminishes even though the dose has not been reduced. The symptoms can be controlled with antiparkinsonian drugs. However, it is not good practice to prescribe antiparkinsonian drugs prophylactically as a routine, because not all patients will need them. Moreover, these drugs themselves have undesirable effects in some patients; for example, they occasionally cause an acute organic syndrome, and may worsen or unmask concomitant tardive dyskinesia.
This is particularly serious because, unlike the other extrapyramidal effects, it does not always recover when the drugs are stopped. It is characterized by chewing and sucking movements, grimacing, choreoathetoid movements, and possibly akathisia. The movements usually affect the face, but the limbs and the muscles of respiration may also be involved. Although the syndrome is seen occasionally among patients who have not taken antipsychotic drugs, it is more common among those who have taken antipsychotic drugs for a number of years. It is also sometimes seen in patients who are taking dopamine-receptor blockers for other indications (e.g. metoclopramide for chronic gastrointestinal problems).
Epidemiology. Tardive dyskinesia is more common among women, the elderly, and patients who have diffuse brain pathology. A diagnosis of mood disorder is also a risk factor. In about 50% of cases, tardive dyskinesia disappears when the antipsychotic drug is stopped. Estimates of the frequency of the syndrome vary in different series, but it seems to develop in about 20% of patients with schizophrenia who have been treated with long-term conventional antipsychotic medication. Current evidence suggests that the incidence of tardive dyskinesia is lower with atypical antipsychotic agents such as clozapine, olanzapine, and risperidone than with haloperidol (Naber and Lambert, 2009). However, cases still occur, albeit at a lower level.
Pathophysiology. The cause of tardive dyskinesia is uncertain, but it could be due to supersensitivity to dopamine as a result of prolonged dopaminergic blockade. This explanation is consistent with the observations that tardive dyskinesia may be aggravated by stopping antipsychotic drugs or by the administration of anticholinergic antiparkinsonian drugs (presumably by upsetting further the balance between cholinergic and dopaminergic systems in the basal ganglia).
Treatment. Many treatments for tardive dyskinesia have been tried, but none of them is universally effective. Therefore it is important to reduce its incidence as far as possible by limiting long-term antipsychotic drug treatment to patients who really need it. At the same time, a careful watch should be kept for abnormal movements in all patients who have taken antipsychotic drugs for a long time. If dyskinesia is observed, the antipsychotic drug should be stopped if the state of the mental illness allows this.
Although tardive dyskinesia may first worsen after stopping the drug, in many cases it will improve over several months. If the dyskinesia persists after this time or if the continuation of antipsychotic medication is essential, a trial can be made of an atypical agent such as olanzapine or quetiapine with weaker dopamine-receptor-antagonist properties. This can sometimes lead to remission of the disorder. Other agents that have been tried include vitamin E, although the evidence for its efficacy is conflicting.
Although the two conditions can coexist, tardive dyskinesia needs to be distinguished from tardive dystonia, which is the long-term persistence of a dystonic movement disorder. Clinically the condition is indistinguishable from the various idiopathic dystonias which present, for example, with blepharospasm or torticollis. The diagnosis of drug-induced tardive dystonia is made on the basis of exposure to dopamine-receptor-blocking agents and a negative family history of dystonia. Treatment is unsatisfactory. Anticholinergic drugs are ineffective, and the condition often persists after withdrawal of the antipsychotic agent. However, clozapine has been reported to be useful, as has local injection of botulinum toxin into the affected muscle group.
These include sedation, postural hypotension with reflex tachycardia, nasal congestion, and inhibition of ejaculation. The effects on blood pressure are particularly likely to appear after intramuscular administration, and may appear in the elderly whatever the route of administration.
These include dry mouth, urinary hesitancy and retention, constipation, reduced sweating, blurred vision, and, rarely, the precipitation of glaucoma.
Cardiac conduction defects. Cardiac arrhythmias are sometimes reported. ECG changes are more common in the form of prolongation of the QTc interval and T-wave changes. The use of pimozide has been associated with serious cardiac arrhythmias. Cautious dose adjustment with ECG monitoring is recommended. Studies have also suggested that thioridazine might be relatively more likely to produce QT prolongation, which has resulted in the indications for thioridazine being greatly restricted in the UK. Antipsychotic drugs are also associated with an increased risk of venous thrombosis, which appears to be greater with the newer agents and in those who have started treatment more recently (Parker et al., 2010). For a review of the cardiac effects of antipsychotic drugs and the role of ECG monitoring, see Abdelmawla and Mitchell (2006a,b).
Depression. Depression of mood has been said to occur, but this is difficult to evaluate because untreated patients with schizophrenia may have periods of depression. It is certainly possible that excessive dopamine-receptor blockade in the mesolimbic forebrain could be associated with anhedonia and loss of drive, which could then resemble depression or negative symptoms of schizophrenia.
Endocrine and metabolic changes. Some patients gain weight when taking antipsychotic drugs, especially chlorpromazine and atypical agents such as olanzapine, zotepine, and clozapine (see Table 19.3). Weight gain can result in obesity, and increases the risk of type 2 diabetes. Schizophrenia itself has been associated with an increased risk of diabetes, and this risk is probably increased by antipsychotic drugs, partly but not completely through the associated weight gain. The increase in weight associated with some antipsychotic drugs has been attributed to antagonist activity at histamine-H1 receptors and 5-HT2Creceptors, which may explain why olanzapine and clozapine have been implicated most frequently (Taylor et al., 2009; however, see Kessing et al., 2010). Weight gain is probably least likely to be a problem with aripiprazole and amisulpiride.
Other pharmacological properties of antipsychotic drugs may increase the risk of diabetes, independently of weight gain—for example, via blockade of peripheral M3 muscarinic receptors. Similarly, newer antipsychotic drugs such as olanzapine, clozapine, and quetiapine are associated with increased lipid levels. These adverse effects are of great clinical importance because they increase the risk of cardiovascular disease and may therefore contribute to the increase in overall mortality seen in patients with schizophrenia. Patients who are receiving treatment with antipsychotic drugs require careful monitoring of metabolic aspects of their general health (see Chapter 11). For a review of the pharmacological mechanisms involved in the adverse metabolic effects of antipsychotic drugs, see Reynolds and Kirk (2010).
Galactorrhoea and amenorrhoea are induced in some women by high prolactin levels, and it is possible that low libido and sexual dysfunction may also result. There may also be an increased risk of osteoporosis. Some atypical agents do not increase prolactin levels significantly (see Table 19.3). For a review of the adverse effects of hyper-prolactinaemia, see Wieck and Haddad (2004).
Hypothermia, seizures, and eye problems. In the elderly, hypothermia is an important unwanted effect. Some antipsychotic drugs, particularly lower-potency agents, such as chlorpromazine and clozapine, lower the seizure threshold and can increase the frequency of seizures in epileptic patients. Prolonged chlorpromazine treatment can lead to photosensitivity and to accumulation of pigment in the skin, cornea, and lens. Thioridazine in high dose (more than 800 mg/day) has caused retinal degeneration.
Sensitivity reactions. Phenothiazines, particularly chlorpromazine, have been associated with cholestatic jaundice, but the incidence is low (about 0.1%). Blood cell dyscrasias also occur rarely with antipsychotic drugs, but are most common with clozapine. Skin rashes can also occur.
Adverse effects of clozapine
The use of clozapine is associated with a significant risk of leucopenia (about 2–3%), which can progress to agranulocytosis. Weekly blood counts for the first 18 weeks of treatment and at 2-weekly intervals thereafter are mandatory. After 1 year, the frequency of blood sampling may be reduced to monthly intervals. With this intensive monitoring, the early detection of leucopenia can be followed by immediate withdrawal of clozapine and by reversal of the low white cell count. This procedure greatly reduces, but does not eliminate, the risk of progression to agranulocytosis. It is usually recommended that clozapine be used as the sole antipsychotic agent in a treatment regimen. Clearly, it is wise to avoid concomitant use of drugs such as carbamazepine, which may also lower the white cell count.
Because of its relatively weak blockade of dopamine D2 receptors, clozapine is unlikely to cause extrapyramidal movement disorders, including tardive dyskinesia. It does not increase plasma prolactin, so galactorrhoea does not occur. However, its use is associated with hypersalivation, drowsiness, postural hypotension, weight gain, and hyperthermia. Seizures may occur at higher doses. Clozapine is a sedating compound, and cases of respiratory and circulatory embarrassment have been reported during combined treatment with clozapine and benzodiazepines. Rarely, fatal myocarditis and myopathy have been reported. The weight gain is at least partly responsible for an increased risk of diabetes mellitus.
The neuroleptic malignant syndrome
This rare but serious disorder occurs in a small minority of patients who are taking antipsychotic drugs, especially high-potency compounds. Most reported cases have followed the use of antipsychotic agents for schizophrenia, but in some cases the drugs were used for mania, depressive disorder, or psychosis secondary to a medical condition. Combined lithium and antipsychotic drug treatment may be a predisposing factor. The overall incidence is probably about 0.2% of patients who are treated with antipsychotic drugs.
The onset is often, but not invariably, during the first 10 days of treatment. The clinical picture includes the rapid onset (usually over 24–72 hours) of severe motor, mental, and autonomic disorders together with hyperpyrexia.
• The prominent motor symptom is generalized muscular hypertonicity. Stiffness of the muscles in the throat and chest may cause dysphagia and dyspnoea.
• The mental symptoms include akinetic mutism, stupor, or impaired consciousness.
• Hyperpyrexia develops, with evidence of autonomic disturbances in the form of unstable blood pressure, tachycardia, excessive sweating, salivation, and urinary incontinence.
• In the blood, creatinine phosphokinase (CPK) levels may be greatly elevated, and the white cell count may be increased.
• Secondary complications may include pneumonia, thromboembolism, cardiovascular collapse, and renal failure.
The mortality rate of neuroleptic syndrome appears to have been declining over recent years, but can still be of the order of 10%. The syndrome lasts for 1 to 2 weeks after stopping an oral neuroleptic, but may last two to three times longer after stopping long-acting preparations. Patients who survive are usually, but not invariably, without residual disability.
The differential diagnosis includes encephalitis, and in some countries heat stroke. Before the introduction of antipsychotic drugs, a similar disorder was reported as a form of catatonia sometimes called acute lethal catatonia. The condition can probably occur with any antipsychotic agent, but in many reported cases the drugs used have been haloperidol or fluphenazine. Cases have also been reported with atypical antipsychotic drugs, including clozapine. The cause could be related to excessive dopaminergic blockade, although why this should affect only a minority of patients cannot be explained.
Treatment is symptomatic. The main priorities are to stop the drug, cool the patient, maintain fluid balance, and treat intercurrent infection. No drug treatment is certainly effective. Diazepam can be used for muscle stiffness. Dantrolene, a drug used to treat malignant hyper-thermia, has also been tried. Bromocriptine, a dopamine agonist, is also recommended. Very ill patients require intensive-care-unit support with intubation and paralysis to maintain respiration and deal with renal failure.
Some patients who developed the syndrome on one occasion have been given the same drug again safely after the acute episode has resolved. Nevertheless, if an antipsychotic has to be used again, it is prudent to restart treatment cautiously with a newer agent, used at first in low doses. At least 2 weeks should elapse before antipsychotic drug treatment is reinstated.
Contraindications to antipsychotic drugs
There are few absolute contraindications to antipsychotic medication, and they vary with individual drugs. Before any of these drugs are used, it is important to consult the British National Formulary or a comparable work of reference. Contraindications include myasthenia gravis, Addison’s disease, glaucoma (where compounds have significant anticholinergic activity), and, in the case of clozapine, any evidence of bone-marrow depression. For patients with liver disease, chlorpromazine should be avoided and other drugs used with caution. Caution is also required when there is renal disease, cardiovascular disorder, epilepsy, or serious infection. Patients with Parkinson’s disease sometimes require antipsychotic medication to deal with psychotic states induced by dopaminergic agents; quetiapine or clozapine is advised in these circumstances (see Chapter 13). Antipsychotic drugs can produce severe movement disorders and changes in consciousness in some patients with dementia, particularly Lewy body dementia.
Antipsychotic drugs are associated with an increased risk of stroke, so they should not be used in patients with cerebrovascular disease unless an underlying psychiatric disorder makes this essential. Cognitive impairment also appears to be a risk factor for this complication. For example, the use of antipsychotic drugs of all classes in patients with dementia is associated with a 1.3- to 2.0- fold increase in the risk of stroke (Sacchetti et al., 2010).
Doses of antipsychotic drugs need to be adjusted for the individual patient, and changes should be made gradually. Doses should be lower for the elderly, for patients with brain damage or epilepsy, and for the physically ill. The dosage of individual drugs can be found in the British National Formulary or a comparable work of reference, or in the manufacturer’s literature.
PET imaging studies
There has been an important trend towards the recommendation of lower doses of antipsychotic drugs. This is based in part on studies with PET which have demonstrated that adequate dopamine D2-receptor blockade (in the basal ganglia at least) can be obtained with low doses of conventional antipsychotic drugs (e.g. about 5 mg of haloperidol) (see Table 19.6) (Farde et al., 1989). For newer drugs, sufficient PET data are usually available to allow clear dosage recommendations.
Low recommended doses produce an adequate antipsychotic effect in the majority of patients. Higher doses may cause further calming, but are likely to be associated with significant adverse effects, some of which may be serious (e.g. cardiac arrhythmias). A prevailing view is that the combination of modest doses of antipsychotic drugs with a benzodiazepine is a safer and more effective means of producing rapid sedation than high doses of antipsychotic drugs.
Antipsychotic drugs and the risk of sudden death
The association of sudden unexplained death with antipsychotic drug treatment is a matter of continuing debate. Patients with schizophrenia treated with antipsychotic drugs appear to have higher rates of cardiac arrest and ventricular arrhythmias than controls. They are also more likely to die through choking (Ruschena et al., 2003). This could be due to the illness or to treatment. However, antipsychotic drugs are known to alter cardiac conduction, and drugs such as chlorpromazine also have hypotensive effects. Epidemiological studies show that the increased risk of sudden death (about twofold) in patients who are taking antipsychotic drugs is similar for the older and newer agents, and is related to increasing dose (Ray et al., 2009). Although this association may not be causal, it is clearly prudent to use as low a dose of an antipsychotic drug as the clinical circumstances permit. Particular caution is needed in patients with pre-existing cardiac disease and those taking other medications that might increase the QTc interval (Abdelmawla and Mitchell, 2006a,b).
An indication of the relative dosage of some commonly used antipsychotic drugs taken by mouth is given in Table 19.6. Some practical guidance on the most frequently used drugs is given in the next section.
Advice on management
Antipsychotic drugs and benzodiazepines are used to control psychomotor excitement, hostility, and other abnormal behaviour resulting from schizophrenia, mania, or organic psychosis. If the patient is very excited and is displaying abnormally aggressive behaviour, the aim should be to bring the behaviour under control as quickly and safely as possible. If the patient is already taking an antipsychotic drug, the addition of lorazepam (1–2 mg) or promethazine(25–50 mg) can be helpful. If the patient is not taking regular antipsychotic medication, the use of olanzapine (10 mg), quetiapine (100–200 mg), risperidone(1–2 mg), or haloperidol (5 mg) can be considered, although the product licence for haloperidol recommends pre-treatment ECG monitoring, which might be difficult to arrange in an emergency situation. If parenteral treatment is needed, lorazepam, promethazine, and olanzapine are available as intramuscular preparations, as is haloperidol. An intramuscular preparation of aripiprazole is licensed for emergency use; it may be somewhat less effective than olanzapine, but is less likely to cause hypotension. When using olanzapine intramuscularly it is important to be aware of the contraindications to its use, particularly with regard to patients with cardiovascular disease. Intramuscular olanzapine should not be given with parenteral benzodiazepines. Whatever treatment is used, it is important to check for possible respiratory depression, particularly in the elderly and in patients with concomitant physical illness. The benzodiazepine antagonist flumazenil should be available. For a summary of the emergency pharmacological management of disturbed behaviour, see Taylor et al. (2009).
Table 19.6 Dosage and D2 receptor blockade of some antipsychotic drugs
There are several other practical points concerning the management of the acutely disturbed patient that can be dealt with conveniently here. Although it may not be easy in the early stages to differentiate between mania and schizophrenia as causes of the disturbed behaviour, it is necessary to try to distinguish them from psychosis secondary to medical conditions and from outbursts of aggression in abnormal personalities. Among medical conditions it is important to consider post-epileptic states, the effects of head injury, transient global amnesia, and hypoglycaemia. If the patient has been drinking alcohol, the danger of potentiating the sedative effects of antipsychotic drugs and benzodiazepines should be remembered. Similarly, antipsychotic drugs that may provoke seizures should be used with caution in post-epileptic states.
For further information about the management of violence in healthcare settings, and clinical guidelines, see p. 727.
Drug treatment of the acute episode
After any necessary emergency measures have been implemented, or from the beginning in less urgent cases, treatment with moderate doses of an oral antipsychotic drug should be started. An appropriate prescription would be haloperidol 2–5 mg daily in divided doses, chlorpromazine 150–300 mg daily, risperidone 2–4 mg daily, or olanzapine 10 mg daily. In general, in patients presenting with a first episode of psychosis, antipsychotic drug doses should be towards the lower end, certainly at the initiation of treatment.
In the early stages of treatment, the amount and timing of doses should be adjusted if necessary from one day to the next, until the most acute symptoms have been brought under control. Thereafter, regular once- or twice-daily doses are usually appropriate. It is important to be alert for acute dystonic reactions in the early days of treatment. A careful watch should also be kept for Parkinsonian side-effects as treatment progresses; if they appear, an antiparkinsonian drug should be given (see next section). For the elderly or physically ill, appropriate observations of temperature and blood pressure should be made in order to detect hypothermia or postural hypotension.
Although patients often become more settled a few days after starting antipsychotic drugs, improvement in psychotic symptoms is usually gradual, with resolution often taking a number of weeks. Again, current trends are to maintain the dose of antipsychotic drugs at a modest steady level and not to escalate the dose in the hope of speeding up the rate of improvement. For patients in whom agitation and distress continue to cause concern, it may be appropriate to add short-term intermittent treatment with a benzodiazepine, rather than increase the dose of antipsychotic agent.
Drug treatment after the acute episode
Episodes of mania and acute psychosis secondary to medical conditions usually subside within weeks. However, patients with schizophrenia often require treatment for many months or years. Such maintenance treatment can be a continuation, often in a smaller dose, of the oral medication that is used to bring the condition under control.
Use of depot preparations. For a number of reasons, some patients do not take their drugs reliably, and in these circumstances one of the intramuscular depot preparations may be useful. At the start of treatment a small test dose is given to find out whether serious side-effects are likely to occur with the full dose, although this is not considered necessary with olanzapine and risperidone (Taylor, 2009). The appropriate maintenance dose is then established by observation and careful follow-up. As noted earlier, depot preparations have long half-lives, and therefore it may take several weeks for maximum plasma concentrations to be reached (see Table 19.4). This has implications for the rate at which dose increases and decreases should be made, and also for the tapering of doses of oral antipsychotic medication once depot treatment has started. It should be noted that treatment with olanzapine pamoate has been associated with excessive sedation, confusion, and sometimes coma. Although these reactions are not common (they affect about 2% of patients) and full recovery occurs within 24–72 hours, all patients receiving this preparation require medical observation for at least 3 hours post injection.
It is important to find the smallest dose of medication that will control the symptoms. As this may diminish with time, regular reassessment of the remaining symptoms of illness and the extent of side-effects is needed. It is not necessary to give antiparkinsonian drugs routinely. If they are needed, it may be only for some days after the injection of the depot preparation (when the drug plasma concentrations are highest).
Although these drugs have no direct therapeutic use in psychiatry, they are sometimes required to control the extrapyramidal side-effects of typical antipsychotic drugs.
Of the drugs that are used to treat idiopathic Parkinsonism, currently only the anticholinergic compounds are used for drug-induced extrapyramidal syndromes. These drugs are antagonists of muscarinic cholinergic receptors both centrally and in the periphery. Some also possess antihistaminic properties.
Many anticholinergic drugs are available, and there is little to choose between the various compounds. However, some authorities suggest that the use of agents which are more selective for the M1 subtype of the muscarinic receptor—for example, biperiden—may be associated with fewer peripheral anticholinergic effects. Other preparations that are employed include procyclidine and benzhexol. Orphenadrine and benztropine have combined antihistaminic and anticholinergic properties.
Limited data are available. Anticholinergic drugs appear to be well absorbed and are extensively metabolized in the liver. They are highly protein bound. Their half-lives are generally in the range of 15–20 hours.
In large doses these drugs may cause an acute organic syndrome, especially in the elderly. Their anticholinergic activity can summate with those of antipsychotic drugs so that glaucoma or retention of urine in men with enlarged prostates may be precipitated. Drowsiness, dry mouth, and constipation also occur. These effects tend to diminish as the drug is continued.
Orphenadrine may be more toxic than other anticholinergic drugs in overdose, whereas benztropine has been associated with heat stroke. All anticholinergic drugs can exacerbate tardive dyskinesia, but are probably not a pre-disposing factor in its development (Barnes and Spence, 2000).
Antiparkinsonian drugs can induce drug-metabolizing enzymes in the liver, so that plasma concentrations of antipsychotic drugs are sometimes reduced. As noted above, anticholinergic agents can potentiate the effects of other drugs with anticholinergic activity, such as chlorpromazine and amitriptyline.
Advice on management
As noted previously, anticholinergic drugs should not be given routinely because they may increase the manifestation of tardive dyskinesia. Also, the presence of persistent extrapyramidal side-effects is a sign that the dose of medication is excessive for that patient, in terms of D2-receptor occupancy (see p. 528). Patients who are receiving injectable long-acting antipsychotic preparations may require anticholinergic drugs for only a few days after injection, if at all. There have been reports of misuse of and dependence on anticholinergic drugs, possibly resulting from a mood-elevating effect.
If anticholinergic drugs are required, biperiden (2–12 mg daily) or procyclidine (5–30 mg daily) are appropriate for routine use. These drugs are usually given three times daily, although their half-lives would suggest that less frequent dosing should be possible. It is best not to give anticholinergic drugs in the evening because of the possibility of excitement and sleep disruption.
Currently used antidepressant drugs can be divided into three main classes, depending on their acute pharmacological properties:
1. Monoamine reuptake inhibitors. These are compounds that inhibit the reuptake of noradrenaline and/or 5-HT. They include tricyclic antidepressants, SSRIs, selective noradrenaline and serotonin reuptake inhibitors (SNRIs), and selective noradrenaline reuptake inhibitors (NARIs).
2. Monoamine oxidase inhibitors (MAOIs). These are compounds that deactivate monoamine oxidase irreversibly (phenelzine and tranylcypromine) or reversibly (moclobemide).
3. 5-HT2 receptor antagonists. These drugs (mirtazapine and trazodone) have complex effects on monoamine mechanisms but share the ability to block 5-HT2 receptors.
In the broad range of major depression, these drugs are of equivalent efficacy. The main differences between them are in their adverse effects, toxicity, and cost (see Table 19.7). Each of these three classes of drugs will be considered in turn after some comments on the possible mechanism of action of antidepressants.
Mechanism of action
The acute effect of reuptake inhibitors and of MAOIs is to enhance the functional activity of noradrenaline and/or 5-HT. These actions can be detected within hours of the start of treatment, yet the full antidepressant effects of drug treatment can be delayed for several weeks. For example, it has been suggested that at least 6 weeks should elapse before an assessment of the effects of an antidepressant drug can be made in an individual patient.
To some extent, this delay in the onset of therapeutic activity may be due to pharmacokinetic factors. For example, the half-life of most antidepressant drugs is around 24 hours, which means that steady-state plasma drug levels will be reached only after 5 to 7 days. However, it seems unlikely that this can completely account for the lag in antidepressant activity.
Table 19.7 Groups of antidepressant drugs
The delay in onset of obvious therapeutic effect with antidepressant medication led to suggestions that the antidepressant effect of current treatments is a consequence of slowly evolving neuroadaptive changes in the brain, which are triggered by acute potentiation of monoamine function. Studies in experimental animals have implicated various mechanisms that might underlie this effect, including desensitization of inhibitory autoreceptors on 5-HT and noradrenaline cell bodies, increased production of neurotropins such as brain-derived neurotrophic factor (BDNF), and increased synaptogenesis and neurogenesis.
Recently, however, attention has focused on the effects of antidepressant drugs on the neuropsychological mechanisms involved in the processing of emotional information. Emotional processing is known to be negatively biased in depressed patients, and it is therefore of great interest that single doses of antidepressant drugs produce positive biases in emotional processing in healthy volunteers and reverse the negative biases present in depressed patients, in the absence of any changes in subjective mood. These findings suggest that relevant psychological effects of antidepressants can be detected from the beginning of treatment, and the delay in the appearance of obvious therapeutic effects of antidepressant medication may stem from the time taken for changes in emotional processing to be experienced as subjective changes in mood as an individual with this new emotional ‘set’ interacts with their environment. The latter process could well involve the ‘relearning’ of emotional associations, which makes the changes in synaptic plasticity and neurogenesis that have been reported in animal studies of antidepressants of great interest. For a review, see Harmer et al. (2009).
In general, SSRIs are now preferred to tricyclic antidepressants in the first-line treatment of depression because they are modestly better tolerated and less toxic in overdose (National Institute for Health and Clinical Excellence, 2009a). However, tricyclic antidepressants continue to be important because of their efficacy in severely ill patients. In addition, their pharmacology provides a useful introduction to the neuropharmacological basis of antidepressant treatment, and this is why they are discussed first here.
Tricyclic antidepressants have a three-ringed structure with an attached side chain. A useful distinction is between compounds that have a terminal methyl group on the side chain (tertiary amines) and those that do not (secondary amines). In general, compared with the secondary amines, tertiary amines (e.g. amitriptyline, clomipramine, and imipramine) have a higher affinity for the 5-HT uptake site and are more potent antagonists of α1-adrenoceptors and muscarinic cholinergic receptors. Therefore, in clinical use, tertiary amines are more sedating and cause more anticholinergic effects than secondary amines (e.g. desipramine, lofepramine, and nortriptyline).
Tricyclic antidepressants inhibit the reuptake of both 5-HT and noradrenaline. They also have antagonist activities at a variety of neurotransmitter receptors. In general, these receptor-blocking actions have been thought to cause adverse effects (see Table 19.8), although some investigators have argued that the ability of some tricyclic antidepressants to antagonize brain 5-HT2 receptors may also mediate some of their therapeutic effects. Tricyclics have quinidine-like membrane-stabilizing effects, and this may explain why they impair cardiac conduction and cause high toxicity in overdose.
Tricyclic antidepressants are well absorbed from the gastrointestinal tract, and peak plasma levels occur 2–4 hours after ingestion. Tricyclics are subject to significant first-pass metabolism in the liver and are highly protein bound. The free fraction is widely distributed in body tissues. In general, the elimination half-life of tricyclics is such that it is unnecessary to give them more than once daily.
Tricyclics are metabolized in the liver by hydroxylation and demethylation. It is noteworthy that demethylation of tricyclics with a tertiary amine structure gives rise to significant plasma concentrations of the corresponding secondary amine. There can be substantial (10- to 40-fold) differences in plasma tricyclic antidepressant levels between individual subjects when fixed-dose regimens are employed.
Table 19.8 Some adverse effects of tricyclic antidepressants
Plasma monitoring of tricyclic antidepressants. Despite a considerable research effort, the role of plasma level monitoring in the use of tricyclics is not well established. In general, it has been difficult to show a consistent relationship between plasma level and therapeutic response. However, there is some agreement that plasma levels of nortriptyline demonstrate a curvilinear relationship with clinical outcome. The highest response rates occur with plasma concentrations in the range of 50–150 ng/ml, and above this level the response rate may actually decline.
However, the relationship between clinical response during amitriptyline treatment and total plasma levels of amitriptyline and nortriptyline is not clear, with different studies reporting variously a linear relationship, a curvilinear relationship, and no relationship at all.
There is some evidence that high levels of tricyclic antidepressants are more likely to be associated with toxic side-effects such as delirium, seizures, and cardiac arrhythmias. The risk of such side-effects is minimized if total plasma levels of tricyclic antidepressants are lower than 300 ng/ml (Burke and Preskorn, 1999). In this context it is worth noting that a small proportion of patients who metabolize drugs slowly may develop significantly increased plasma levels of tricyclics while taking routine clinical doses.
Table 19.9 Indications for plasma monitoring of tricyclic antidepressants
To check compliance
Toxic side-effects at low dose
Lack of therapeutic response and doses > 200 mg
Coexisting medical disorder (e.g. epilepsy)
Possibility of drug interaction
Overall, plasma-level monitoring has a limited role in the management of tricyclic antidepressant treatment (see Table 19.9). Plasma monitoring may be useful to assess concordance, and is often helpful in patients who have not responded to what are usually adequate tricyclic doses, particularly if increases in dose above 200 mg daily are contemplated. Finally, plasma level monitoring is useful in patients with coexisting medical disorders, especially if there is a possibility of drug interaction. For example, in patients with seizure disorders, it is prudent to maintain plasma tricyclic levels within the usual range for the particular compound being used, because tricyclics lower the seizure threshold. An additional level of complexity is added by the effects of co-administered anti-epileptic drugs, which can increase or lower plasma tricyclic levels through pharmacokinetic interactions.
These include amitriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, and trimipramine. Clomipramine and lofepramine are sufficiently distinct from amitriptyline and imipramine to warrant separate mention.
Clomipramine is the most potent of the tricyclic antidepressants in inhibiting the reuptake of 5-HT. However, its secondary amine metabolite, desmethylclomipramine, is an effective noradrenaline reuptake inhibitor. In studies of depressed inpatients, the antidepressant effect of clomipramine was found to be superior to that of the SSRIs citalopram and paroxetine (Danish University Antidepressant Group, 1990). Unlike other tricyclic antidepressants, clomipramine is also useful in ameliorating the symptoms of obsessive–compulsive disorder (whether or not there is a coexisting major depressive disorder).
Lofepramine is a tertiary amine which is metabolized to desipramine. However, during lofepramine treatment, desipramine levels are probably too low to contribute significantly to the therapeutic effect. Lofepramine is a fairly selective inhibitor of noradrenaline reuptake, and has fewer anticholinergic and antihistaminic properties than amitriptyline. Lofepramine has been widely compared with other tricyclic antidepressants, and in general its antidepressant efficacy appears to be equivalent (Anderson, 1999).
The most important feature of lofepramine is that, unlike conventional tricyclic antidepressants, it is not cardiotoxic in overdose. This means that it is likely to be safer than other tricyclics for patients with cardiovascular disease, although caution is still recommended. There have been reports of hepatitis in association with lofepramine, but it is not clear whether the incidence is higher than with other tricyclic antidepressants.
Unwanted effects of tricyclic antidepressants
These are numerous and important (see Table 19.8).
• Autonomic effects. These include dry mouth, disturbance of accommodation, difficulty in micturition leading to retention, constipation leading rarely to ileus, postural hypotension, tachycardia, and increased sweating. Retention of urine, especially in elderly men with enlarged prostates, and worsening of glaucoma are the most serious of these effects; dry mouth and accommodation difficulties are the most common. Nortriptyline and lofepramine have relatively fewer anticholinergic side-effects.
• Psychiatric effects. These include tiredness and drowsiness with amitriptyline and other sedative compounds, insomnia with desipramine and lofepramine, and acute organic syndromes. Mania may be provoked in patients with bipolar disorders.
• Cardiovascular effects. Tachycardia and hypotension occur commonly. The electrocardiogram frequently shows prolongation of PR and QTc intervals, depressed ST segments, and flattened T-waves. Ventricular arrhythmias and heart block develop occasionally, more often in patients with pre-existing heart disease.
• Neurological effects. These include fine tremor (commonly), incoordination, headache, muscle twitching, epileptic seizures in predisposed patients, and, rarely, peripheral neuropathy.
• Other effects. Allergic skin rashes, cholestatic jaundice, and, rarely, agranulocytosis; weight gain and sexual dysfunction are also common.
• Withdrawal effects. Tricyclic antidepressants should be withdrawn slowly if at all possible. Sudden cessation may be followed by nausea, anxiety, sweating, gastrointestinal symptoms, and insomnia.
In overdosage, tricyclic antidepressants produce a large number of effects, some of which are extremely serious. Therefore urgent expert treatment in a general hospital is required, but the psychiatrist should know the main signs of overdosage. These can be listed as follows. The cardiovascular effects include ventricular fibrillation, conduction disturbances, and low blood pressure. Heart rate may be increased or decreased depending partly on the degree of conduction disturbance. The respiratory effects lead to respiratory depression. The resulting hypoxia increases the likelihood of cardiac complications. Aspiration pneumonia may develop.
The central nervous system complications include agitation, twitching, convulsions, hallucinations, delirium, and coma. Parasympathetic effects include dry mouth, dilated pupils, blurred vision, retention of urine, and pyrexia. Most patients need only supportive care, but cardiac monitoring is important, and arrhythmias require urgent treatment by a physician in an intensive-care unit. Tricyclic antidepressants delay gastric emptying, so gastric lavage is valuable for several hours after the overdose. Lavage must be carried out with particular care in order to prevent aspiration of gastric contents; if necessary, a cuffed endotracheal tube should be inserted before lavage is attempted.
Antidepressants and heart disease
The cardiovascular side-effects of tricyclic drugs, noted above, coupled with their toxic effects on the heart when these drugs are taken in overdose, have led to the suggestion that tricyclic antidepressant drugs may be dangerous in patients with heart disease. Indeed, patients with abnormal cardiac function do seem to be more at risk of orthostatic hypotension and heart block during treatment.
Some of the newer antidepressants, particularly the SSRIs, appear to be safer in patients with cardiac disease. With the availability of safer drugs it is probably wise not to use tricyclic antidepressants for patients with clinical or electrocardiographic evidence of cardiac disease. An epidemiological study found a higher risk of myocardial infarction in patients maintained on tricyclics than in those on SSRIs, with an increase in relative risk of 2.2 (95% CI, 1.2–3.8) (Cohen et al., 2000), although interpretation of this effect is complicated by the possibility that SSRIs may have cardioprotective effects (Von Ruden et al., 2008).
Antidepressants and epilepsy
Most classes of antidepressants lower the seizure threshold to some extent. This can lead to an increased risk of seizures in patients who have epilepsy or are predisposed to it. In general, SSRIs and trazodone are believed to be less likely to lower the seizure threshold than tricyclic antidepressants. MAOIs are also thought to lower the seizure threshold less than tricyclics.
Another complication is that antidepressant drugs can cause pharmacokinetic interactions with anticonvulsants in various ways. For example, SSRIs can increase carbamazepine levels, whereas valproate can elevate tri-cyclic concentrations. Before prescribing an antidepressant with an anticonvulsant, it is prudent to check for any possible interactions in the British National Formulary (see also Table 19.11).
Interactions with other drugs
Tricyclic antidepressants antagonize the hypotensive effects of α2-adrenoceptor agonists such as clonidine, but can be safely combined with thiazides and angiotensin-converting-enzyme (ACE) inhibitors.
The ability of tricyclics to block noradrenaline reuptake can lead to hypertension with systemically administered noradrenaline and adrenaline.
Tricyclics should not be used in conjunction with anti-arrhythmic drugs, particularly amiodarone.
Plasma levels of tricyclics can be increased by numerous other drugs, including cimetidine, sodium valproate, calcium-channel blockers and SSRIs. Tricyclics may increase the action of warfarin. Interactions of tricyclic drugs with MAOIs are considered later.
Contraindications include agranulocytosis, severe liver damage, glaucoma, prostatic hypertrophy, and significant cardiovascular disease. The drugs must be used cautiously in epileptic patients and in the elderly.
Clinical use of tricyclic antidepressants
With regard to the use of tricyclic antidepressants, the old adage is recommended that it is best to get to know one or two drugs well and stick to them. It is probably sufficient to be familiar with one sedating compound (e.g. amitriptyline) and one less sedating drug (e.g. nortriptyline). Other tricyclics can then be reserved for special purposes. For example, lofepramine can be used for patients who present the risk of overdose, while clomipramine can be reserved for patients in whom a depressive disorder is related to obsessive–compulsive disorder.
The prescribing of amitriptyline can be taken as an example. At the outset it is important to explain to the patient that, although side-effects may be noticed early in treatment, any significant improvement in mood may be delayed for a week or more, and therefore it is important to persist. Early signs of improvement may include better sleep and a lessening of tension. Common side-effects should be mentioned because a forewarned patient is more likely to continue with medication.
The usual practice of starting with a low dose of amitriptyline and building up is probably wise, because side-effects are generally milder and the patient is more likely to develop tolerance to them. The starting dose will depend to some extent on the patient’s age, weight, physical condition, and history of previous exposure to tricyclics; daily doses of 25–50 mg for an outpatient and 50–75 mg for an inpatient would be reasonable. The whole dose can be given at night about 1–2 hours before bedtime, because the sedative effects of the drug will aid sleep.
Patients should be reviewed frequently during the first few weeks of treatment, when support and advice are helpful both to maintain morale and to ensure compliance with medication. Often the clinician can detect improvements in rapport and initiative early in treatment. It can then be useful to discuss these changes with the patient. The dose of amitriptyline to be aimed for is about 125 mg daily or above. With careful monitoring and encouragement, this dose can usually be reached over a period of 2–4 weeks. Whether lower doses of tricyclics are effective in less severe depressive states in primary care is still debated.
In some patients, side-effects limit the rate of dosage increase, but if there is clinical improvement it is reasonable to settle for lower doses. In general, side-effects should not be greater than the patient can comfortably tolerate. For patients who show little or no improvement, it is usually advisable to continue amitriptyline for 4 weeks at the maximum tolerated dose before deciding that the drug is ineffective.
Some patients respond only to higher doses (up to 300 mg daily), and cautious increases towards this level are warranted provided that the side-effects are tolerable. In doses above 225 mg daily, it is wise to monitor plasma tri-cyclic levels and the electrocardiogram before each further dosage increase.
In the ECG it is important to note any evidence of impaired cardiac conduction—for example, lengthening of the QTc interval and the appearance of bundle branch block or arrhythmias. Because of the half-life of amitriptyline, each dose increase will take about a week to reach steady state. If the patient has not improved, and if they cannot tolerate an increase in dose or fail to respond to higher doses, other treatments should be considered. Some possible strategies are outlined in Chapter 10 (see p. 247).
Maintenance and prophylaxis
If the patient responds to amitriptyline, they should be maintained on treatment for at least 6 months, as continuation therapy greatly reduces the risk of early relapse. The same dose of amitriptyline should be maintained if possible, but if side-effects become a problem the dose can be lowered until tolerance is again satisfactory.
It is often not clear when antidepressant drug treatment should be withdrawn, because in some patients depression is a recurrent disorder. Long-term prophylactic treatment may then be justified. Obviously the risk of recurrence increases with the number of episodes that the patient suffers, but other clinical and biochemical predictors of relapse are not well established (see Chapter 10).
Selective serotonin reuptake inhibitors (SSRIs)
Six SSRIs—citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline—are available at present for clinical use in the UK. SSRIs are a structurally diverse group, but they all inhibit the reuptake of 5-HT with high potency and selectivity. None of them has an appreciable affinity for the noradrenaline uptake site, and the present data suggest that they have a low affinity for other monoamine neurotransmitter receptors.
In general, SSRIs are absorbed slowly and reach peak plasma levels after about 4–8 hours, although citalopram and escitalopram are absorbed more quickly. The half-lives of citalopram, escitalopram. fluvoxamine, paroxetine, and sertraline are between 20 and 30 hours, whereas the half-life of fluoxetine is 48–72 hours. The SSRIs are primarily eliminated by hepatic metabolism. Fluoxetine is metabolized to norfluoxetine, which is also a potent 5-HT uptake blocker and has a half-life of 7–9 days. Sertraline is converted to desmethylsertraline, which has a half-life of 2–3 days and is 5–10 times less potent than the parent compound in inhibiting the reuptake of 5-HT. The contribution of desmethylsertraline to the antidepressant effect of sertraline during treatment is unclear.
Efficacy of SSRIs in depression
The SSRIs have been extensively compared with placebo and with reference tricyclic antidepressants. The SSRIs are all superior to placebo and are generally as effective as tricyclics in the treatment of major depression (Anderson et al., 2008). Most comparative studies have been of moderately depressed outpatients, and there has been concern that SSRIs may be less effective than conventional tricyclic antidepressants for more severely depressed patients, particularly inpatients (Anderson et al., 2008).
Unwanted effects of SSRIs
The adverse effects of SSRIs differ significantly from those of tricyclic antidepressants. A major difference is that SSRIs are less cardiotoxic than tricyclic antidepressants and are generally safer in overdose, although concerns have been raised about the safety of citalopram and escitalopram in this respect. SSRIs also lack anticholinergic effects and are not sedating. Side-effects can be grouped as follows (see Table 19.10):
• Gastrointestinal effects. Nausea occurs in about 20% of patients, although it may resolve with continued administration. Other side-effects include dyspepsia, bloating, flatulence, and diarrhoea. With the exception of paroxetine, SSRIs are not usually associated with as much weight gain as tricyclic antidepressants.
• Neuropsychiatric effects. These include insomnia, daytime somnolence, agitation, tremor, restlessness, irritability, and headache. SSRIs have also been associated with seizures and mania, although they are probably less likely than tricyclics to cause the latter effects. By contrast, extrapyramidal side-effects such as Parkinsonism and akathisia are more common during treatment with SSRIs than with tricyclics. In particular, paroxetine has been associated with acute dystonias in the first few days of treatment.
• Other effects. Sexual dysfunction, including ejaculatory delay and anorgasmia, is common during SSRI treatment. Sweating and dry mouth are also reported. Cardiovascular side-effects are rare with SSRIs, but some reduction in pulse rate may occur, and postural hypotension has been reported. SSRIs have been associated with skin rashes and, rarely, a more generalized allergic reaction with arthritis. SSRIs can cause low sodium states secondary to inappropriate ADH secretion, especially in the elderly. As with tricyclic antidepressants, elevation of liver enzymes can occur but is generally reversible on treatment withdrawal. SSRIs may increase the risk of upper gastrointestinal bleeding, particularly when combined with non-steroidal anti-inflammatory drugs or aspirin. Long-term use of SSRIs has been associated with an increased risk of osteoporotic fracture. Part of this risk probably stems from depression itself, but 5HT mechanisms play a role in bone physiology, and SSRIs are associated with a greater risk of fracture than antidepressants with a low affinity for the 5-HT transporter (Verdel et al., 2010).
• Suicidal behaviour. There have been anecdotal reports that SSRI treatment may be associated with hostile and suicidal behaviour. Meta-analyses of placebo and comparator controlled trials of SSRIs in adults have found no significant increase in completed suicide in SSRI-treated patients, and no difference in rates of non-fatal suicidal behaviour between patients taking SSRIs and those taking tricyclics. Relative to placebo there may be a small risk that SSRIs can increase rates of self-harm, but in the largest meta-analysis, involving over 700 studies, the number needed to harm with SSRIs (759) was much greater than the number needed to treat (estimated to be between 4 and 7) (Gunnell et al., 2005). Ecological studies, although difficult to control, show fairly consistently that SSRI prescription at a population level is associated with a decline in completed suicide (Isacsson et al., 2010).
• In adolescents and children the risk of self-harm with SSRIs might be greater. In a meta-analysis of 27 placebo-controlled trials in children and adolescents with a variety of diagnoses, including depression, Bridge et al. (2007) found no completed suicides but a small, significant increase in suicidal ideation and self-harm attempts with SSRIs compared with placebo (number needed to harm = 143). Again there are hints that, in adolescents, rates of SSRI prescribing at a population level may be inversely related to completed suicide, but this has been disputed (Gibbons et al., 2007; Isacsson et al., 2010).
• As noted above, SSRIs can cause agitation and restlessness early in treatment, and it is possible that in predisposed individuals this might trigger dangerous behaviour. An epidemiological study of depressed patients in primary care who received a first prescription for an antidepressant found no significant difference in rates of suicidal behaviour or completed suicide in patients taking SSRIs compared with those taking tricyclic antidepressants (Jick et al., 2004). Noteworthy, however, was the fourfold increase in risk of attempted suicide seen with all antidepressants in the first 9 days of treatment, relative to the risk with longer-term treatment (greater than 90 days). In the small number of completed suicides, the relative risk in the first 9 days of treatment was increased almost 40-fold (Jick et al., 2004).
• There are a number of possible reasons for this important phenomenon. For example, depressed people may visit their doctor and start treatment when they are at a particularly low ebb. Thus it is possible that suicidal feelings and behaviour are important factors in bringing people into treatment in the first place. Alternatively, the observation may be a reflection of the traditional view that the greatest risk of suicidal behaviour occurs during the early stages of antidepressant treatment, because improvement in motor retardation precedes resolution of depressed mood. Whatever the explanation, it reinforces advice that patients should be closely monitored when starting antidepressant medication. Interestingly, a similar phenomenon of increased rates of self-harm has been reported in patients with depression in the early stages of psychological treatment (Simon and Savarino, 2007).
Interactions with other drugs
Pharmacodynamic interactions. The most serious interaction reported is where simultaneous administration of SSRIs and MAOIs has provoked a 5-HT toxicity syndrome (the ‘serotonin syndrome’), with agitation, hyperpyrexia, rigidity, myoclonus, coma, and death (for further details, see the section on MAOIs). Other drugs that increase brain 5-HT function and that must therefore be used with caution in combination with SSRIs include lithium and tryptophan, which have been reported to be associated with mental state changes, myoclonus, and seizures. Other medical drugs that have been implicated in the serotonin syndrome when combined with SSRIs include tramadol and linezolid. Serotonin toxicity can also occur if SSRIs are combined with 5-HT receptor agonists such as sumatriptan.
SSRIs may potentiate the induction of extrapyramidal movement disorders by antipsychotic drugs, although this effect could be partly due to a pharmacokinetic interaction whereby SSRIs increase plasma levels of certain antipsychotic drugs (see below).
Pharmacokinetic interactions. SSRIs can produce substantial inhibition of some hepatic cytochrome P450 enzymes, and can decrease the metabolism of several other drugs, thereby elevating their plasma levels (see Table 19.11). Examples where clinically important reactions have been reported include tricyclic antidepressants, antipsychotic agents (including clozapine and risperidone), anticonvulsants, and warfarin. Citalopram, escitalopram, and sertralinecause fewer reactions of this nature.
Table 19.10 Side-effects of SSRIs
The clinical use of SSRIs in depression
Particularly in primary care, SSRIs have supplanted tricyclic antidepressants because of their better tolerability and greater ease of dosing. In clinical trials, the rate of dropout due to adverse effects is modestly but significantly lower with SSRIs than with tricyclics; this difference may be greater in routine clinical practice (Anderson et al., 2008). Economic analyses of the cost–benefit ratio of SSRIs compared with tricyclics have yielded conflicting results, but with the availability of generic forms of SSRI, the costs of medication have become less important in such calculations. However, tricyclics retain an important role in the treatment of patients who do not respond to the newer agents. Meta-analysis suggests that, at appropriate dosage, amitriptyline is still the most efficacious of the currently available antidepressants (Barbui and Hotopf, 2001).
Whether meta-analyses reveal clinically important differences in efficacy between SSRIs has been disputed (Gartlehner et al., 2008; Cipriani et al., 2009). However, there are significant differences in pharmacokinetic profile which have a bearing on the likelihood of a withdrawal syndrome and the potential for drug interactions (see Table 19.12).
Table 19.11 Inhibition of P450 enzyme by SSRIs
Fluvoxamine appears to have higher dropout rates from trials, and may be somewhat less well tolerated. Fluoxetine has the most activating effect, and also has a distinctive pharmacokinetic profile in relation to its long-acting metabolite, which has a half-life of about 1 week. On the one hand, this results in potential for troublesome drug interactions several weeks after fluoxetine has been stopped. For example, at least 5 weeks should elapse between stopping fluoxetine and starting an MAOI. On the other hand, this slow tapering of plasma concentration results in fluoxetine being the least likely of the SSRIs to cause a withdrawal syndrome. Escitalopram is the active isomer of citalopram, and is marketed as being more effective than the parent compound, although whether any difference between the two drugs is of clinical significance is disputed.
Table 19.12 Differences between SSRIs
When treating depressive disorder, dosing is easier with SSRIs than with tricyclic antidepressants, because most SSRIs can be started at a standard dose that can often be maintained throughout treatment. For example, although fluoxetine has been given in doses of up to 80 mg daily, there is little evidence of increasing therapeutic efficacy above the 20 mg dose.
As with tricyclic antidepressant treatment, patients who are starting SSRIs should be warned about the likely side-effects, including nausea and some restlessness during sleep. A number of patients become more anxious and agitated during SSRI treatment; therefore it is important to explain that such effects are sometimes experienced during treatment but do not mean that the underlying depression is worsening. If the patient persists with treatment, such anxiety and agitation usually diminish, but short-term treatment with a benzodiazepine may be helpful, particularly if sleep disturbance is a problem. Small doses of trazodone (50–150 mg) may also help sleep, although there are occasional reports of serotonin toxicity with this combination.
As with tricyclic antidepressants, when patients respond to SSRIs there is good evidence that continuing treatment for several months lowers the rate of relapse. In addition, placebo-controlled studies have shown that SSRIs are effective in the prophylaxis of recurrent depressive episodes. SSRIs should not be stopped suddenly, as there have been reports of withdrawal reactions (insomnia, nausea, agitation, and dizziness) after the cessation of treatment, particularly with paroxetine (for a review of antidepressant discontinuation syndromes, see Haddad and Anderson, 2007). Liquid preparations of SSRIs can facilitate a slow withdrawal.
Monoamine oxidase inhibitors (MAOIs)
MAOIs were introduced just before the tricyclic antidepressants, but their use has been less widespread because of both troublesome interactions with foods and drugs and uncertainty about their therapeutic efficacy. However, in adequate doses MAOIs are useful antidepressants, often producing clinical benefit in depressed patients who have not responded to other medication or ECT. In addition, MAOIs can be useful in refractory anxiety states (Baldwin et al., 2005).
These beneficial effects have to be weighed against the need to adhere to strict dietary and drug restrictions in order to avoid reactions with tyramine and other sympathomimetic agents. In practice this means that conventional MAOIs are not used as first-line treatment.
MAOIs inactivate enzymes that oxidize noradrenaline, 5-HT, dopamine, and tyramine, and other amines that are widely distributed in the body as transmitters, or are taken in food and drink or as drugs. Monoamine oxidase (MAO) exists in a number of forms that differ in their substrate and inhibitor specificities. From the point of view of psychotropic drug treatment, it is important to recognize that there are two forms of MAO—type A and type B—which are encoded by separate genes. In general, MAO-A metabolizes intraneuronal noradrenaline and 5-HT, whereas both MAO-A and MAO-B metabolize dopamine and tyramine.
Phenelzine is the most widely used and widely studied compound. Isocarboxazid is reported to have fewer side-effects than phenelzine, and can be useful for patients who respond to the latter drug but suffer from its side-effects of hypotension or sleep disorder. Tranylcypromine differs from the other compounds in combining the ability to inhibit MAO with an amphetamine-like stimulating effect which may be helpful in patients with anergia and retardation. However, some patients have become dependent on the stimulant effect of tranylcypromine. Moreover, compared with phenelzine, tranylcypromine is more likely to give rise to hypertensive crises, although it is less likely to damage the liver. For these reasons, tranylcypromine should be prescribed with particular caution.
Moclobemide is the most recently developed MAOI to be marketed. It differs from the other compounds in selectively binding to MAO-A, which it inhibits in a reversible way. This results in a lack of significant interactions with foodstuffs, and a quick offset of action (Bonnet, 2003) (see below).
Phenelzine, isocarboxazid, and tranylcypromine are rapidly absorbed and widely distributed. They have short half-lives (about 2–4 hours), as they are quickly metabolized in the liver by acetylation, oxidation, and deamination. People differ in their capacity to acetylate drugs. For example, in the UK, approximately 60% of the population are ‘fast acetylators’, who would be expected to metabolize hydrazine MAOIs more quickly than ‘slow acetylators.’ Some studies have shown a better clinical response to phenelzine in ‘slow acetylators’, but this finding has not been consistently replicated. However, it may underlie the observation that the best response rate with MAOIs occurs in studies that have used higher dose ranges, presumably because even patients who metabolize MAOIs quickly will receive an adequate dose.
Phenelzine, isocarboxazid, and tranylcypromine bind irreversibly to MAO-A and MAO-B by means of a covalent linkage. This means that the enzyme is permanently deactivated and MAO activity can be restored only when new enzyme is synthesized. Thus, despite their short half-lives, irreversible MAOIs cause a long-lasting inhibition of MAO.
In contrast to these compounds, moclobemide binds reversibly to MAO-A. This compound has a short half-life (about 2 hours), and therefore its inhibition of MAO-A is brief, declining to some extent even during the latter periods of a three times daily dosing regimen. Full MAO activity is restored within 24 hours of stopping moclobemide, whereas with the irreversible MAOIs, a period of 2 weeks or more may be needed for synthesis of new MAO.
Efficacy of MAOIs in depression
For many years MAOIs were in relative disuse because several studies, in particular a large controlled trial by the Medical Research Council (Clinical Psychiatry Committee, 1965), found phenelzine to be no more effective than placebo in the treatment of depressive disorders. It seems likely that the doses of MAOIs were too low in these early investigations; in the Medical Research Council study the maximum dose of phenelzine was 45 mg daily, in contrast to the current practice of using doses of up to 90 mg daily if side-effects permit. Subsequent studies have shown that in this wider dose range MAOIs are superior to placebo and are generally equivalent to tricyclic antidepressants in their therapeutic activity (Anderson et al., 2008).
Investigations in the USA confirmed early clinical impressions that MAOIs may be of particular value in the treatment of atypical depression. It also seems that MAOIs are more effective than tricyclic antidepressants for patients with bipolar depression if the clinical features include hypersomnia and anergia. Finally, there is good evidence that they may be beneficial for depressed patients who do not respond to tricyclics and other reuptake inhibitors, whether or not the depression has endogenous features (Thase et al., 1995).
These include dry mouth, difficulty in micturition, postural hypotension, confusion, mania, headache, dizziness, tremor, paraesthesia of the hands and feet, constipation, and oedema of the ankles. Hydrazine compounds can give rise to hepatocellular jaundice (see Box 19.4).
Interactions with foodstuffs
Some foods contain tyramine, a substance that is normally inactivated by MAO in the liver and the gut wall. When MAO is inhibited, tyramine is not broken down and is free to exert its hypertensive effects. These effects are due to release of noradrenaline from sympathetic nerve terminals with a consequent elevation in blood pressure. This may reach dangerous levels and may occasionally result in subarachnoid haemorrhage. Important early symptoms of such a crisis include a severe and usually throbbing headache.
The incidence of hypertensive reactions is about 10% in patients who are taking MAOIs, even in those who have received dietary counselling. Therefore regular reminders about dietary restrictions may be helpful, particularly in patients on longer-term treatment (see Box 19.5). There have been reports of a wide range of foods being implicated in hypertensive reactions with MAOIs, but many of these have cited single cases and therefore are of uncertain validity. Another complication is that the tyramine content of a particular food item may vary, as may the susceptibility of an individual patient to a hypertensive reaction. If a forbidden food has been consumed on one occasion without adverse effects, this does not preclude a future reaction.
Box 19.4 Adverse effects of MAOIs
Central nervous system
Insomnia, drowsiness, agitation, headache, fatigue, weakness, tremor, mania, confusion
Autonomic nervous system
Blurred vision, difficulty in micturition, sweating, dry mouth, postural hypotension, constipation
Sexual dysfunction, weight gain, peripheral neuropathy (pyridoxine deficiency), oedema, rashes, hepatocellular toxicity (rare), leucopenia (rare)
It is notable that about 80% of all reported reactions between foodstuffs and MAOIs, and nearly all of the deaths, have followed the consumption of cheese. Hypertensive reactions should be treated with parenteral administration of an α1-adrenoceptor antagonist, such as phentolamine. If this drug is not available, chlorpromazine can be used. The use of oral nifedipine has also been advocated. Whatever treatment is given, blood pressure must be monitored carefully.
Box 19.5 Foods to be avoided during MAOI use
• All cheeses except cream, cottage, and ricotta cheeses
• Red wine, sherry, beer, and liquors
• Pickled or smoked fish
• Brewer’s yeast products (e.g. Marmite, Bovril, and some packet soups)
• Broad bean pods (e.g. Italian green beans)
• Beef or chicken liver
• Fermented sausage (e.g. bologna, pepperoni, salami)
• Unfresh, overripe, or aged food (e.g. pheasant, venison, unfresh dairy products)
Moclobemide and tyramine reactions
Tyramine is metabolized by both MAO-A and MAO-B. Experimental studies have shown that the hypertensive effect of oral tyramine is potentiated much less by moclobemide than by non-selective MAOIs (Bonnet, 2003). In patients who are taking moclobemide in doses of up to 900 mg daily, the dose of tyramine required to produce a significant pressor response is above 100 mg. Even a five-course meal with wine would be unlikely to result in a tyramine intake of more than 40 mg.
Tyramine has relatively little effect in patients who are receiving moclobemide because MAO-B (present in the gut wall and the liver) is still available to metabolize much of the tyramine ingested. Another factor may be that the interaction between moclobemide and MAO-A is reversible, thus allowing displacement of moclobemide from MAO when tyramine is present in excess.
Interactions with drugs
Patients who are taking MAOIs must not be given drugs whose metabolism depends on enzymes that are affected by the MAOI. These drugs include sympathomimetic amines such as adrenaline, noradrenaline, and amphetamine, as well as phenylpropanolamine and ephedrine (which may be present in proprietary cold cures). L-Dopa and dopamine may also cause hypertensive reactions. Local anaesthetics often contain a sympathomimetic amine, which should also be avoided. Opiates, cocaine, and insulin can also be involved in dangerous interactions. Sensitivity to oral antidiabetic drugs is increased, with a consequent risk of hypoglycaemia. The ability of MAOIs to cause postural hypotension can increase the hypotensive effects of other agents. Finally, the metabolism of carbamazepine, phenytoin, and other drugs that are broken down in the liver may be slowed.
The serotonin syndrome. A number of drugs that potentiate brain 5-HT function can produce a severe neurotoxicity syndrome when combined with MAOIs. The main features of this syndrome are listed in Box 19.6. It is worth noting that some of these symptoms resemble the neuroleptic malignant syndrome with which 5-HT neurotoxicity is occasionally confused. In view of the interactions between dopamine and 5-HT pathways, it is possible that similar mechanisms may be involved.
Current clinical data indicate that combination of MAOIs with SSRIs, venlafaxine, and clomipramine is contraindicated. The combination of MAOIs with L-tryptophan has also been reported to cause 5-HT toxicity. Adverse reactions have been reported between the 5-HT1A receptor agonist, buspirone, and MAOIs. In addition, the use of 5-HT1 receptor agonists, such as sumatriptan, should be avoided. If used with caution, the combination of lithiumwith MAOIs appears to be safe, and it can be effective in patients with resistant depression.
Box 19.6 Clinical features of the serotonin syndrome
Myoclonus, nystagmus, headache, tremor, rigidity, seizures
Irritability, confusion, agitation, hypomania, coma
Hyperpyrexia, sweating, diarrhoea, cardiac arrhythmias, death
If a 5-HT syndrome develops, all medication should be stopped and supportive measures instituted. In theory, drugs with 5-HT-receptor-antagonist properties such as cyproheptadine or propranolol may be helpful, but controlled studies have not been carried out. For a review of the serotonin syndrome, see Gillman and Whyte (2004).
Combination of MAOIs with tricyclic antidepressants. The combined use of MAOIs and tricyclic antidepressants fell into disuse because of the severe reactions associated with the 5-HT syndrome. Current views are that combination therapy is safe provided that the following rules are observed:
• Clomipramine and imipramine are not used. The most favoured tricyclics in combination with MAOIs are amitriptyline and trimipramine.
• The MAOI and tricyclic are started together at low dosage, or the MAOI is added to the tricyclic (adding tricyclics to MAOIs is more likely to provoke dizziness and postural hypotension).
The advantages and disadvantages of combined tricyclic and MAOI therapy have not been fully established. On the one hand, patients who are taking tricyclics with MAOIs are less likely to suffer from MAOI-induced insomnia, but on the other hand, they are more likely to experience postural hypotension and troublesome weight gain. The combination is said to be useful in patients with resistant depression. Although formal studies have not been carried out in this patient group, there are case reports of patients for whom combined MAOI and tricyclic treatment was successful when either treatment alone had not been helpful. Low doses of trazodone (50–150 mg) are also used to ameliorate MAOI-induced insomnia; present experience suggests that this combination is generally well tolerated, although there are occasional reports of adverse effects that could represent serotonin toxicity.
These include liver disease, phaeochromocytoma, congestive cardiac failure, and conditions that require the patient to take any of the drugs that react with MAOI.
Clinical use of MAOIs in depression
As mentioned above, because of the potential danger of drug interactions and the need for a tyramine-free diet, irreversible MAOIs are not used as first-line antidepressant agents. The exception may be when a patient has previously shown a favourable response to these drugs as compared with other classes of antidepressants. Even in atypical depression, for which MAOIs may well be superior to tricyclic antidepressants, it is probably better to try an SSRI first, because many patients will respond to this approach (Henkel et al., 2006).
The clinical use of phenelzine can be taken as an example. Treatment should start with 15 mg daily, increasing to 30 mg daily in divided doses (with the final dose taken not later than 3.00 pm) in the first week. Patients should be given clear written instructions about foods to be avoided (see below), and should be warned to take no other medication unless it has been specifically checked with a pharmacist or doctor who knows that the patient is taking MAOIs. As always, patients should be warned about the delay in therapeutic response (up to 6 weeks) and about common side-effects (sleep disturbance and dizziness).
In the second week, the dose of phenelzine can be increased to 45 mg daily. At this stage a greater increase to 60 mg may produce a quicker response, but is also associated with more adverse effects. Accordingly, if feasible, it is better to find out whether an individual patient will respond to lower doses (about 45 mg) before increments are made (up to 90 mg daily). If the patient does not respond to 45 mg, the dose can be increased by 15 mg weekly if side-effects permit.
The response to MAOIs can often be sudden; over the course of a day or two the patient suddenly feels better. If there are signs of overactivity or excessive buoyancy in mood, the dose can be reduced and the patient monitored for signs of developing hypomania. Side-effects that are likely to be particularly troublesome are insomnia and postural hypotension. Insomnia is best managed by lowering the dose of MAOI, if feasible. Otherwise, the addition of a benzodiazepine or trazodone (50–150 mg at night) can be helpful, although the latter drug can sometimes increase problems of dizziness and postural hypotension.
Postural hypotension can be a disabling problem with MAOIs. Again, dose reduction is worth considering. Various measures have been suggested—for example, the use of support stockings, an increase in salt intake, or even the use of a mineralocorticoid. Of course, the latter two measures have their own adverse effects.
Withdrawal from MAOIs
Patients who respond to MAOIs have often suffered from disabling depression for many months or even years. For such patients the usual practice is to continue therapy for at least 6 months to a year. With MAOIs, it is wise to lower the dose if the patient can tolerate the reduction without relapsing. Sudden cessation of MAOIs can lead to anxiety and dysphoria. Even gradual withdrawal can be associated with increasing anxiety and depression.
Clinical experience indicates that it is more difficult to stop MAOI than tricyclic antidepressant treatment. An explanation for this difference may be that MAOIs may produce a more severe discontinuation syndrome than other antidepressants; another possible explanation is that MAOIs are given to patients with chronic disabling disorders who frequently relapse. It is emphasized that, because of the time taken to synthesize new MAO, 2 weeks should elapse between the cessation of irreversible MAOI treatment and the easing of dietary and drug restrictions.
In their freedom from tyramine reactions and their quick offset of activity, reversible type A MAOIs, such as moclobemide, have clear advantages over conventional MAOIs. As with all newer antidepressants, however, the therapeutic efficacy of moclobemide, particularly in more severely depressed patients, is not as well established. Also, it is not clear that moclobemide is effective for patients with the various forms of atypical depression and drug-resistant depression for which conventional MAOIs can be useful (Anderson et al., 2008). A case series suggested that moclobemide may have a place in the treatment of patients with resistant depression when used in combination with other agents such as lithium and tricyclic antidepressants (Kennedy and Paykel, 2004).
The starting dose of moclobemide is 150–300 mg daily, which can be increased to 600 mg over a number of weeks. Treatment-resistant patients may require higher doses, but above levels of 900 mg daily it is prudent to institute the usual MAOI dietary restrictions. Moclobemide is better tolerated than tricyclic antidepressants or irreversible MAOIs, but side-effects such as nausea and insomnia occur in about 20–30% of patients.
Drug interactions of moclobemide
Moclobemide should not be combined with SSRIs, venlafaxine, or clomipramine because a serotonin syndrome may result. Caution is needed with sumatriptan. Like the irreversible MAOIs, moclobemide may react adversely with opiates. Similarly, moclobemide may potentiate the pressor effects of sympathomimetic amines; therefore combined use should be avoided. Moclobemide should not be combined with L-dopa because of the risk of hypertensive crisis. Cimetidine delays the metabolism of moclobemide.
Other antidepressant drugs
Other antidepressant drugs are available for use in the UK and other countries. Their mechanism of action is such that they cannot easily be grouped with tricyclic antidepressants, SSRIs, or MAOIs. These drugs also have differing adverse-event profiles. Therefore they are discussed individually below.
Agomelatine is a recently licensed antidepressant which is a melatonin-receptor agonist and a somewhat weaker antagonist at 5-HT2C receptors. The mechanism of anti-depressant action of agomelatine is not established, but could be mediated through a melatonin-like action on circadian rhythms. It is also possible that 5-HT2C-receptor blockade might lead to increased dopamine release in the prefrontal cortex (Stahl, 2007).
Pharmacokinetics. Agomelatine is rapidly absorbed, reaching maximum levels within 1–2 hours of ingestion. However, it has a high first-pass metabolism, with a bio-availability of only 5–10%. It has a short half-life of about 2 hours and no metabolites likely to contribute to its therapeutic action.
Efficacy. Controlled trials in moderately depressed out-patients have shown that agomelatine is superior to placebo and appears comparable in efficacy to venlafaxine and paroxetine, although the doses of the latter agents were relatively modest (Dolder et al., 2008). Continuation of agomelatine treatment in responders for 6 months was associated with less relapse than a switch to placebo. In clinical trials, agomelatine was dosed once daily at 9.00 pm, which is sufficiently in advance of the endogenous night-time melatonin peak to produce effects on circa-dian rhythm. Therefore it seems sensible when prescribing agomelatine to use the same treatment schedule.
Unwanted effects. The most common adverse effects of agomelatine are nausea and dizziness. Agomelatine is not sedating, but some patients experience somnolence, and insomnia has also been reported. Other possible side-effects include anxiety and fatigue, diarrhoea, and constipation. Sexual dysfunction seems to be less frequent than with SSRIs. The most serious potential adverse effect of agomelatine is an increase in liver enzymes (ALT and AST), with a rate of 1.1% in agomelatine-treated patients compared with 0.7% in patients taking placebo. For this reason, treatment with agomelatine should be preceded by measurement of liver function tests, which should be repeated after approximately 6, 12, and 24 weeks. Any clinical suspicion of impaired hepatic function should be followed by urgent liver function tests, and treatment with agomelatine should be stopped if the results are abnormal.
Drug interactions. The main interaction of agomelatine is with drugs that inhibit the hepatic microsomal enzymes, CYP1A2 and CYP2C9/19. This is because these enzymes metabolize agomelatine, and higher blood levels of agomelatine are likely to increase the risk of hepatic dysfunction. Therefore agomelatine should not be given with potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin. Co-administration of agomelatine with more moderate inhibitors (oestrogens, propranolol, and grepafloxacin) should be employed with caution.
Mianserin is a quadricyclic compound with complex pharmacological actions. It has weak noradrenaline reuptake inhibiting effects, and is a fairly potent antagonist at several 5-HT-receptor subtypes, particularly 5-HT2receptors. Mianserin is also a competitive antagonist at histamine H1 receptors andα1- and α2-adrenoceptors. The latter action leads to an increase in noradrenaline cell firing and release. It is not a muscarinic cholinergic antagonist and is not cardiotoxic. Because of these various actions, mianserin has a sedating profile, but it is not anticholinergic and is relatively safe in overdose.
Pharmacokinetics. Mianserin is rapidly absorbed, and the peak plasma concentration occurs after 2–3 hours. Its half-life is 10–20 hours, and the entire daily dose can be given in a single administration at night.
Efficacy. Controlled trials have shown that mianserin is superior to placebo in the management of depression, and comparative studies against imipramine and clomipramine have shown no difference in effect. These studies are difficult to assess because of the wide range of doses that have been used. Many early studies of mianserin used doses of 30–60 mg daily, whereas much higher doses of up to 200 mg daily have sometimes been advocated for inpatients.
Unwanted effects. The main adverse effects of mianserin are drowsiness and dizziness, although these effects can be lessened by starting at a modest dosage and then increasing gradually. Weight gain is a common problem. Dyspepsia and nausea have also been reported. Like tricyclics, mianserin appears to lower seizure threshold to some extent. Postural hypotension occurs occasionally.
The most serious adverse effect of mianserin is lowering of the white cell count, and fatal agranulocytosis has been reported. These adverse reactions occur more commonly in elderly patients. It is recommended that a blood count be obtained before starting mianserin treatment, and that the white cell count be monitored monthly for 3 months after treatment has started. Rare side-effects of mianserin include arthritis and hepatitis.
Drug interactions. Mianserin can potentiate the effect of other central sedatives. There is a theoretical risk that mianserin could reverse the effects of α2-adrenoceptor agonists such as clonidine.
Mirtazapine is an analogue of mianserin, with a generally similar pharmacological profile but a weaker affinity for α1-adrenoceptors. It is said that this permits mirtazapine to activate 5-HT as well as noradrenaline neurons, although whether this occurs during clinical use is unclear. Like mianserin, mirtazapine has a sedating profile. Mirtazapine is known as a noradrenaline- and serotonin-specific antidepressant (NASSA).
Pharmacokinetics. Mirtazapine is well absorbed, with peak plasma levels being reached between 1 and 2 hours. The half-life is about 16 hours, and the daily dose can be given at night. Mirtazapine is extensively metabolized by the liver, and has only minor inhibitory effects on cyto-chrome P450 isoenzymes.
Efficacy. Mirtazapine has demonstrated clinical efficacy in both placebo-controlled and comparator trials with SSRIs and tricyclic antidepressants in moderate to severely depressed patients. The effective dose is usually between 10 mg and 45 mg daily.
Unwanted effects. The common adverse effects of mirtazapine are attributable to its potent antihistaminic actions, and include drowsiness and dry mouth. Increased appetite and body weight are also common. Thus far leucopenia does not appear to be more common with mirtazapine than with other antidepressants. However, the data sheet recommends that physicians be vigilant for possible signs that might reflect low white cell count.
Drug interactions. Mirtazapine may potentiate other centrally acting sedatives. As with mianserin, there is a theoretical risk that mirtazapine could reverse the effect of α2-adrenoceptor agonists.
Trazodone is a triazolopyridine derivative with complex actions on 5-HT pathways. Studies in vitro suggest that trazodone has some weak 5-HT reuptake-inhibiting properties which are probably not manifested during clinical use; for example, repeated administration of trazodone does not lower platelet 5-HT content.
Trazodone has antagonist actions at 5-HT2 receptors, but its active metabolite, m-chloro-phenylpiperazine (m-CPP), is a 5-HT receptor agonist. Therefore the precise balance of effects on 5-HT receptors during trazodone treatment is difficult to determine, and may depend on relative blood levels of the parent compound and metabolite. Trazodone also blocks post-synaptic-α1-adrenoceptors. Overall it has a distinct sedating profile.
Pharmacokinetics. Trazodone has a short half-life (about 4–14 hours). It is metabolized by hydroxylation and oxidation, with the formation of a number of metabolites including m-CPP. During treatment, plasma levels of m -CPP may exceed those of trazodone itself.
Efficacy. Several controlled studies have shown that trazodone in doses of 150–600 mg is superior to placebo in the treatment of depressed patients. Trazodone also appears to have equivalent antidepressant activity to reference compounds such as imipramine. Many of these studies were carried out in moderately depressed outpatients, and the efficacy of trazodone relative to other antidepressants is not well established (Anderson, 1999).
Some have maintained that the efficacy of trazodone is improved if treatment is started at low doses (50 mg) and increased slowly to 300 mg over 2–3 weeks. Despite the short half-life of trazodone, once-daily adminstration of the drug is often sufficient. The drug is usually given in the evening to take advantage of its sedative properties. Doses above 300 mg daily are usually better given in divided amounts. Lower doses (50–150 mg) are sometimes used in combination with SSRIs and MAOIs to ameliorate the sleep-disrupting effects of the latter agents.
Unwanted effects. The major unwanted effect of trazodone is excessive sedation, which can result in significant cognitive impairment. Nausea and dizziness are also reported, particularly if the drug is taken on an empty stomach. The α1-adrenoceptor-antagonist properties of trazodone may lower blood pressure to some extent, and postural hypotension has been reported. Trazodone is less cardiotoxic than conventional tricyclics, but there are reports that cardiac arrhythmias may be worsened in patients with cardiac disease. Nevertheless, trazodone is less toxic in overdose than tricyclic antidepressants.
The most serious side-effect of trazodone is priapism. This reaction is seen rarely (about 1 in 6000 male patients). It can cause considerable problems, requiring the local injection of noradrenaline agonists such as adrenaline, or even surgical decompression. Long-term sexual dys-function has sometimes resulted. It is recommended that male patients be warned of this potential side-effect and advised to seek medical help urgently if persistent erection occurs.
Drug interactions. As with all sedative antidepressants, trazodone may potentiate the sedating effects of alcohol and other central tranquillizing drugs. Studies in animals have raised the possibility that trazodone could attenuate the hypotensive effect of clonidine, but it is not known whether such an interaction occurs in humans.
Reboxetine is a morpholine and is structurally related to fluoxetine. It is a selective noradrenaline reuptake inhibitor (NARI) with no clinically significant effects on other neurotransmitter receptors.
Pharmacokinetics. After oral administration, reboxetine reaches peak plasma levels after about 2 hours. Its half-life is around 13 hours, and twice-daily administration is recommended. Reboxetine is metabolized by the liver, where it is a substrate for cytochrome P450 CYP3A.
Efficacy. Reboxetine reportedly shows efficacy in both placebo-controlled trials and against active comparators such as SSRIs. However, different meta-analyses have come to differing conclusions, and overall in moderately depressed outpatients reboxetine may be less effective than some other classes of antidepressants, including SSRIs (Papakostas et al., 2008; Cipriani et al., 2009). It is claimed that reboxetine produces better improvement in social function in depressed patients than SSRIs, but this possibility has not been confirmed (Papakostas et al., 2008). The usual dose of reboxetine is 4 mg twice daily, with a maximum dose of 12 mg daily.
Unwanted effects. Despite its low affinity for muscarinic receptors, reboxetine produces adverse effects characteristic of cholinergic-receptor blockade, presumably through interactions of noradrenergic and cholinergic pathways. The most common side-effects are dry mouth, constipation, sweating, and insomnia. Urinary hesitancy, impotence, tachycardia, and vertigo are also occasionally described.
Drug interactions. Limited information is available. It is recommended that reboxetine should not be given with other agents that might potentiate noradrenaline function, such as MAOIs, or that might increase blood pressure, such as ergot derivatives. Plasma reboxetine levels might be increased by drugs that inhibit cytochrome P450 3A4, such as some antifungal agents, fluvoxamine, and macrolide antibiotics.
Venlafaxine is a phenylethylamine derivative which produces a potent blockade of 5-HT reuptake, with lesser effects on noradrenaline. In this respect the pharmacological properties of venlafaxine resemble those of clomipramine to some extent. However, unlike clomipramine and other tricyclic antidepressants, venlafaxine has a negligible affinity for other neurotransmitter receptor sites, and so lacks sedative and anticholinergic effects. Because of these pharmacological properties, venlafaxine has been classified as a selective serotonin and noradrenaline reuptake inhibitor (SNRI).
Pharmacokinetics. Venlafaxine is well absorbed, achieving peak plasma levels about 1.5–2 hours after oral administration. The half-life of venlafaxine is 3–7 hours, but it is metabolized to desmethylvenlafaxine, which has essentially the same pharmacodynamic properties as the parent compound and a half-life of 8–13 hours. The extended-release formulation of venlafaxine (venlafaxine XL) reaches a peak plasma level after about 6 hours. This gives a long apparent half-life (about 15 hours), but the drug is still quickly eliminated. Once-daily dosing is possible with this preparation.
Efficacy. Venlafaxine has been studied in both inpatients and outpatients with major depression and compared with placebo and active comparators. Current studies suggest that it is more effective than placebo and of at least equal efficacy to other available antidepressant drugs, including tricyclic antidepressants. Some meta-analyses suggest that venlafaxine is more effective than SSRIs, particularly for more severely depressed patients, but the data are inconsistent (Anderson et al., 2008).
Venlafaxine has a wider dosage range than SSRIs, from 75 to 375 mg daily in two divided doses, or up to 225 mg of the extended-release preparation given as a single dose. The usual starting dose of venlafaxine is 75 mg daily, which may be sufficient for many patients. Upward titration can be considered in cases where there is insufficient response.
Unwanted effects. The adverse-effect profile of venlafaxine resembles that of SSRIs, with the most common adverse effects being nausea, headache, somnolence, dry mouth, dizziness, and insomnia. Anxietyand sexual dys-function may also occur. Venlafaxine occasionally causes postural hypotension but, in addition, dose-related increases in blood pressure can occur. Blood pressure monitoring is advisable in patients who are receiving more than 150 mg venlafaxine daily. Overdoes of venlafaxine have been associated with cardiac arrhythmias, so it probably prudent to avoid using venlafaxine in patients with significant cardiac disease. Like SSRIs, venlafaxine can lower plasma sodium levels. Venlafaxine may be somewhat less well tolerated than SSRIs (Anderson et al., 2008).
Venlafaxine appear to be more toxic than SSRIs in acute overdose (Cheeta et al., 2004), with a toxicity intermediate between that of conventional tricyclic antidepressants and SSRIs. Similarly to SSRIs, sudden discontinuation of venlafaxine has been associated with symptoms of fatigue, nausea, abdominal pain, and dizziness. It is recommended that patients who received venlafaxine for 6 weeks or more should have the dose reduced gradually over at least a 1-week period, and longer if possible.
Drug interactions. Unlike the SSRIs, venlafaxine appears to produce relatively modest effects on hepatic drug-metabolizing enzymes, and therefore should be less likely to inhibit the metabolism of co-administered drugs. Venlafaxine is metabolized partly by CYP34A4, and caution is recommended where venlafaxine is co-prescribed with CYP3A4 inhibitors such as ketoconazole and clarithromycin. Like other drugs that potently inhibit the uptake of 5-HT, venlafaxine should not be given concomitantly with MAOIs because of the danger of a toxic serotonin syndrome. It is also recommended that 14 days should elapse after the end of MAOI treatment before venlafaxine is started, and that at least 7 days should elapse after venlafaxine cessation before MAOIs are given.
Like venlafaxine, duloxetine is also classified as an SNRI. It is about five times more potent in inhibiting the reuptake of 5-HT than in inhibiting that of noradrenaline. It has little effect on other neurotransmitter receptors (Cowen et al., 2005).
Pharmacokinetics. Duloxetine is well absorbed, with maximum blood levels occurring about 6 hours post ingestion. It has a half-life of about 12 hours. It is extensively metabolized to therapeutically inactive compounds.
Efficacy. Duloxetine given in a single dose of 60 mg daily has greater antidepressant efficacy than placebo, and is equivalent in therapeutic activity to SSRIs. Currently there is no consistent evidence that the efficacy of duloxetine is greater than that of SSRIs (Cipriani et al., 2009).
Unwanted effects. The adverse-effect profile of duloxetine is similar to that seen with other 5-HT-promoting antidepressants, and includes nausea, dry mouth, dizziness, gastrointestinal disturbances, insomnia, somnolence, and sexual dysfunction. Like venlafaxine, duloxetine can increase blood pressure; there are few data on toxicity in overdose. As would be expected, abrupt cessation of duloxetine is associated with dizziness, insomnia, anxiety, and headache (Cowen et al., 2005).
Drug interactions. Duloxetine produces a moderate inhibition of CYP2D6 and to a lesser extent of CYP1A2. It is therefore likely to increase blood levels of other drugs that are metabolized by these enzymes (see Table 19.11). On the basis of its pharmacology, duloxetine should not be given concomitantly with MAOIs because of the danger of a toxic serotonin syndrome. For the same reason it seems advisable that 14 days should elapse after the end of MAOI treatment before duloxetine is started, and that at least 7 days should elapse after duloxetine cessation before MAOIs are given.
L-Tryptophan is a naturally occurring amino acid which is present in the normal diet; about 500 mg of tryptophan are consumed daily in the typical Western diet. Most ingested tryptophan is used for protein synthesis and the formation of nicotinamide nucleotides, and only a small proportion (about 1%) is used to synthesize 5-HT via 5-hydroxtryptophan (5-HTP). Tryptophan hydroxylase, the enzyme that catalyses the formation of 5-HTP from L-tryptophan, is normally unsaturated with tryptophan. Accordingly, increasing tryptophan availability to the brain increases 5-HT synthesis.
Pharmacokinetics. L-Tryptophan is rapidly absorbed, with plasma levels peaking about 1–2 hours after ingestion. It is extensively bound to plasma albumin. The amount of L-tryptophan available for brain 5-HT synthesis depends on several factors, including the proportion of L-tryptophan free in plasma, the activity of tryptophan pyrrolase, and the concentration of other plasma amino acids that compete with L-tryptophan for entry into the brain.
Efficacy. There is only weak evidence that L-tryptophan has antidepressant activity when given alone, though it may be superior to placebo in moderately depressed out-patients. There is rather better evidence that L-tryptophan combined with MAOI treatment can enhance the antidepressant effects of MAOIs. Similar synergistic effects have been reported in some studies of L-tryptophan combined with tricyclic antidepressants, although overall the therapeutic benefit of this combination is inconsistent.
Unwanted effects. L-Tryptophan is generally well tolerated, although nausea and drowsiness soon after dosing are not unusual. However, the prescription of L-tryptophan has been associated with the development of a severe scleroderma-like illness, the eosinophilia–myalgia syndrome (EMS), in which there is a very high circulating eosino-phil count (about 20% of peripheral leucocytes), with severe muscle pain, oedema, skin sclerosis, and peripheral neuropathy. Fatalities have been reported.
It is now reasonably well established that EMS is not caused by L-tryptophan itself but rather by a contaminant formed in the manufacturing process used by a particular manufacturer (Kilbourne et al., 1996). L-Tryptophan remains available for the treatment of severe refractory depression, when it can be used as an adjunct to other antidepressant medication. Patients who are receiving L-tryptophan should be monitored for possible symptoms of EMS. L-Tryptophan should be withdrawn if there is any evidence that EMS may be developing, and an urgent blood eosinophil count should be obtained.
Drug interactions. The only significant drug interactions of L-tryptophan are with drugs that also increase brain 5-HT function. Thus, although administration of L-tryptophan with MAOIs may produce clinical benefit, there are also reports that this combination may lead to 5-HT neurotoxicity as described above. Similarly, the combination of L-tryptophan with SSRIs has been reported to cause myoclonus, shivering, and mental state changes (Gillman and Whyte, 2004).
St John’s wort
St John’s wort is an extract from the plant, Hypericum perforatum. It has been used in medicine for centuries for numerous indications, including burns, arthritis, snake-bite, and depression. The active principles are probably derived from six major product groups, including hyper-icins and hyperforins. The pharmacology of St John’s wort is complex, but animal experimental and some human studies indicate that it potentiates aspects of monoamine neurotransmission (Linde, 2009).
Efficacy. There have been numerous trials of St John’s wort, although these are difficult to interpret because the preparations and dosages have been difficult to standardize. In addition, the trials have been conducted in mild to moderately depressed subjects. More recent meta-analyses suggest that standardized extracts of hypericum (in doses of 600–1800 mg) are more effective than placebo, and about equal in efficacy to other antidepressants, in patients with clearly diagnosed major depression (Linde et al., 2005; Anderson et al., 2008). However, there is a lack of longer-term efficacy data, and the available hypericum preparations are not standardized.
Adverse effects and drug interactions. St John’s wort is well tolerated, with the most common side-effects being gastrointestinal disturbance, dizziness, and tiredness. Cases of mania during treatment have been described. Photosensitivity is also rarely reported. Hypericum extracts may induce hepatic enzymes, and there are reports that treatment with St John’s wort was associated with lowered levels of theophylline, cyclosporin, digoxin, and ethinyloestradiol. Finally, St John’s wort may cause serotonin neurotoxicity when combined with SSRIs and other 5-HT-potentiating drugs (Linde, 2009).
Bupropion is not marketed in the UK or Europe, but has significant use as an antidepressant in the USA. In the UK it is licensed as an adjunct to smoking withdrawal. It is structurally and pharmacologically distinct from other antidepressants, being a unicyclic aminoketone derivative. Bupropion enhances both dopamine and noradrenaline function in the brain, probably via reuptake blockade.
Efficacy and adverse effects. Numerous controlled trials have shown that the antidepressant effect of bupropion is superior to that of placebo and equivalent to that of SSRIs. In some respects the adverse-effect profile of bupro-pion is similar to that of the SSRIs, with insomnia, agitation, tremor, and nausea being most frequently reported. However, mania and psychosis can also occur, as can raised blood pressure. Bupropion is less likely than SSRIs to cause sexual dysfunction, which gives it an important advantage in some patients.
The main concern with the use of bupropion has been the increased risk of seizures. In its original formulation the risk of seizures at higher doses (0.4%) was about four times greater than that associated with SSRIs (about 0.1%). The risk appears to be less with the slow-release formulation (bupropion SR) which has been marketed for smoking cessation. At doses of 300 mg or less, the risk of seizures with bupropion SR appears to be about 0.1%. This is the maximum dose recommended for smoking cessation, and is the standard dose used when treating depression. Bupropion should not be used in patients with a history of seizures or eating disorder.
Drug interactions. Bupropion should not be given with other drugs that might lower the seizure threshold, such as tricyclic antidepressants, antipsychotic drugs, and anti-malarial drugs. Administration with MAOIs is also contraindicated. Bupropion has been combined safely with lithium, and in the USA is used by specialists to augment ineffective SSRI treatment. Bupropion inhibits CYP2D6, and drugs metabolized by this pathway (metoprolol, and some other antidepressants) should be co-prescribed only with caution.
Several agents are grouped under this heading, such as lithium and a number of anticonvulsant drugs, including carbamazepine and sodium valproate. These three drugs are effective in the prevention of recurrent affective illness and also in the acute treatment of mania. In addition, lithium has useful antidepressant effects in some circumstances, but the antidepressant activity of carbamazepine and sodium valproate is less well established. Another anticonvulsant, lamotrigine, shows promise in the prevention of bipolar depression, but does not appear to be effective against manic states.
Placebo-controlled trials have shown that lithium is effective in a number of conditions, including the following:
• the acute treatment of mania
• the prophylaxis of unipolar and bipolar mood disorder
• augmentation therapy in resistant depression
• the prevention of aggressive behaviour in patients with learning disabilities.
Mechanism of action
Animal studies have shown that lithium has important effects on the intracellular signalling molecules or ‘second messengers’ that are activated when a neurotransmitter or agonist binds to a specific receptor. At clinically relevant doses, lithium inhibits the formation of cyclic adenosine monophosphate (cAMP) and also attenuates the formation of various inositol lipid-derived mediators. Through these actions lithium could exert profound effects on a wide range of neurotransmitter pathways, many of which use the above messenger systems. More recent interest has focused on the ability of lithium to promote cell survival and increase synaptic plasticity, perhaps through inhibition of the activity of the enzyme glycogen synthase kinase-3 (Li and Jope, 2010).
Lithium is rapidly absorbed from the gut and diffuses quickly throughout the body fluids and cells. Lithium moves out of cells more slowly than sodium. It is removed from the plasma by renal excretion and by entering cells and other body compartments. Therefore there is rapid excretion of lithium from the plasma, and a slower phase reflecting its removal from the whole-body pool.
Like sodium, lithium is filtered and partly reabsorbed in the kidney. When the proximal tubule absorbs more water, lithium absorption increases. Therefore dehydration causes the plasma lithium concentration to rise. Because lithium is transported in competition with sodium, more is reabsorbed by the kidney when sodium concentrations fall. This is the mechanism whereby thiazide diuretics can lead to toxic concentrations of lithium in the blood.
Dosage and plasma concentrations
Because the therapeutic and toxic doses are close together, it is essential to measure plasma concentrations of lithium during treatment. Measurements should first be made after about 7 days, then about every 2 weeks, and then, provided that a satisfactory steady state has been achieved, once every 6 weeks. Subsequently, lithium levels are often very stable, and plasma monitoring can be carried out at intervals of approximately 3 months unless there are clinical indications for more frequent monitoring.
After an oral dose, plasma lithium levels rise by a factor of two or three within about 4 hours. For this reason, concentrations are normally measured approximately 12 hours after the last dose, usually that given at night. It is important to follow this routine, as published information about lithium levels refers to the concentration 12 hours after the last dose, and not to the ‘peak’ reached in the 4 hours after that dose. If an unexpectedly high concentration is found, it is important to establish whether the patient has inadvertently taken a morning dose before the blood sample was taken.
Previously, the accepted range for prophylaxis was 0.7–1.2 mmol/l measured 12 hours after the last dose. However, current trends are to maintain lithium at lower plasma levels because this decreases the burden of side-effects. Severus et al. (2008) concluded that in the prophylaxis of bipolar disorder, the minimum efficacious plasma level of lithium was 0.4 mmol/l, but in most patients the best therapeutic response was obtained with levels in the range 0.6–0.75 mmol/l. Higher levels benefited some patients with more persistent manic symptomatology. In the treatment of acute mania, plasma concentrations below 0.8 mmol/l appear to be ineffective, and a range of 0.8–1.0 mmol/l is probably required. Serious toxic effects appear with concentrations above 2.0 mmol/l, although early symptoms may appear at concentrations above 1.2 mmol/l (Macritchie and Young, 2004).
A number of delayed-release preparations of lithium are now available, but their pharmacokinetics in vivo do not differ significantly from those of standard lithium carbonate preparations. Liquid formulations of lithium citrate are available for patients who have difficulty in taking tablets. Lithium may be administered once or twice daily. Frequency of administration does not appear to affect urine volume. In general, it is more convenient to take lithium as a single dose at night, but patients who experience gastric irritation on this regimen may be helped by divided daily doses.
Table 19.13 Some adverse effects of lithium, carbamazepine, and valproate
Unwanted effects (see Table 19.13)
A mild diuresis due to sodium excretion occurs soon after the drug is started. Other common effects include tremor of the hands, dry mouth, a metallic taste, feelings of muscular weakness, and fatigue.
Some degree of mild thirst and polyuria is common in patients taking lithium, probably because lithium blocks the effect of antidiuretic hormone (ADH) on the renal tubule. This is rarely of clinical significance, but up to one-third of patients show progression to a diabetes insipidus-like syndrome with pronounced polyuria and polydipsia. This may necessitate withdrawal of lithium treatment, although the use of lower plasma lithium levels may cause the syndrome to remit.
Some patients, especially women, gain some weight when taking the drug. Persistent fine tremor, mainly affecting the hands, is common, but coarse tremor suggests that the plasma concentration of lithium has reached toxic levels. Most patients adapt to the fine tremor; for those who do not, propranolol up to 40 mg three times daily may reduce the symptom. Both hair loss and coarsening of hair texture can occur.
Thyroid gland enlargement occurs in about 5% of patients who are taking lithium. The thyroid shrinks again if thyroxine is given while lithium is continued, and it generally returns to normal a month or two after lithium has been stopped. Lithium interferes with thyroid production, and hypothyroidism occurs in up to 20% of women patients, with a compensatory rise in thyroid-stimulating hormone.
Tests of thyroid function should be performed every 6 months to help to detect these changes, but these intermittent tests are no substitute for a continuous watch for suggestive clinical signs, particularly lethargy and substantial weight gain. If hypothyroidism develops and the reasons for lithium treatment are still strong, thyroxine treatment should be added. Lithium has also been associated with elevated serum calcium levels in the context of hyperparathyroidism. This is occasionally associated with severe depression, making distinction from the underlying mood disorder difficult.
Reversible ECG changes also occur. These may be due to displacement of potassium in the myocardium by lithium, as they resemble those of hypokalaemia, with T-wave flattening and inversion or widening of the QRS. They are rarely of clinical significance. Other changes include a reversible leucocytosis and occasional papular or maculopapular rashes.
Effects on memory are sometimes reported by patients, who complain in particular of everyday lapses of memory, such as forgetting well-known names. It is possible that this impairment of memory is caused by the mood disorder rather than by the drug itself, but there is also evidence that lithium can be associated with impaired performance on certain cognitive tests.
Long-term effects on the kidney. As noted above, lithium treatment decreases tubular concentrating ability and can occasionally cause diabetes inspidus. In addition, there have been reports that over many years of treatment, lithium can sometimes cause an increasing and in some cases irreversible decline in tubular function. This may be more likely in patients with higher plasma concentrations of lithium, and where concomitant psychotropic medication has been employed (Macritchie and Young, 2004).
Several follow-up studies have examined the effect of longer-term lithium maintenance treatment on glomerular function. In general, it has been thought that any decline in glomerular function is usually mild and related to lithium intoxication. However, a more recent study utilizing measures of estimated glomerular filtration rate (e-GFR) suggested that about one-third of young people (aged 20–39 years) taking lithium had an impaired e-GFR consistent with stage 3 renal disease (Bassilios et al., 2007). Also, long-term lithium treatment (i.e. for a period of over 20 years) is associated with an increased of risk of end-stage renal disease with an estimated risk of about 1% for long-term lithium users (Bendz et al., 2010; Tredget et al., 2010). With the current trends towards long-term prophylaxis of mood disorders, it is clearly wise to monitor plasma creatinine levels regularly and to supplement with this e-GFR (see Box 19.7). It seems likely that the risk of nephrotoxicity will be minimized by maintaining plasma lithium levels at the lower end of the therapeutic range, provided that they are therapeutically effective for the individual patient (Macritchie and Young, 2004).
These are related to dose. They include ataxia, poor coordination of limb movements, muscle twitching, slurred speech, and confusion. They constitute a serious medical emergency, as they can progress through coma and fits to death.
If these symptoms appear, lithium must be stopped at once and a high intake of fluid provided, with extra sodium chloride to stimulate an osmotic diuresis. In severe cases, renal dialysis may be needed. Lithium is rapidly cleared if renal function is normal, so that most cases either recover completely or die. However, cases of permanent neurological and renal damage despite haemodialysis have been reported.
As noted earlier (see p. 514), lithium can increase fetal abnormalities, particularly of the heart, although the magnitude of the individual risk is low. The decision as to whether or not to continue with lithium treatment during pregnancy must therefore be carefully considered. Important factors include the likelihood of affective relapse if lithium is withheld, and the difficulty that could be experienced in managing an episode of affective illness in the particular individual.
Box 19.7 Lithium, renal function, and estimated glomerular filtration rate
The estimated glomerular filtration rate (e-GFR) in a healthy young adult is about 100 ml/min, and it falls by about 1 ml/min per year as people get older, so many healthy 75-year-olds will have an e-GFR of 50–60 ml/min.
Chronic kidney disease (CKD)
CKD stage 1: e-GFR > 90 ml/min, normal kidney function, but urine findings or structural abnormalities or genetic trait indicate kidney disease.
CKD stage 2: e-GFR 60–90 ml/min, mildly reduced kidney function, and other findings (as for stage 1) indicate kidney disease.
CKD stage 3: e-GFR 30–59 ml/min, a moderate reduction in kidney function.
CKD stage 4: e-GFR 15–29 ml/min, a severe reduction in kidney function.
CKD stage 5: e-GFR < 15 ml/min, established kidney failure, when dialysis or a kidney transplant may be needed.
Stage 3 CKD is asymptomatic, but is associated with a greater subsequent risk of cardiovascular disease. People with stage 3 CKD require regular cardiovascular monitoring and tests of renal function, including urinalysis every 3 months.
Indications for referral to a specialist renal physician in a patient taking lithium
Referral is required if any of the following are present:
• e-GFR is decreasing by > 4 ml/min annually
• progressive rise in blood creatinine concentration in three or more serial tests
• symptoms suggestive of chronic renal failure (e.g. tiredness, anaemia)
• e-GFR < 30 ml/min.
See Morriss and Benjamin (2008).
If pregnant patients continue with lithium, plasma levels should be monitored closely. Ultrasound examination and fetal echocardiography are valuable screening tests as the pregnancy progresses. Patients with a history of bipolar disorder have a substantially increased risk of relapse in the postpartum period. In such patients it may be worth considering the introduction of lithium shortly after delivery to provide a prophylactic effect. However, significant concentrations of lithium can be measured in the plasma of breastfed infants, which may make bottle-feeding advisable.
Drug interactions (see Box 19.8)
Because of the narrow therapeutic index of lithium, pharmacokinetic drug interactions are of major clinical importance. Pharmacodynamic interactions may involve potentiation of 5-HT-promoting agents, leading to a serotonin syndrome. In addition, therapeutic plasma levels of lithium can be associated with neurotoxicity in the presence of certain other centrally acting agents.
ECT and surgery. It is possible that the continuation of lithium during ECT may lead to neurotoxicity. If feasible, lithium treatment should be suspended or plasma levels reduced during ECT, because the customary overnight fast beforehand may leave patients relatively dehydrated the following morning. If possible, lithium treatment should be discontinued before major surgery, because the effects of muscle relaxants may be potentiated. However, the risk of acute withdrawal and ‘rebound’ mania must be considered (see below).
In some studies, abrupt lithium withdrawal has been associated with the rapid onset of mania. Undoubtedly there is an increased risk of recurrent mood disorder after lithium discontinuation, probably because lithium is an effective prophylactic agent and because it is used for disorders that have a high risk of recurrence. However, there is probably also a lithium withdrawal syndrome with ‘rebound’ mania, although this may be restricted to patients with bipolar disorder.
The risk of rapid relapse is reduced if lithium is discontinued slowly over a period of several weeks. Even patients who have remained entirely well for many years may experience a further episode of affective disorder after lithium discontinuation. Most of these individuals will respond to the reintroduction of lithium (Tondo et al., 1997).
Box 19.8 Some drug interactions of lithium
Increased lithium levels
• Diuretics (frusemide is safest)
• Non-steroidal anti-inflammatory drugs (aspirin/ sulindac is safest)
• ACE inhibitors
• Angiotensin-II-receptor antagonists
• Antibiotics (metronidazole)
Decreased lithium levels
• Sodium bicarbonate
• 5-HT neurotoxicity
SSRIs (can be used safely with care)
• 5-HT1 agonists
Extrapyramidal side-effects enhanced
• Antipsychotic agents, metoclopramide, domperidone Enhanced neurotoxicity
• Carbamazepine, phenytoin, calcium-channel blockers, methyldopa
These include renal failure or recent renal disease, current cardiac failure or recent myocardial infarction, and chronic diarrhoea sufficient to alter electrolytes. Lithium should not be prescribed if the patient is judged to be unlikely to observe the precautions required for its safe use. This includes a propensity to discontinue it suddenly against advice.
The management of patients on lithium
Preparation. A careful routine of management is essential because of the effects of therapeutic doses of lithium on the thyroid and kidney, and the toxic effects of excessive dosage. The following routine is one of several that have been proposed, and can be adopted safely. Successful treatment requires attention to detail, so the steps are described below at some length.
Before starting lithium, a physical examination should be performed, including the measurement of blood pressure. It is also useful to weigh the patient and calculate the BMI.
Blood should be taken for estimation of electrolytes, serum creatinine, e-GFR, and a full blood count. Thyroid function tests are also necessary. If indicated, an ECG and pregnancy tests should be performed as well.
If these tests show no contraindication to lithium treatment, the doctor should check that the patient is not taking any drugs that might interact with lithium. A careful explanation should then be given to the patient. They should understand the possible early toxic effects of an unduly high blood concentration, and also the circumstances in which this can arise—for example, during intercurrent gastroenteritis, renal infection, or the dehydration secondary to fever. They should be advised that if any of these arise, they should stop the drug and seek medical advice.
It is usually appropriate to include another member of the family in these discussions. Providing printed guidelines on these points is often helpful (either written by the doctor, or in one of the forms provided by pharmaceutical firms). In these discussions a sensible balance must be struck between alarming the patient by overemphasizing the risks, and failing to give them the information that they need in order to take a collaborative part in the treatment.
Starting treatment. Lithium should normally be prescribed as the carbonate, and treatment should begin and continue with a single daily dose unless there is gastric intolerance, in which case divided doses can be given. If the drug is being used for prophylaxis, it is appropriate to begin with 200–400 mg daily in a single dose. The lower end of the range is appropriate when patients are taking concomitant medication such as SSRIs that might interact with lithium.
Blood should be taken for lithium estimations every week or two, adjusting the dose until an appropriate concentration is achieved. A lithium level of 0.4–0.7 mmol/l (in a sample taken 12 hours after the last dose) may be adequate for prophylaxis, as explained above. If this is not effective, the previously accepted higher range of 0.8–0.9 mmol/l can be tried if side-effects permit and the predominant symptomatology is manic. When judging the response, it should be remembered that several months may elapse before lithium achieves its full effect.
Continuation treatment. As treatment continues, lithium estimations should be carried out about every 12 weeks. It is important to have some means of reminding patients and doctors about the times at which repeat investigations are required. Computerized databases may be helpful in this respect. Every 6 months, blood samples should be taken for electrolytes, urea, creatinine, e-GFR, and thyroid function tests. If two consecutive thyroid function tests 1 month apart show evidence of hypothyroidism, lithium should be stopped or L-thyroxine prescribed. Troublesome polyuria is a reason for attempting a reduction in dose, whereas severe persistent polyuria is an indication for specialist renal investigation, including tests of concentrating ability. A persistent leucocytosis is not uncommon and is apparently harmless. It reverses soon after the drug is stopped.
When lithium is given, the doctor must keep in mind the interactions that have been reported with psychotropic and other drugs (see above). It is also prudent to be extra vigilant for toxic effects if ECT is being given. If the patient requires an anaesthetic for any reason, the anaesthetist should be told that they are taking lithium; this is because, as noted above, there is some evidence that the effects of muscle relaxants may be potentiated.
Lithium is usually continued for at least a year, and often for much longer. The need for the drug should be reviewed once a year, taking into account any persistence of mild mood fluctuations, which suggest the possibility of relapse if treatment is stopped. Continuing medication is more likely to be needed if the patient has previously had several episodes of mood disorder within a short time, or if previous episodes were so severe that even a small risk of recurrence should be avoided.
Some patients have taken lithium continuously for 15 years or more, but there should always be compelling reasons for continuing treatment for more than 5 years. As noted above, lithium should be withdrawn slowly, over a number of months if possible. The patient should be advised not to discontinue lithium suddenly on their own initiative.
Carbamazepine was originally introduced as an anticonvulsant, and was found to have useful effects on mood in certain patients. Subsequently it was found to be beneficial in some bipolar patients, including those who had proved refractory to lithium. There is reasonable evidence that carbamazepine is effective in the management of acute mania and also in the prophylaxis of bipolar disorder, although overall its efficacy is probably less than that of lithium (Goodwin, 2009).
Mode of action. Like certain other anticonvulsants, carbamazepine blocks neuronal sodium channels. It is unclear whether this action plays a role in the mood-stabilizing effects. In both humans and animals, carbamazepine facilitates 5-HT neurotransmission, an action that it shares with lithium.
Carbamazepine is slowly but completely absorbed and widely distributed. It is extensively metabolized, and at least one metabolite, carbamazepine epoxide, is therapeutically active. The half-life during long-term treatment is about 20 hours. Carbamazepine is a strong inducer of hepatic microsomal enzymes, and can lower the plasma concentrations of numerous other drugs.
Dosage and plasma concentrations
The dosage of carbamazepine in the treatment of mood disorders is similar to that used in the treatment of epilepsy, within the range 400–1600 mg daily. Treatment is usually given in divided doses twice daily, because this practice may improve tolerance. No clear relationship has been established between plasma carbamazepine concentrations and therapeutic response, but it seems prudent to monitor levels (about 12 hours after the last dose) and to maintain them in the usual anticonvulsant range as a precaution against toxicity.
Unwanted effects (see Table 19.13)
Side-effects are common at the beginning of treatment. They include drowsiness, dizziness, ataxia, diplopia, and nausea. Tolerance to these effects usually develops quickly. A potentially serious side-effect of carbamazepine is agranulocytosis, although this complication is very rare (variously estimated to be from 1 in 10 000 to 1 in 125 000 patients).
A relative leucopenia is more common, with the white cell count often falling during the first few weeks of treatment, although it usually remains within normal levels. Rashes occur in about 5% of patients, and rarely severe exfoliative dermatitis develops. Elevations in liver enzymes may also occur, and rarely hepatitis has been reported. Carbamazepine can cause disturbances of cardiac conduction, and is therefore contraindicated in patients with pre-existing abnormalities of cardiac conduction. Carbamazepine is an established human teratogen.
Carbamazepine lowers plasma thyroxine levels, but thyroid-stimulating hormone levels are not elevated and clinical hypothyroidism is unusual. Carbamazepine has also been associated with low sodium states. The unwanted effects of carbamazepine are compared with those of lithium and valproate in Table 19.13.
Carbamazepine increases the metabolism of many other drugs, including tricyclic antidepressants, benzodiazepines, antipsychotic drugs, oral contraceptive agents, thyroxine, warfarin, other anticonvulsants, and some antibiotics. A similar mechanism may underlie the decline in plasma carbamazepine levels that occurs after the first few weeks of treatment.
Carbamazepine levels may be increased by SSRIs and erythromycin. The pharmacodynamic effects and plasma levels of carbamazepine may be increased by some calcium-channel blockers, such as diltiazem and verapamil. Conversely, carbamazepine may decrease the effect of certain other calcium-channel antagonists, such as felodipine and nicardipine. Neurotoxicity has been reported when carbamazepine and lithium have been combined even in the presence of normal lithium levels. The manufacturers of carbamazepine recommend that combination of carbamazepine with MAOIs should be avoided. However, there are case reports of these drugs being used safely together. It is possible that some MAOIs may increase plasma carbamazepine levels.
Clinical use of carbamazepine
Current clinical guidelines (see, for example, Goodwin, 2009) place carbamazepine rather low down the list of therapeutic options, after drugs such as lithium, valproate, and lamotrigine. To some extent this reflects the liability of carbamazepine to cause significant drug interactions, as well its perceived poorer tolerability. Also, there is less recent controlled evidence concerning its use. With this is mind, the usual indications for carbamazepine are as follows:
• the prophylactic management of bipolar illness in patients for whom lithium and valproate treatment is ineffective or poorly tolerated
• the treatment of patients with frequent mood swings and mixed affective states for which carbamazepine may be more effective than lithium
• added to lithium treatment in patients who have shown a partial response to the latter drug; in these circumstances it is important to remember that this combination can cause neurotoxicity
• in the acute treatment of mania, again usually as an alternative or addition to lithium and valproate.
If clinical circumstances permit, it is preferable to start treatment with carbamazepine slowly at a dose of 100–200 mg daily, increasing in steps of 100–200 mg twice weekly. Patients show wide variability in the blood levels at which they experience adverse effects; accordingly, it is best to titrate the dose against the side-effects and the clinical response.
Because of the risk of a lowered white cell count, it is prudent to monitor the blood count before treatment and after 3 and 6 months of treatment. Some guidelines also recommend monitoring liver function tests and plasma electrolytes; however, clinical vigilance is probably the best safeguard (Goodwin, 2009). Patients should be instructed to seek help urgently if they develop a fever or other sign of infection. When patients have responded to the addition of carbamazepine to lithium, it is possible subsequently to attempt a cautious withdrawal of lithium. However, the current clinical impression is that, for many patients, the maintenance of mood stability requires continuing treatment with both drugs.
Like carbamazepine, sodium valproate was first introduced as an anticonvulsant. In recent years there has been increasing interest in using the drug in the management of mood disorders.
There have been several controlled studies indicating that valproate is effective in the acute management of mania. As yet there is less clear evidence that it is effective in longer-term prophylaxis of bipolar disorder. In a randomized trial, Bowden et al. (2000) showed a marginal benefit for valproate over lithium and placebo in bipolar patients over a 1-year follow-up. However, in the large pragmatic BALANCE trial, valproate was less effective than lithium (BALANCE Study Group, 2010). There have been numerous case studies and open series that have reported useful prophylactic effects of valproate in patients who were unresponsive to lithium and carbamazepine, including those with rapid-cycling mood disorders.
Mode of action. Valproate is a simple branch-chain fatty acid with a mode of action that is unclear. However, there is some evidence that it can slow down the breakdown of the inhibitory neurotransmitter GABA. This action could account for the anticonvulsant properties of valproate, but whether it also underlies the psychotropic effects is unclear.
Valproate is rapidly absorbed, with the peak plasma concentrations occurring about 2 hours after ingestion. It is widely and rapidly distributed and has a half-life of 8–18 hours. Valproate is metabolized in the liver to produce a wide variety of metabolites, some of which have anticonvulsant activity. Unlike carbamazepine, valproate does not induce hepatic microsomal enzymes and, if anything, it tends to delay the metabolism of other drugs.
Dosing and plasma concentrations
Valproate can be started at a dose of 200–400 mg daily, which may be increased once or twice weekly to a range of 1–2 g daily. Plasma levels of valproate do not correlate well with either the anticonvulsant or the mood-stabilizing effects, but it has been suggested that efficacy in the treatment of acute mania is usually apparent when plasma levels are greater than 50 µg/ml.
Unwanted effects (see Table 19.13)
Common side-effects of valproate include gastrointestinal disturbances, tremor, sedation, and tiredness. Other troublesome side-effects include weight gain and transient hair loss, with changes in hair texture on regrowth.
Patients who are taking valproate may show some elevation in hepatic transaminase enzymes. Provided that this increase is not associated with hepatic dysfunction, the drug can be continued while enzyme levels and liver function are carefully monitored. However, there have been several reports of fatal hepatic toxicity associated with the use of valproate; most of these cases have occurred in children taking multiple anticonvulsant drugs. Valproate must be withdrawn immediately if vomiting, anorexia, jaundice, or sudden drowsiness occur.
Valproate may also cause thrombocytopenia, and may inhibit platelet aggregation. Acute pancreatitis is another rare but serious side-effect, and increases in plasma ammonia levels have also been reported. Other possible side-effects include oedema, amenorrhoea, and rashes. Valproate has been associated with polycystic ovary disease, and is an important human teratogen. The National Institute for Health and Clinical Excellence (2006) has recommended that valproate should not be used routinely for the treatment of bipolar disorder in women of childbearing age.
Valproate potentiates the effects of central sedatives. It has been reported to increase the side-effects of other anticonvulsants (without necessarily improving anticonvulsant control). It may increase plasma levels of lamotrigine, phenytoin, and tricyclic antidepressants. The interaction with lamotrigine necessitates careful adjustment of lamotrigine dosage (see below).
The efficacy of valproate in the acute and continuation treatment of mania has been established by several controlled trials (Goodwin, 2009), and it is licensed for this indication in the UK in the form of the semi-sodium preparation. In the treatment of acute mania it has a quicker onset of action than lithium and carbamazepine because it can be dosed at high levels initially. For example, a therapeutic effect can be apparent within 1 or 2 days of employing a loading dose of valproate of 20 mg/kg. Valproate may also be more effective than lithium in the management of patients with mixed affective states.
In terms of prophylaxis, valproate appears to be effective in the prevention of both manic and depressive episodes (Benyon et al., 2009). It has often been used in combination with lithium in bipolar patients who have shown a partial response to lithium, and this combination appears to be safe. Valproate has also been used in combination with carbamazepine. For patients who continue to show episodes of mood disturbance, valproate can also be combined with atypical antipsychotic drugs (Goodwin, 2009). Guidelines recommend that body weight, blood count, and liver function tests are assessed prior to treatment and thereafter at 6-monthly intervals.
Lamotrigine is a triazine derivative that blocks voltage-dependent sodium channels and reduces excitatory neurotransmitter release, particularly that of glutamate. It is licensed in the UK as a monotherapy and adjunctive treatment for epilepsy.
Lamotrigine is not licensed for the treatment of mood disorders in the UK, but there are open studies showing therapeutic benefit when it has been added to the medication of patients with bipolar illness that is refractory to standard treatments. In addition, placebo-controlled trials have shown that lamotrigine has some efficacy as monotherapy in the acute treatment of bipolar depression (Geddes et al., 2009), and also in the longer-term prevention of bipolar depression (Benyon et al., 2009). Used alone, lamotrigine does not seem to have significant acute or prophylactic anti-manic actions.
Following oral administration, lamotrigine is rapidly absorbed, with peak plasma levels occurring after about 1.5 hours. The drug is extensively metabolized by the liver but does not induce cytochrome P450 enzymes. Its half-life is about 30 hours. A plasma therapeutic range has not been identified.
Skin eruptions, usually maculopapular in nature, occur in about 3% of patients and may be associated with fever. They are most common in the first few weeks of treatment, and their incidence can be reduced by careful initial dosing (see below). Other side-effects include nausea, headache, diplopia, blurred vision, dizziness, ataxia, and tremor. Rarely, very serious adverse effects such as angioedema, Stevens–Johnson syndrome, and toxic epidermal necrolysishave been reported.
Plasma levels of lamotrigine can be lowered by drugs that induce hepatic-metabolizing enzymes such as carbamazepine. Combination of carbamazepine and lamotrigine can also cause neurotoxicity. Lamotrigine levels are increased by concomitant administration of valproate.
Lamotrigine has a useful role to play in the acute and prophylactic management of the depressive pole of bipolar disorder. Because lamotrigine appears to be ineffective in the treatment or prevention of mania, it is often used in combination with other drugs such as lithium. However, in bipolar patients where the burden of illness is almost exclusively depressive, it can be used as a mono-therapy (Goodwin, 2009).
When initiating lamotrigine treatment, in order to minimize the risk of rash, it is important to follow the dosage recommendations in the British National Formulary (25 mg daily for the first 2 weeks, followed by 50 mg daily for the next 2 weeks). The usual therapeutic dose in bipolar disorder is in the range 50–300 mg daily. If the patient is also taking valproate, dosage initiation must be even more cautious (for guidance, see the British National Formulary).
Gabapentin was developed as a structural analogue of GABA. Despite its structural relationship to GABA, its anticonvulsant mechanism of action is thought to be mediated through inhibition of theα-Δ subunit of voltage-gated calcium channels.
Gabapentin is licensed as an adjunctive treatment for seizure disorders, and is not licensed for the treatment of mood disorders. There are published case series that show benefit when gabapentin has been used as an adjunctive therapy in patients with bipolar disorder resistant to standard medication regimens. However, controlled trials in mania and refractory bipolar depression have yielded disappointing results (Goodwin, 2009). Gabapentin has a sedating profile and may also have anxiolytic properties. Its analogue, pregabalin, has not been studied in bipolar disorder, but is licensed for the treatment of generalized anxiety disorder and neuropathic pain.
After oral absorption, peak plasma levels of gabapentin are reached after 2–3 hours. Gabapentin is not metabolized by the liver and is excreted entirely by the kidney. Its half-life is about 5–7 hours, and three times daily dosing is recommended.
The most common side-effects of gabapentin are somnolence, dizziness, fatigue, and nystagmus. No serious adverse effects have been reported.
Probably because of its lack of hepatic metabolism, to date no significant pharmacokinetic interactions of gabapentin with other medications have been described. It may potentiate the effects of other central sedatives.
Gabapentin has a wide dosage range, but the usual dose in bipolar illness is between 600 mg and 2400 mg daily. Sedative and anxiolytic effects are often apparent at lower doses. Although effects of this nature might be useful in patients with refractory bipolar illness, there is currently no evidence from controlled trials that gabapentin has a place in the treatment of bipolar disorder.
This class of drugs includes mild stimulants, of which the best known is caffeine, and more powerful stimulants, such as amphetamine and methylphenidate. Cocaine is a powerful psychostimulant with a particularly high potential for inducing dependence (see p. 478). It is useful as a local anaesthetic, but has no other clinical indications. All of these psychostimulants increase the release and block the reuptakeof dopamine and noradrenaline. A newer compound, modafinil, produces increases in alertness and decreases sleepiness, and although its mechanism of action is uncertain, it may also involve dopaminergic mechanisms (Young and Geyer, 2010). Modafinil is licensed for the treatment of sleepiness associated with narcolepsy, obstructive sleep apnoea, and sleep disorders associated with shift work.
Amphetamines were used to treat numerous conditions in the past, but they are now prescribed much less frequently because of the high risk of dependence. They are not appropriate for the treatment of obesity. In adults, the agreed indication for amphetamines is narcolepsy. Methylphenidate is approved for the treatment of attention deficit disorder in children. It is also effective in adults who have continued to display symptoms of attention deficit disorder (Janakiraman and Benning, 2010).
In the past, amphetamines were widely prescribed for the treatment of depression, but have been superseded by the antidepressant drugs. Some specialists, mainly in the USA, believe that psychostimulants may have a role either as sole agent or in combination with other antidepressant drugs for patients with refractory depressive disorder. Also, there is some interest in using psychostimulants for elderly depressed patients with concomitant medical illness. A blanket proscription of psychostimulant treatment in depression therefore seems unjustified. However, psychostimulants should be used only by practitioners with special experience in the psychopharmacological management of resistant depression. Modafinil has been used with apparent benefit to treat sleepiness and fatigue in depressed patients receiving SSRIs (Fava et al., 2005).
The main preparations are dexamphetamine sulphate, given for narcolepsy in divided doses of 10 mg daily increasing to a maximum of 50 mg daily in steps of 10 mg each week, and methylphenidate, which has similar effects. In narcolepsy, modafinil is used in doses of 200–400 mg.
These include restlessness, insomnia, poor appetite, dizziness, tremor, palpitations, and cardiac arrhythmias. Toxic effects from large doses include disorientation and aggressive behaviour, hallucinations, convulsions, and coma. Persistent abuse can lead to a paranoid state similar to paranoid schizophrenia. Amphetamines can cause severe hypertension in combination with MAOIs and to a lesser extent with tricyclic antidepressants. They are contraindicated in cardiovascular disease and thyrotoxicosis. Modafinil has been associated with dry mouth, nausea, abdominal pain, headache, tachycardia, palpitations, anxiety, and insomnia. It should not be used in patients with significant cardiovascular disease.
Other physical treatments
Electroconvulsive therapy (ECT)
Convulsive therapy was introduced in the late 1930s on the basis of the mistaken idea that epilepsy and schizophrenia do not occur together. It seemed to follow that induced fits should lead to improvement in schizophrenia. However, when the treatment was tried it became apparent that the most striking changes occurred not in schizophrenia but in severe depressive disorders, in which it brought about a substantial reduction in chronicity and mortality (Slater, 1951).
At first, fits were produced either by using the drug, pentylenetetrazole, or by passing an electric current through the brain (Cerletti and Bini, 1938). As time went by, electrical stimulation became the rule. The subsequent addition of brief anaesthesia and muscle relaxants made the treatment safer and more acceptable.
This section summarizes the indications for ECT. Further information about the efficiency of the procedure will be found in the chapters that deal with the individual psychiatric syndromes.
ECT is a rapid and effective treatment for severe depressive disorders. In the Medical Research Council trial (Clinical Psychiatry Committee, 1965) it acted faster than imipramine or phenelzine, and was more effective than imipramine in women and more effective than phenelzine in both sexes. The indications for ECT have been reviewed by the National Institute for Clinical Excellence (2003) (see Box 19.9). Indications suggested by the Royal College of Psychiatrists (2005) are shown in Box 19.10.
Box 19.9 Indications for ECT (National Institute for Clinical Excellence, 2003)
It is recommended that electroconvulsive therapy is used only to achieve rapid and short-term improvement of severe symptoms after an adequate trial of other treatment options has proven ineffective and/or when the condition is considered to be potentially life-threatening in individuals with:
1. severe depressive illness
3. a prolonged or severe manic episode.
Both sets of guidelines are in agreement with the impression of many clinicians, and with the recommendations of this book, that ECT should be used mainly when it is essential to bring about improvement quickly. Therefore the strongest indications are an immediate high risk of suicide, depressive stupor, or danger to physical health because the patient is not drinking enough to maintain adequate renal function.
ECT can lead a rapid resolution of mania, but is generally reserved for patients who do not respond to drug treatment, or for those whose manic illness is particularly severe, requiring high doses of antipsychotic drugs (Goodwin, 2009).
On the basis of clinical case studies, it has long been held that ECT is useful for the treatment of acute catatonic states. Controlled studies have also shown that ECT is effective in patients with acute schizophrenia with predominantly positive symptoms. In these studies ECT is effective not only for affective symptoms but also for positive symptoms such as delusions and thought disorder (Brandon et al., 1985). In general, however, ECT adds little to the effects of adequate doses of antipsychotic drugs, although it probably produces a greater rate of symptomatic improvement in the short term. It is unclear whether ECT has a role in the treatment of patients with schizophrenia whose positive symptoms do not respond to antipsychotic medication. There is more evidence for the use of clozapine in this situation, and ECT is not generally recommended (National Institute for Clinical Excellence, 2003), although the Royal College of Psychiatrists suggests that it can be considered as a fourth-line option.
Box 19.10 Indications for ECT (Royal College of Psychiatrists, 2005)
In severe depressive illness, ECT may be the treatment of choice when the illness is associated with:
• life-threatening illness because of refusal of foods and fluids
• a high suicide risk.
ECT may be considered for the treatment of severe depressive illness associated with:
• marked psychomotor retardation
• depressive delusions and hallucinations.
ECT may be considered as second- or third-line treatment of depressive illness that is not responsive to antidepressant drugs.
ECT may be considered for the treatment of mania:
• that is associated with life-threatening physical exhaustion
• that has not responded to appropriate drug treatment.
ECT may be considered for the treatment of acute schizophrenia as a fourth-line option for treatment-resistant schizophrenia after treatment with two antipsychotic drugs and then clozapine has proved ineffective.
ECT may be indicated in patients with catatonia where treatment with a benzodiazepine (usually lorazepam) has proved ineffective.
Source: Scott (2005).
Mode of action
Role of the seizure. Presumably the specific therapeutic effects of ECT must be brought about through physiological and biochemical changes in the brain. The first step in identifying the mode of action must be to find out whether the therapeutic effect depends on the seizure, or whether other features of the treatment are sufficient, such as the passage of the current through the brain, and the use of anaesthesia and muscle relaxants.
Clinicians have generally been convinced that the patient does not improve unless a convulsion is produced during the ECT procedure. This impression has been confirmed by several double-blind trials which, taken together, show that ECT is strikingly more effective than a full placebo procedure that includes anaesthetic and muscle relaxant (UK ECT Review Group, 2003) (see Figure 19.1).
This evidence does not necessarily support the view that a full seizure is the sufficient and necessary therapeutic component of ECT, and recent studies have shown that this notion is incorrect. Modern ECT machines deliver brief pulses of electrical current that enable a seizure to be induced by administration of relatively low doses of electrical energy. With this mode of administration, both electrode placementand electrical dosage can have profound effects on the therapeutic efficacy of ECT. In particular, it appears that the amount by which the applied electrical dose exceeds the seizure threshold of the individual patient is an important determinant of both efficacy and cognitive side-effects of ECT. Furthermore, the seizure threshold varies greatly (about 15-fold) between individuals.
This situation has important implications for the practical management of ECT when the clinician’s aim is to find the best balance between therapeutic efficacy and cognitive side-effects (see below). From a theoretical viewpoint, however, it can be concluded that an important determinant of ECT efficacy is how far the applied electrical energy exceeds the seizure threshold of the individual patient.
Neurochemical effects of ECT. Electrical seizures in animals produce many biochemical and electrophysiological changes, and therefore it is difficult to identify the processes that are important in the antidepressant effect of ECT. It is of interest that some of the changes in brain monoamine pathways found in rodents after ECT (e.g. down-regulation of noradrenaline β-adrenoceptors) resemble those found after antidepressant drug treatment. In addition, both ECT and antidepressants increase the expression of dopamine D2 receptors in the nucleus accumbens, which could be associated with improvements in motivational behaviour. In the case of ECT, this may involve interaction with glutamatergic pathways. Like antidepressant medication, electrical seizures in animals result in changes in neurotropins such as BDNF, and increases in neurogenesis in the hippocampus. The hippocampus is likely to play an important role in the pathophysiology of depression, and changes in hippocampal activity could therefore underpin some of the therapeutic effects of ECT. Of course, altered hippocampal function could also play a role in the amnestic side-effects of ECT. For a review, see Merkl et al. (2009).
Figure 19.1 Meta-analysis of randomized, placebo-controlled studies of ECT in depression. Reprinted from The Lancet, 361 (9360), The UK ECT Review Group, Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis, pp. 799–808, Copyright (2003), with permission from Elsevier.
Physiological changes during ECT
If ECT is given without atropine premedication, the pulse first slows and then rises quickly to 130–190 beats/minute, falling to the original resting rate or beyond towards the end of the seizure, before a final less marked tachycardia that lasts for several minutes. Marked increases in blood pressure are also common, and the systolic pressure can rise to 200 mmHg. Cerebral blood flow also increases by up to 200%.
Unilateral or bilateral ECT
Overall, bilateral ECT has a superior efficacy to unilateral ECT. However, bilateral treatment is associated with more cognitive impairment (UK ECT Review Group, 2003). The cognitive impairment seen with right unilateral ECT increases as the dose exceeds the seizure threshold, but is less than that with any form of bilateral ECT. Thus when right unilateral ECT is dosed to about six times the seizure threshold, its efficacy approaches that of bilateral ECT, but the associated cognitive disturbance is still less than that seen with bilateral treatment.
These data suggest that the most appropriate electrode placement for ECT is right unilateral, with the dose titrated to about six times the initial seizure threshold. This is likely to give the best overall combination of efficacy and lower cognitive impairment (Sackheim et al., 2008; Merkl et al., 2009). However, if the need for improvement is particularly urgent, bilateral ECT should be considered, dosed to about two and a half times the seizure threshold.
For a meta-analytical review of treatment factors that affect the efficacy of ECT, see UK ECT Review Group (2003) (see also Box 19.11).
Unwanted effects after ECT
Subconvulsive shock may be followed by anxiety and headache. ECT can cause a brief retrograde amnesia as well as loss of memory for up to 30 minutes after the fit. Brief disorientation can occur, particularly with bilateral electrode placement. Headache can also occur. Some patients complain of confusion, nausea, and vertigo for a few hours after the treatment, but with modern methods these unwanted effects are mild and brief.
A few patients complain of muscle pain, especially in the jaws, which is probably attributable to the relaxant. There have been a few reports of sporadic major seizures in the months after ECT, but these may have had other causes. Occasional damage to the teeth, tongue, or lips can occur if there have been problems in positioning the gag or airway. Poor application of the electrodes can lead to small electrical burns. Fractures, including crush fractures of the vertebrae, have occurred occasionally when ECT was given without muscle relaxants.
Box 19.11 Efficacy of ECT in depression in relation to antidepressant treatment and different stimulus parameters
All of these physical consequences are rare if a good technique of anaesthesia is used and the fit is modified adequately. Other complications of ECT are rare and mainly occur in people suffering from physical illness. They include cardiac arrhythmia, pulmonary embolism, aspiration pneumonia, and cerebrovascular accident. Prolonged apnoea is a rare complication of the use of muscle relaxants. Rarely, status epilepticus may occur in predisposed individuals or in those taking medication that prolongs seizure duration.
Since the introduction of ECT, there has always been concern as to whether it may cause brain damage. When ECT is given to animals in the usual clinical regimen, there is no evidence that brain damage occurs. Also, structural imaging studies in patients have been reassuring on this point (UK ECT Review Group, 2003).
Memory disorder after ECT
Short-term effects. As already mentioned, the immediate effects of ECT include loss of memory for events shortly before the treatment (retrograde amnesia), and impaired retention of information acquired soon after the treatment (anterograde amnesia). These effects depend on both electrode placement (unilateral versus bilateral) and electrical dose, but electrode placement appears to be the more important factor.
Controlled studies indicate that the anterograde amnesia produced by ECT is temporary. Sackheim et al. (1993) found either no differences in memory tests or some improvements in the weeks after ECT. Depressive disorders substantially impair cognitive function, and many patients report their memory as subjectively improved after ECT. A meta-analysis showed improvements in various objective measures of cognitive function, including, for example, processing speed, working memory, and executive function 2 weeks after the end of ECT treatment (Semkovska and McLoughlin, 2010).
Long-term effects. Possible long-term effects of ECT on memory take two forms. First, some patients describe loss of memories for personal and impersonal remote events (retrograde amnesia for remote events). For example, Squire et al. (1981) found that after bilateral ECT, in particular, there was a patchy loss of memory for some personal events, television programmes, or major news items. Lisanby et al. (2000) found that 2 months after ECT there was some persistent loss of remote memories for impersonal events, which were more marked than those for personal events. Bilateral ECT caused more deficits in this respect than unilateral ECT.
The other possible complication is decreased ability to learn new information (long-term anterograde amnesia). For example, in a study of former patients who were complaining that they had suffered permanent harm to memory as a result of ECT given in the past, Freeman et al. (1980) found that these patients performed worse than controls on some tests in a battery designed to test memory. However, they also had residual depressive symptoms, so it is possible that continuing depressive disorder accounted for the memory problems.
It seems reasonable to conclude that, when used in the usual way, ECT is not normally followed by persisting antero-grade memory disorder, and that where this does occur it is mild and may be accounted for by concurrent depressive symptomatology (Cohen et al., 2000). However, there may be some persisting retrograde amnesia for personal and impersonal memories, particularly with bilateral ECT. Although this is not a significant problem for most patients, some people for reasons that are unclear have greater ECT-induced memory loss and are understandably distressed by it (Robertson and Pryor, 2006).
The mortality of ECT
The death rate attributable to ECT was estimated to be 3–4 per 100 000 treatments by Barker and Barker (1959). This is similar to that seen with general anaesthesia in general medical conditions. The risks are related to the anaesthetic procedure, and are greatest in patients with cardiovascular disease. When death occurs it is usually due to ventricular fibrillation or myocardial infarction.
The contraindications to ECT are any medical illnesses that increase the risk of anaesthetic procedure by an unacceptable amount—for example, respiratory infections, serious heart disease, and serious pyrexial illness. Other contraindications are diseases that are likely to be made worse by the changes in blood pressure and cardiac rhythm that occur even in a well-modified fit. These include serious heart diseases, recent myocardial infarction, cerebral or aortic aneurysm, and raised intracranial pressure.
In Mediterranean and Afro-Caribbean patients who might have sickle-cell trait, additional care is needed to ensure that oxygen tension does not fall. Extra care is also required with diabetic patients who take insulin. Although risks rise somewhat in old age, so do the risks of untreated depression and drug treatment.
Technique of administration
In this section we outline the technical procedures used at the time of treatment. Although the information in this account should be known, it is important to remember that ECT is a practical procedure that must be learned by apprenticeship as well as by reading. For a review of the medical evaluation of patients for ECT, see Tess and Smetana (2009).
ECT clinic. ECT should be given in pleasant safe surroundings. Patients should not have to wait where they can see or hear treatment being given to others. There should be waiting and recovery areas separate from the room in which treatment is given, and adequate emergency equipment should be available, including a sucker, endotracheal tubes, adequate supplies of oxygen, and facilities to carry out full resuscitation. The nursing and medical staff who give ECT should receive special training and accreditation.
Arrival of the patient. The first step in giving ECT is to put the patient at ease and to check their identity. The case notes should then be seen to make sure that there is a valid consent form and that the patient continues to consent to treatment. The drug sheet should be checked to ensure that the patient is not receiving any drugs that might complicate the anaesthetic procedures. It is also important to check for evidence of drug allergy or adverse effects of previous general anaesthetics. The drug sheet should be available for the anaesthetist to see. A full physical evaluation should have been carried out by the patient’s treating doctor. Specialist advice should be sought if there may be medical contraindications to ECT.
Electrode placement. A decision about electrode placement should have been made by the treating doctor prior to treatment. When using unilateral treatment, it is important to apply the electrodes to the non-dominant hemisphere. In right-handed people, the left hemisphere is nearly always dominant; in left-handed people, either hemisphere may be dominant. Therefore, if there is evidence that the patient is not right-handed, it is usually better to use bilateral electrode placements.
Anaesthetic procedures. Prior to administering the anaesthetic it is necessary to make sure that the patient has taken nothing by mouth for at least 5 hours, and then, with the anaesthetist, to remove any dentures and check for loose or broken teeth. Finally, the record of any previous ECTs should be examined for evidence of delayed recovery from the relaxant (due to deficiency in pseudo-cholinesterase) or other complications.
The anaesthetic should be given by a trained anaesthetist (although this cannot always be achieved in developing countries). Suction apparatus, a positive-pressure oxygen supply, and emergency drugs should always be available. A tilting trolley is also valuable. As well as the psychiatrist and the anaesthetist, at least one nurse should be present.
Anaesthesia for ECT was previously induced with methohexitone, a short-acting barbiturate. However, this agent became increasingly difficult to obtain, and propofol is the most widely used alternative. The injection of propofol can be painful, and it can also decrease seizure length and delay or abolish convulsions. Etomidate may be preferred in patients in whom it is difficult to induce a seizure. In a naturalistic study, Eser et al. (2010) found that ECT treatment preceded by propofol induction was no less clinically effective than that preceded by other anaesthetic agents.
The induction agent is followed immediately by a muscle relaxant (often suxamethonium chloride) from a separate syringe, although the same needle can be used. The anaesthetist is responsible for the choice of drugs, and should also ensure that the lungs are well oxygenated before a mouth gag is inserted.
Application of ECT. While the anaesthetic is being given, the psychiatrist checks both the dose of electricity and the electrode placement that has been prescribed for the patient. The skin is cleaned in the appropriate areas and moistened electrodes are applied. (If good electrical contact is to be obtained, it is also important that grease and hair lacquer are removed by ward staff before the patient is sent for ECT.) Although dry electrodes can cause skin burns, it is also important to remember that excessive moisture causes shorting and may prevent a seizure response.
Although enough muscle relaxant should have been given to ensure that convulsive movements are minimal, a nurse or other assistant should be ready to restrain the patient gently if necessary. The electrodes are then secured firmly. For unilateral ECT, the first electrode is placed on the non-dominant side, 3 cm above the midpoint between the external angle of the orbit and the external auditory meatus. The second electrode is placed at least 10 cm away from the first one, vertically above the meatus of the same side (see Figure 19.2). A wide separation of the electrodes increases the efficacy of unilateral ECT (Lock, 1999). The stimulus is then given.
For fixed-dose right unilateral ECT the initial dose should be set at 400 millicoulombs and subsequently adjusted according to clinical efficacy and cognitive side-effects. However, dose titration offers advantages in terms of individualizing the dose for each patient. In dose titration the seizure threshold for the individual patient is determined during the first ECT session by starting with a very low dose and increasing it until a fit occurs (Scott, 2005).
Figure 19.2 Electrode placements for ECT.
For bilateral ECT, electrodes are placed on opposite sides of the head, each 3 cm above the midpoint of the line joining the external angle of the orbit to the external auditory meatus—usually just above the hairline (see Figure 19.2). When using bilateral electrode placement, the present practice is to administer a dose of electricity that is only modestly (about 1.5 to 2.5 times) above the seizure threshold for the individual. The seizure threshold for ECT is best determined by dose titration as described above. Otherwise an appropriate dose can be estimated from the fact that two-thirds of the population have seizure thresholds in the range 100–200 millicoulombs. In addition, seizure thresholds are higher in men than in women, and increase with age. For example, a reasonable starting dose for a male patient under 40 years of age who is to receive bilateral ECT would be 150 millicoulombs.
Subsequently this dose could be adjusted, depending on the length of the seizure, the cognitive side-effects, and the clinical response. The dose might be increased if the seizure was short or absent, or if there was no improvement after several treatments. Conversely, troublesome post-ECT cognitive disturbance would indicate that the dose of electricity should be reduced or that unilateral placement of the electrodes should be used.
It is important to note that seizure duration may decrease during a course of ECT, because repeated treatment tends to increase the seizure threshold. Thus if a dose of electricity initially produced a seizure of satisfactory duration, it may subsequently need to be increased.
The seizure. It is essential to observe carefully for evidence of seizure. If satisfactory muscle relaxation has been achieved, the seizure takes the following form. First, the muscles of the face begin to twitch and the mouth drops open. Then the upper eyelids, thumbs, and big toes jerk rhythmically for about half a minute. It is important not to confuse these convulsive movements with muscle twitches due to the depolarization produced by suxamethonium.
EEG monitoring has been used to check whether a seizure has been induced, but the records can be difficult to interpret because of the muscle artefact produced by direct stimulation of the frontalis muscle. An alternative is to isolate one forearm from the effects of the muscle relaxant. This can be done by blowing up a blood pressure cuff to above systolic pressure before the relaxant is injected; this pressure is maintained during the period in which the seizure should occur and then released. Seizure activity can then be observed in the muscles of the isolated part of the arm. When determining the appropriate cuff pressure, it is important to remember that systolic pressure rises during the seizure, so if the cuff is not at sufficient pressure the relaxant will pass into the forearm at this stage.
There is no direct correlation between treatment outcome and duration of seizure activity, but it is recommended that the dose of electricity is adjusted so as to achieve a seizure duration of between 20 and 50 seconds. This duration is recommended because short seizures are likely to be therapeutically ineffective, whereas long seizures are more likely to be associated with cognitive disturbance.
Psychotropic drugs may alter the seizure threshold and seizure duration. For example, most antidepressant and antipsychotic drugs lower the seizure threshold, whereas benzodiazepines, valproate, and lamotrigine have the opposite effect. Adverse effects, including increased cognitive impairment, have been reported when ECT has been given with lithium. SSRIs have been associated with prolonged seizures during ECT. Some anaesthetists prefer not to anaesthetize patients who are taking MAOIs, but ECT can in fact be given safely to patients who are receiving MAOI treatment. The usual practice in the UK has been to continue antidepressant medication during a course of ECT. Sackheim et al. (2009) found that the introduction of nortriptyline to unmedicated patients during a course of ECT improved efficacy and lessened cognitive adverse effects. On the other hand, venlafaxine had a somewhat less marked effect on efficacy, and tended to worsen cognitive adverse effects.
Recovery phase. After the seizure, the lungs are oxygenated thoroughly with an airway in place. The patient remains in the care of the anaesthetist and under close nursing observation until breathing resumes and consciousness is restored. During recovery, the patient should be turned on their side and cared for in the usual way for any patient recovering from an anaesthetic after a minor surgical procedure. A qualified nurse should be in attendance to supervise the patient and reassure them. Meanwhile the psychiatrist makes a note of the date, type of electrode placement, drugs used, and amount of current, together with a brief description of the fit and any problems that have arisen. When the patient is awake and orientated, they should rest for an hour or so on their bed or in a chair.
If ECT is given to a day patient, it is especially important to make certain that no food or drink has been taken before they arrive at the hospital. They should rest for several hours and should not leave until it is certain that their recovery is complete; they should leave in the company of a responsible adult, and certainly not riding a bicycle or driving a car.
Failed stimulations. The most important problem, apart from those relating to the anaesthetic procedure, is failure to produce a clonic convulsion (a tonic jerk produced by the current must not be mistaken for a seizure). If it is certain that no seizure has appeared, checks should be made of the machine, the electrodes, and contact with the skin. The possibility of shorting due to excess moisture on the scalp should also be considered. If all of these are excluded, the patient may have either an unusually high resistance to the passage of current through the extracranial tissues and skull, or a high convulsive threshold. The charge can then be increased by 50% and a further stimulus given.
Frequency and number of treatments
ECT is usually given twice a week. In general, ECT given three times weekly has little therapeutic advantage over a twice weekly regimen, and may produce more cognitive impairment (UK ECT Review Group, 2003).
Decisions about the length of a course of ECT must depend on clinical experience, as relevant information is not available from clinical trials. A course of ECT usually consists of between 6 and a maximum of 12 treatments. Progress should be reviewed after each treatment. There is usually little response until two or three treatments have been given, after which increasing improvement occurs. If the response is more rapid than this, fewer treatments may be given. If there has been no response after 6 to 8 treatments, the course should usually be abandoned, as it is unlikely that more ECT will produce a useful change. Memory should also be assessed after each treatment. Significant cognitive impairment should lead to a reappraisal of the electrical dose and electrode placement.
Prevention of relapse
It is important that, whereas ECT may produce striking benefit in depressed patients, there is a high relapse rate unless continuation therapy with antidepressant medication is undertaken. Sometimes the choice of antidepressant drug can be difficult because if a patient does not respond to an adequate dose of an antidepressant drug prior to ECT, continuing the same drug after the course of ECT is completed may not provide a useful prophylactic effect (Sackheim et al., 1990). Thus, if a patient has required ECT because of non-response to antidepressant medication, it is good practice to consider a different class of antidepressant drug or lithium carbonate in the continuation and prophylactic phases of drug treatment. A randomized study of 200 patients found post-ECT prophylaxis with a combination of lithium and nortriptyline as effective as maintenance ECT in sustaining remission in the 6 months following a successful course of treatment. Despite this, just over 50% of the patients in each group relapsed (Kellner et al., 2006).
A few patients respond well to ECT but continually relapse even when maintained on multiple drug therapy. In these circumstances, some practitioners have given maintenance ECT at a reduced frequency (e.g. fortnightly or monthly). However, this practice was not recommended by the National Institute for Clinical Excellence (2003).
Consent to ECT
Before a patient is asked to agree to ECT, it is essential to provide a full explanation of the procedure and indicate its expected benefits and possible risks, especially the effects on memory. Appropriately written information sheets should be a standard part of the consent procedure (National Institute for Clinical Excellence, 2003).
Many patients expect severe and permanent memory impairment after treatment, and some even expect to experience unmodified fits. Once the doctor is sure that the patient understands what they have been told, the patient is asked to sign a standard form of consent. It should be made clear to them that consent is being sought for the whole course of ECT, and not just for one treatment, although it is also essential to make sure that they understand that consent can be withdrawn at any time.
In the UK, if a patient refuses consent, or is unable to give it because they are in a stupor or for some other reason, and if the procedure is essential, further steps must be considered. The first is to decide whether there are grounds for involving the appropriate section of the Mental Health Act (see p. 78). The section does not allow anyone to give consent on behalf of the patient, but it does establish formally that they are mentally ill and in need of treatment. In England and Wales, the opinion of a second independent consultant is required by the Mental Health Act 1983. Readers working outside the UK should familiarize themselves with the relevant legal requirements.
If the decision is made in this careful way and fully explained, it is rare for patients to question the need for treatment once they have recovered. Instead, most acknowledge that treatment has helped, and they understand why it was necessary to give it without their expressed consent. In general, audits suggest that most patients feel that they have been helped by ECT; in terms of unpleasantness, ECT tends to be rated at the same level as a visit to the dentist. The most common side-effects about which patients complain are memory problems, headache, dizziness, and confusion (Benbow and Crentsil, 2004).
Ethical aspects of ECT
As with drug treatment, the key issue for a competent patient is the concept of full informed consent. In general, ECT is widely regarded as a safe and effective treatment—a view that is supported by randomized controlled trials. However, it is important that patients are warned about the possibility of loss of remote memories outlined above. In addition, in the case of medication-resistant patients, the issue of relapse should be discussed.
ECT in the case of non-competent patients raises particularly difficult issues. Usually, in these circumstances, ECT is needed to treat a patient whose life is placed at risk as a result of their illness. The legal safeguards for patients are outlined above, but the clinician has a duty to explain to the patient and their family the reasons for the action taken, and to follow carefully the ethical principles outlined in Chapter 4.
Bright light treatment
The use of phototherapy, or artificial bright light, as a psychiatric treatment was first studied systematically by Rosenthal et al. (1984). These workers used bright light to treat patients with the newly identified syndrome of seasonal affective disorder. Since then, phototherapy has become the mainstay of treatment of winter depression, particularly in patients with atypical depressive features such as hyperphagia and hypersomnia (Eagles, 2004).
Mechanism of action
The light–dark cycle is believed to be one of the most important ‘zeitgebers’ regulating circadian and seasonal rhythmicity in mammals. Initially, phototherapy was believed to ameliorate the symptoms of winter depression by extending the photoperiod. This was based on the view that patients with winter depression were particularly sensitive to the effects of short winter days, and that bright light treatment produced a day length equivalent to that of summer.
More recent formulations have suggested that the anti-depressant effect of bright light may be attributable to a phase advance in circadian rhythm. This is supported by the fact that controlled trials show that, in most patients, morning phototherapy is more effective than evening phototherapy. However, other studies have shown that bright light given at midday is also therapeutically effective. It is difficult to devise a truly plausible placebo condition for bright light treatment, and some have argued that the antidepressant effects of bright light may be mediated in large measure by placebo effects, particularly patient expectation. Golden et al. (2005) found in a meta-analysis of nine randomized studies that bright light was significantly superior to a dim light control in reducing depressive symptomatology in patients with seasonal affective disorder, with an effect size of 0.84 (95% CI, 0.6–1.08).
A conventional light box contains fluorescent tubes mounted behind a translucent plastic diffusing screen. The tubes provide an output that can vary between 2500 and 10 000 lux. Light sources that produce 10 000 lux are more expensive, but may allow a reduced duration of exposure (30 minutes, compared with 120 minutes) to secure a therapeutic effect.
Phototherapy has also been administered using head-mounted units or light visors. These instruments are attached to the head and project light into the eyes, allowing the subject to remain mobile while receiving treatment. Although light visors are more convenient to use than light boxes, results from placebo-controlled trials of light visors have proved disappointing and their use is not currently recommended.
Therapeutic efficacy and indications
The major indication for light therapy is seasonal affective disorder in which patients experience winter depressions. Numerous controlled trials have shown that bright light treatment is more effective than placebo in patients with winter depression, particularly if they experience:
• increased sleep
• carbohydrate cravings
• an afternoon slump in energy.
Patients with more typical melancholic symptoms—for example, weight loss and insomnia—do less well with phototherapy as a sole treatment, even where the disorder is seasonal in nature. Although there are studies to suggest that morning light treatment may augment the therapeutic effect of antidepressant medication in non-seasonal depression, the effect may not be well sustained (Martiny et al., 2006). Phototherapy may also be of benefit in other disorders characterized by depressed mood and appetite changes—for example, premenstrual syndrome and bulimia nervosa. The literature contains a number of controlled trials in such disorders where light treatment has improved ratings of depression. However, the difficulty of distinguishing specific and placebo effects of bright light makes the current data difficult to interpret.
In general, phototherapy is well tolerated, although mild side-effects occur in up to 45% of patients early in treatment. These include headache, eye strain, blurred vision, eye irritation, and increased tension. Insomnia can also occur, particularly with late evening treatment. Rare adverse events that have been reported include manic mood swings and suicide attempts, the latter putatively through light-induced alerting and energizing effects prior to mood improvement. Whether these rare events are actually adverse reactions to light is uncertain. There is no evidence that phototherapy employed in recommended treatment schedules causes ocular or retinal damage.
Clinical use of phototherapy
Since the best established indication for phototherapy is seasonal affective disorder, the following account will describe the use of bright light treatment in winter depression. One of the major practical difficulties in phototherapy is the time needed to administer the treatment. For this reason, a 10 000 lux light box may be preferred because the daily duration of therapy can be reduced to 30–45 minutes. It seems likely that cool-white light and full-spectrum light have equivalent clinical efficacy, but because cool-white light is free of ultraviolet light it is theoretically safer.
The evidence suggests that bright light treatment of winter depression is most effective when administered in the early morning. However, treatments given at other times of day, including the evening, may prove beneficial and can be more convenient for individual patients. In an initial trial, therefore, it is best to recommend early morning treatment but to advise the patient that the exact timing of therapy can eventually represent a balance of therapeutic efficacy and practical convenience. Treatment should not be given late in the evening because of the possibility of sleep disruption.
Early morning phototherapy should start within a few minutes of awakening. Patients should allow an initial duration of treatment of 30 minutes with a 10 000 lux light box or 2 hours with 2500 lux equipment. They should seat themselves about 30–40 cm away from the light-box screen. They should not gaze at the screen directly, but face it at an angle of about 45 degrees and glance across it once or twice each minute.
The antidepressant effect of light treatment can appear within a few days, but in controlled trials longer periods (up to 3 weeks) can be necessary before the therapeutic effects of bright light exceed those of placebo treatment. As noted above, mild side-effects are common in the early stages of treatment, but usually settle without specific intervention. If they are persistent and troublesome, the patient can sit a little further away from the light source or reduce the duration of exposure. Exposure should also be reduced if elevated mood occurs.
Once a therapeutic response has occurred, it is necessary to continue phototherapy up to the point of natural remission, otherwise relapse will occur. However, it may be possible to lower the daily duration of treatment. Phototherapy may also be started in advance of the anticipated episode of depression, as this appears to have a prophylactic effect, although doubts about the robustness of this effect have been expressed (Eagles, 2004).
Neurosurgery for psychiatric disorders (psychosurgery)
History of procedure
Psychosurgery refers to the use of neurosurgical procedures to modify the symptoms of psychiatric illness by operating on either the nuclei of the brain or the white matter. Psychosurgery began in 1936 with the work of Egas Moniz, whose operation consisted of an extensive cut in the white matter of the frontal lobes (frontal leucotomy). This extensive operation was modified by Freeman and Watts (1942), who made smaller coronal incisions in the frontal lobes through lateral burr holes.
Although their so-called standard leucotomy was far from standardized anatomically, and although it produced unacceptable side-effects (see below), the procedure was widely used in the UK and other countries. There was enthusiasm for the initial improvements observed in patients, but this was followed by growing evidence of adverse effects, including intellectual impairment, emotional lability, disinhibition, apathy, incontinence, obesity, and epilepsy.
These problems led to a search for more restricted lesions capable of producing the same therapeutic benefits without these adverse consequences. Some progress was made, particularly with the incorporation of stereotactic techniques (see Christmas et al., 2004), but at the same time advances in pharmacology made it possible to use drugs to treat the disorders for which surgery was intended.
The term psychosurgery is now often replaced by the phrase neurosurgery for mental disorders. This change in terminology is intended to emphasize that:
• the techniques involved now involve placement of localized lesions in specific cerebral sites
• the treatment is for specific psychiatric conditions (treatment-resistant major depression and obsessive–compulsive disorder), not for primary behavioural disturbance.
In the UK the indications for neurosurgery for mental disorders are restricted to major depression and obsessive–compulsive disorder that is chronic, treatment refractory, and disabling. Neurosurgery is not indicated where these conditions arise as a consequence of organic brain disease or a pervasive developmental disorder.
Types of operation
Nowadays the older ‘blind’ operations have been replaced by stereotactic procedures that allow the lesions to be placed more accurately (see Box 19.12). In the UK, current procedures are limited to anterior capsulotomy and anterior cingulotomy. The lesions are produced either by radio-frequency thermo-coagulation or by gamma radiation (the ‘gamma knife’). Lesions are made bilaterally.
In the absence of controlled trials, assessment has been in the form of long-term follow-up studies. A report by the Royal College of Psychiatrists (2000) found a ‘marked improvement’ rate in 63% of patients with major depression and in 58% of patients with obsessive–compulsive disorder (see Box 19.13).
With modern procedures, severe adverse effects are rare. After the operation, headache and nausea are common, and confusion occurs in about 10% of patients. These adverse effects typically last for a few days, but can persist for up to a month. Long-term cognitive impairment does not seem to occur (see Table 19.14).
Box 19.12 Stereotactic procedures used in psychosurgery
Lesion made beneath the head of each caudate nucleus, in the rostral part of the orbital cortex
Bilateral lesions within the cingulate bundles
Subcaudate tractotomy combined with cingulotomy
Bilateral lesions in the anterior limb of the internal capsule
Neurosurgical procedures for mental disorders should not be performed until the effects of several years of vigorous multi-modal treatment have been observed. If this rule is followed, the operation will hardly ever be used. In fact, less than 20 psychosurgical operations a year are currently performed in the UK, about 25% of the annual rate in the early 1980s. If the surgery is to be considered at all, it should only be for chronic intractable obsessional disorder and severe chronic depressive disorders in older patients. There is no clear justification for neuro-surgery for anxiety disorders or schizophrenia. For a review, see Christmas et al. (2004).
Box 19.13 Outcome of psychosurgery in the UK, 1961–1997
Table 19.14 Adverse effects of stereotactic psychosurgery
Operative mortality (less than 0.1%)
Haemorrhage, hemiplegia (less than 0.3%)
Transient confusion, lethargy
Weight gain (10%)
Frontal lobe syndrome (very rare)
Personality changes (usually mild)
The brain is the organ of judgement and decision making, but it is regarded as ethically permissible to operate, for example, on a brain tumour, if a patient gives their consent. The situation with regard to psychosurgery is different because the tissue that is lesioned is not overtly diseased. However, surgeons do sometimes operate on tissue which is not diseased. The practical problems with regard to psychosurgery (which distinguish it from ECT) are as follows:
• the lack of randomized studies to demonstrate that it is effective
• the irreversibility of the procedure
• the potentially serious nature of some of the adverse effects.
For these reasons it seems ethically appropriate that psychosurgery should be offered only to competent patients who are able to give their full informed consent. Determining competence may, of course, be difficult in a patient with chronic severe mood disorder. In the UK, this has led to the development of safeguards under Section 57 of the 1983 Mental Health Act, which require that:
1. the patient gives their full informed consent
2. a multidisciplinary panel appointed by the Mental Health Act Commission confirms that the patient’s consent is valid
3. the doctor on the multidisciplinary panel certifies that the treatment should be given. Before doing so, the doctor must consult two people, one a nurse and the other neither a nurse nor a doctor, who have been concerned with the patient’s treatment.
Brain stimulation techniques
Transcranial magnetic stimulation
The use of transcranial magnetic stimulation (TMS) is based on the principle that if a conducting medium such as the brain is adjacent to a magnetic field, a current will be induced in the conducting medium. In TMS, an electromagnetic coil is placed on the scalp. The passage of high-intensity pulses of current in the coil produces a powerful magnetic field—typically about 2 tesla (T)—which results in current flow in neural tissue and neuronal depolarization. Neuropsychological effects of TMS are particularly likely when pulses of current are delivered rapidly, so-called repetitive TMS (rTMS). If the stimulation occurs more quickly than once per second (1 Hz), it is called fast rTMS. The use of appropriately shaped coils allows reasonably localized stimulation of the main specific cortical areas.
Uses of TMS. TMS has been used for many years in clinical neurophysiology to explore, for example, the integrity of the motor cortex after stroke. In research settings, TMS is used to localize the cortical substrates of specific neuropsychological functions. For example, short-term verbal recall can be disrupted by rTMS administered over the left temporal cortex.
Clinically, rTMS has been used to relieve depressive states. Initially, studies used fast rTMS applied to the left prefrontal cortex. However, other investigations have employed different kinds of electromagnetic coil, stimulation parameters, and sites of coil application, making comparison between studies difficult. Meta-analyses suggest that, overall, TMS is more effective in the treatment of depression than sham treatment, but it is significantly less effective than ECT (Ebmeier and Herrmann, 2008; Rasmussen, 2008).
TMS has also been employed in treatment studies of other disorders, such as obsessive–compulsive disorder and schizophrenia. Findings in these conditions are still preliminary (see McLoughlin and Mogg, 2009).
Adverse effects of TMS. The use of single-pulse TMS in neurophysiological studies has not raised significant safety concerns. The major hazard with rTMS is the risk of inducing seizures. This is greater with fast rTMS than with slow rTMS. Current safety protocols, which adjust the amount of magnetic stimulation in relation to the motor threshold of the individual, appear to have greatly reduced the likelihood of fits, although patients with risk factors (e.g. a family history of epilepsy) are generally excluded from TMS studies of healthy volunteers.
Minor side-effects are more common, and include muscle tension headaches, and sufficient noise is generated by the equipment to cause short-term changes in hearing threshold. This can be prevented by the use of earplugs (by both patients and investigators). rTMS appropriately localized also has the potential to disrupt cognitive function, but so far such changes have been temporary, and have not persisted after the stimulation was terminated. There are insufficient data to establish whether there might be any long-term sequelae to the brain or other organs from the high-intensity magnetic field generated during TMS. No specific hazard has been revealed by current follow-up studies.
Vagal nerve stimulation
Vagal nerve stimulation (VNS) is an established treatment for patients with refractory epilepsy, in whom it was noted to improve mood. It has therefore subsequently been applied to the treatment of patients with resistant depression.
As well as providing an efferent parasympathetic outflow from the brain, the vagus nerve conveys afferent sensory fibres that synapse in the nucleus tractus solitarius and subsequently project to the forebrain. Stimulating the vagus nerve therapeutically involves an operative procedure during which a pulse generator is implanted subcutaneously in the left anterior chest wall. Bipolar electrodes, connected to the generator, are placed around the left vagus nerve in the cervical region. These electrodes are intermittently stimulated by the generator, with the stimulation parameters being regulated by a telemetric ‘wand’ which is connected to a personal computer. Modification of the stimulus parameters is used to balance adverse effects (see below) with therapeutic effects.
Use in depression. Open studies have suggested that over 12 months of treatment about 50% of patients show a good clinical response. Currently the best antidepressant effects have occurred in patients who have a moderate degree of treatment resistance but who have not proved refractory to multiple trials of antidepressant and augmentation therapies (Marangell et al., 2002). A short-term double-blind study did not reveal significant effects of VNS compared with sham stimulation, but it is possible that durable treatment effects emerge only after several months of treatment (Fitzgerald, 2008).
Adverse effects of VNS. During periods of vagal nerve stimulation, hoarseness is common and throat pain, cough, and dsypnoea can occur. These adverse effects decline with time, and withdrawal from treatment is uncommon. Hypomania has rarely been reported, but its relationship to VNS treatment is uncertain (Christmas et al., 2004).
Deep brain stimulation
Deep brain stimulation (DBS) is established in the treatment of Parkinson’s disease, where implantation of electrodes in the subthalamic nucleus significantly alleviates the motor symptoms of advanced disease. DBS was also noted to sometimes improve mood and obsessive symptomatology in patients with Parkinson’s disease and this, together with increasing knowledge of the neural circuitry underlying psychiatric disorders, has led to studies of its effects in patients with refractory depression and obsessive–compulsive disorder (Krack et al., 2010).
DBS involves bilateral implantation of electrodes into designated target locations using stereotactic guidance. The location of the electrodes is confirmed with MRI scanning. The electrodes are connected to a generator implanted into the abdomen, and the stimulation settings are adjusted according to clinical response and adverse effects. The fact that the settings can be modified and the generator switched on or off makes DBS more susceptible to controlled trial than neurosurgical treatment.
It seems likely that stimulation frequency is a key factor in determining the clinical efficacy of DBS. In Parkinson’s disease, for example, stimulation starts to reduce tremor at a frequency of approximately 50 Hz and reaches a plateau at about 200 Hz. Low-frequency stimulation is believed to activate neurons, whilst high-frequency stimulation probably causes inhibition. Whereas improvement in rigidity and tremor in Parkinson’s disease can be seen within minutes of DBS commencing, amelioration in depression and obsessive–compulsive symptomatology develops gradually over a period of weeks. This might be a consequence of neuroplastic changes induced by DBS, or might perhaps be due to changes in the oscillatory properties of the relevant neural networks (Krack et al., 2010).
Use in obsessive–compulsive disorder. In studies of patients with intractable obsessive–compulsive disorder, electrodes have been implanted in the anterior limb of the internal capsule, with the aim of influencing the brain regions targeted by neurosurgery for obsessive–compulsive disorder (see above). Subsequent studies have also examined the effect of DBS in the ventral striatum and nucleus accumbens. A further study examined stimulation in the subthalamic nucleus because of the improvement in obsessive symptomatology seen in some patients with comorbid Parkinson’s disease. Overall, clinically significant benefit has been observed in about 60% of DBS-treated patients, while improvement has not been apparent during periods of sham stimulation (Denys et al., 2010; Goodman et al., 2010).
Use in depression. DBS in treatment-refractory depressed patients has also involved a number of different brain regions, based on abnormalities revealed by functional neuroimaging as well as theoretical considerations of the neural underpinnings of symptoms such as anhedonia. Lozano et al. (2008) carried out DBS of the subcallosal cingulate gyrus in 20 depressed patients and reported that, at 6-month follow-up, 60% of patients had responded and 35% had remitted. Bewernick et al. (2010) found a 50% response in 10 patients with refractory depression who received DBS in the nucleus accumbens.
Adverse effects of DBS. Typical adverse effects associated with DBS include throbbing or buzzing sensations, nausea, and jaw tingling. Orofacial muscle contractions are also reported. Mood changes may occur but are difficult to relate specifically to DBS. However, some patients with no history of bipolarity have experienced hypomania. More profound mood swings, including severe depression and suicidal ideation, may occur if the stimulator fails suddenly. Some patients have reported a feeling of being cognitively ‘clouded’, which has responded to changes in stimulus parameters (Greenberg et al., 2010). To date there is no evidence that DBS causes enduring cognitive impairment. As with any neurosurgical procedure, implantation of electrodes for DBS carries risks of haemorrhage and infection. Such complications appear to be rare; in one series of 141 patients undergoing DBS for Parkinson’s disease, the overall mortality attributable to the procedure was 0.7% (Vergani et al., 2010).
Ethical aspects of DBS. DBS is considered to be less invasive than neurosurgery in that the stimulation can be stopped and there is no lesioning of tissue. However, the procedure does carry risks, and there is a lack of long-term efficacy and safety data. The situation is further complicated by involvement of commercial factors, because the stimulator equipment is expensive and manufactured by industry. This highlights once again the need for a scrupulous fiduciary relationship between the patient and the treating clinical team, as well as full informed consent to the procedure by a competent patient. It also suggests that some DBS trials should be sponsored by non-commercial organizations, and that all clinical data should be made publicly available so that there is no risk of publication bias. In view of the troubled history of direct neurosurgical interventions for psychiatric disorders, Rabins et al. (2009) propose that DBS should only be used to treat psychiatric disorders in the context of an approved research protocol with full independent ethical review.
Haddad P, Dursan S and Deakin JFW (2004). Adverse Syndromes and Psychiatric Drugs: a clinical guide. Oxford University Press, Oxford. (Useful coverage of common adverse events associated with psychotropic drug use.)
Stahl SM (2008). Stahl’s Essential Psychopharmacology. Cambridge University Press, Cambridge. (A well-illustrated account of basic and clinical use of psychotropic drugs.)
Taylor D, Paton C and Kapur S (2009). The Maudsley Prescribing Guidelines. Informa Healthcare, London. (An excellent handbook of good prescribing practice.)