David Nutt, Simon Davies, Sue Wilson, Blanca Bolea-Alamanac
Synopsis
Psychiatric disorders are some of the most common illnesses. Advances in drug treatment have revolutionised the practice of psychiatry over the past six decades. This chapter considers the following drug groups:
• Antidepressants.
• Antipsychotics (‘neuroleptics’).
• Mood stabilisers.
• Drugs for anxiety and sleep disorders.
• Drugs for dementia.
• Drugs for attention deficit/hyperactivity disorder.
Diagnostic issues
Older classifications of psychiatric disorder divided diseases into ‘psychoses’ and ‘neuroses’. The term ‘psychosis’ is still widely used to describe a severe mental illness with hallucinations, delusions, extreme abnormalities of behaviour including marked overactivity, retardation and catatonia, usually with lack of insight. Psychotic disorders include schizophrenia, severe depression and mania. Psychosis may also be due to illicit substances or organic conditions. Clinical features of schizophrenia are subdivided into ‘positive symptoms’, which include hallucinations, delusions and thought disorder, and ‘negative symptoms’ such as apathy, flattening of affect and poverty of speech.
Disorders formerly grouped under ‘neuroses’ include anxiety disorders (e.g. panic disorder, generalised anxiety disorder, obsessive–compulsive disorder, phobias and post-traumatic stress disorder), eating disorders (e.g. anorexia nervosa and bulimia nervosa), depression (provided there are no ‘psychotic’ symptoms) and sleep disorders.
Also falling within the scope of modern psychiatric diagnostic systems are organic mental disorders (e.g. dementia in Alzheimer's disease), disorders due to substance misuse (e.g. alcohol and opiate dependence; see Ch. 11), personality disorders, disorders of childhood and adolescence (e.g. attention deficit/hyperactivity disorder, Tourette's syndrome), and mental retardation (learning disabilities).
Drug therapy in relation to psychological treatment
No account of drug treatment strategies for psychiatric illness is complete without considering psychological therapies. Psychotherapies range widely, from simple counselling (supportive psychotherapy) through psychoanalysis to newer techniques such as cognitive behavioural therapy.
As a general rule, psychotic illnesses (e.g. schizophrenia, mania and depressive psychosis) require drugs as first-line treatment, with psychotherapy being adjunctive, for instance in promoting drug compliance, improving family relationships and helping individuals cope with distressing symptoms. By contrast, for depression and anxiety disorders, such as panic disorder and obsessive–compulsive disorder, forms of psychotherapy are available that provide alternative first-line treatment to medication. The choice between drugs and psychotherapy depends on treatment availability, previous history of response, patient preference and the ability of the patient to work appropriately with the chosen therapy. In many cases there is scope and sometimes advantage to the use of drugs and psychotherapy in combination.
Taking depression as an example, an extensive evidence base exists for the efficacy of several forms of psychotherapy. These include cognitive therapy (which normalises depressive thinking), interpersonal therapy (which focuses on relationships and roles), brief dynamic psychotherapy (a time-limited version of psychoanalysis) and cognitive analytical therapy (a structured time-limited therapy that combines the best points of cognitive therapy and traditional analysis).
All doctors who prescribe drugs engage in a ‘therapeutic relationship’ with their patients. A depressed person whose doctor is empathic, supportive and appears to believe in the efficacy of the drug prescribed is more likely to take the medication and to adopt a hopeful mindset than if the doctor seemed aloof and ambivalent about the value of psychotropic drugs. Remembering that placebo response rates of 30–40% are common in double-blind trials of antidepressants, we should never underestimate the importance of our relationship with the patient in enhancing the pharmacological efficacy of the drugs we use.
Antidepressant drugs
Antidepressants can be broadly divided into four main classes (Table 20.1), tricyclics (TCA, named after their three-ringed structure), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and novel compounds, some of which are related to TCAs or SSRIs. Clinicians who wish to have a working knowledge of antidepressants would be advised to be familiar with the use of at least one drug from each of the four main categories tabulated. A more thorough knowledge-base would demand awareness of the distinct characteristics of the subgroups of novel compounds (e.g. serotonin and noradrenaline/norepinephrine reuptake inhibitors (SNRIs), mirtazapine, reboxetine and agomelatine) and differences between individual SSRIs and TCAs. As antidepressants are largely similar in their therapeutic efficacy, awareness of profiles of unwanted effects is of particular importance.
Table 20.1 Classification of antidepressants
|
Tricyclics |
Selective serotonin reuptake inhibitors |
Monoamine oxidase inhibitors |
|
Dosulepin |
Fluoxetine |
Phenelzine |
|
Novel compounds |
||
|
Mainly noradrenergic |
Mainly serotonergic |
|
|
Reboxetine (NaRI) |
Trazodoneb |
|
|
Mixed |
|
Venlafaxine (SNRI) |
RIMA, reversible inhibitor of monoamine oxidase; NaRI, noradrenaline/norepinephrine reuptake inhibitor; SNRI, serotonin and noradrenaline/norepinephrine reuptake inhibitor; NaSSA, noradrenaline/norepinephrine and specific serotonergic antidepressant.
a Escitalopram is the active S-enantiomer of citalopram.
b Trazodone, nefazodone and mirtazapine have been classed as ‘receptor blocking’ antidepressants based on their antagonism of postsynaptic serotonin receptors (trazodone, nefazodone, mirtazapine) and presynaptic α2-receptors (trazodone, mirtazapine).
c Nefazodone has additional weak SSRI activity but has now been withdrawn due to risk of hepatitis.
d Not available in the UK.
An alternative categorisation of antidepressants is based solely on mechanism of action (Fig. 20.1). The majority of antidepressants, including SSRIs, TCAs and related compounds, are reuptake inhibitors. Certain novel agents, including trazodone and mirtazapine, are receptor blockers, whereas MAOIs are enzyme inhibitors.
Fig. 20.1 Flow chart of the evolution of antidepressant drugs, and classification by mechanism of action.
The first TCAs (imipramine and amitriptyline) and MAOIs appeared between 1957 and 1961 (see Fig. 20.1). The MAOIs were developed from antituberculous agents that unexpectedly improved mood. Imipramine was a chlorpromazine derivative that showed antidepressant rather than antipsychotic properties. Over the next 25 years the TCA class enlarged to more than 10 agents with heterogeneous pharmacological profiles, and further modifications of the original three-ringed structure gave rise to the related (but pharmacologically distinct) antidepressant trazodone.
In the 1980s an entirely new class of antidepressant arrived with the SSRIs: The first was zimelidine but unfortunately this was withdrawn due to associations with Guillain–Barré syndrome. Next came fluvoxamine, followed by fluoxetine (Prozac®). Within 10 years, the SSRI class accounted for half of antidepressant prescriptions in the UK. Further developments in the evolution of antidepressants have been novel compounds such as the SNRIs (e.g. venlafaxine and duloxetine), reboxetine, mirtazapine and agomelatine, and a reversible MAOI, moclobemide.
Mechanism of action
The monoamine hypothesis proposes that, in depression, there is deficiency of the neurotransmitters noradrenaline/norepinephrine and serotonin in the brain which can be restored by antidepressants. Drugs that alleviate depression also enhance monoamine availability and release (Fig. 20.2), increasing activity at postsynaptic receptors. It is relevant that (older) antihypertensive agents, e.g. reserpine, which reduced the availability of noradrenaline/norepinephrine, caused depression.
Fig. 20.2 Mechanism of action of antidepressant drugs at the synapse.
SSRIs act, as their name indicates, predominantly by preventing serotonin reuptake by blocking the cell-surface serotonin transporter; with little effect on noradrenaline/norepinephrine reuptake. Tricyclic antidepressants and reboxetine inhibit noradrenaline/norepinephrine reuptake, but tricyclic effects on serotonin reuptake vary widely; desipramine and protriptyline have no effect, whereas clomipramine is about five times more potent at blocking serotonin than noradrenaline/norepinephrine reuptake. SNRIs are capable of inhibiting reuptake of both transmitters. However, for venlafaxine a dose of at least 150 mg/day is required for noradrenaline/norepinephrine uptake blockade to be exerted. Mirtazapine also achieves an increase in noradrenergic and serotonergic neurotransmission, but through antagonism of presynaptic α2-autoreceptors (receptors that mediate negative feedback for transmitter release, i.e. an autoinhibitory feedback system). Other novel antidepressants include trazodone, which blocks several types of serotonin receptor (including the 5HT2A and 5HT2C receptors) as well as α-adrenoceptors and histaminergic receptors and acts as a partial agonist at the 5HT1A receptor, and agomelatine which acts both as an agonist of melatonin receptors and a blocker of the serotonin 5HT2C receptor, the combined effects of these actions leading to a rise in frontal cortex dopamine availability.
MAOIs increase the availability of noradrenaline/norepinephrine and serotonin by preventing their destruction by the monoamine oxidase type A enzyme in the presynaptic terminal (see Ch. 21, Table 21.3). The older MAOIs, phenelzine, tranylcypromine and isocarboxazid, bind irreversibly to monamine oxidase by forming strong (covalent) bonds. The enzyme is thus rendered permanently ineffective such that amine metabolising activity can be restored only by production of fresh enzyme, which takes weeks. These MAOIs are thus called ‘hit and run’ drugs as their effects greatly outlast their detectable presence in the blood.
But how do changes in monoamine transmitter levels produce an eventual elevation of mood? Raised neurotransmitter concentrations produce immediate alterations in postsynaptic receptor activation, leading to changes in second-messenger (intracellular) systems and to gradual modifications in cellular protein expression. Antidepressants increase a cyclic AMP response element binding (CREB) protein, which in turn is involved in regulating the transcription of genes that influence survival of other proteins, including brain-derived neurotrophic factor (BDNF), which exerts effects on neuronal growth.
Although the monoamine hypothesis of depression is conceptually straightforward, it is in reality an oversimplification of a complicated picture. Other systems that are implicated in the aetiology of depression (and which provide potential targets for drug therapy) include the hypothalamic–pituitary–thyroid axis and the hypothalamic–pituitary–adrenal (HPA) axis. The finding that 50% of depressed patients have raised plasma cortisol concentrations constitutes evidence that depression may be associated with increased HPA drive.
Drugs with similar modes of action to antidepressants find other uses in medicine. Bupropion (amfebutamone) inhibits reuptake of both dopamine and noradrenaline/norepinephrine. It was originally developed and used as an antidepressant but is now more frequently used to assist smoking cessation (see p. 321). It is also prescribed in attention deficit hyperactivity disorder (see p. 345). Sibutramine, licensed as an anorectic agent, is a serotonin and noradrenaline/norepinephrine reuptake inhibitor (SNRI).
Pharmacokinetics
The antidepressants listed in Table 20.1 are generally well absorbed after oral administration. Steady-state plasma concentrations of TCAs show great individual variation but correlate with therapeutic effect. Where there is a failure of response, measurement of plasma concentration can be useful as the failure may be attributable to low plasma levels due to ultra-rapid metabolism (though it is often not available). Antidepressants in general are metabolised principally by hepatic cytochrome P450 enzymes. Of the many isoenzymes identified, the most important in antidepressant metabolism are CYP P450 2D6 (Table 20.2A) and CYP 3A4 (Table 20.2B). Other important P450 enzymes are CYP 1A2 (inhibited by the SSRI fluvoxamine, induced by cigarette smoking; substrates include caffeine and the atypical antipsychotics clozapine and olanzapine) and the CYP 2 C group (inhibition by fluvoxamine and fluoxetine, involved in breakdown of escitalopram and moclobemide). Sometimes several CYP enzymes are capable of mediating the same metabolic step. For example, at least six isoenzymes, including CYP 2D6, 3A4 and 2 C9, can mediate the desmethylation of the SSRI sertraline to its major metabolite.
Table 20.2A Psychotropic (and selected other) drugs known to be CYP 2D6 substrates, inhibitors and inducers
|
CYP 2D6 inhibitors |
|
Antidepressants |
|
Paroxetine |
|
CYP 2D6 substrates |
||
|
Antidepressants |
Antipsychotics |
Miscellaneous |
|
Paroxetine |
Chlorpromazine |
Dexfenfluramine |
A substrate is a substance that is acted upon and changed by an enzyme. Where two substrates of the same enzyme are prescribed together, they will compete and, if present in sufficient quantities, the metabolism of one or other, or both, drugs may also be inhibited, resulting in increased plasma concentration and possibly in enhanced therapeutic or adverse effects. An enzyme inducer accelerates the metabolism of co-prescribed drugs that are substrates of the same enzyme, reducing their effects. An enzyme inhibitor retards metabolism of co-prescribed drugs, increasing their effects.
a CYP 2D6 is involved only in the breakdown of venlafaxine to its active metabolite and therefore implications of 2D6 interactions for efficacy are of limited significance.
Table 20.2B Psychotropic (and selected other) drugs known to be CYP 3A4 substrates, inhibitors and inducers
|
CYP 3A4 inhibitors |
|
|
Antidepressants |
Other drugs |
|
Fluoxetine |
Cimetidine |
|
CYP 3A4 substrates |
||
|
Antidepressants |
Anxiolytics, hypnotics and antipsychotics |
Miscellaneous |
|
Fluoxetine |
Alpraxolam |
Buprenorphine |
|
CYP 3A4 inducers |
|
|
Antidepressants |
Miscellaneous |
|
St John's wort |
Carbamazepine |
A substrate is a substance that is acted upon and changed by an enzyme. Where two substrates of the same enzyme are prescribed together, they will compete and, if present in sufficient quantities, the metabolism of one or other, or both, drugs may also be inhibited, resulting in increased plasma concentration and possibly in enhanced therapeutic or adverse effects. An enzyme inducer accelerates the metabolism of co-prescribed drugs that are substrates of the same enzyme, reducing their effects. An enzyme inhibitor retards metabolism of co-prescribed drugs, increasing their effects.
a mCPP (meta-chlorophenylpiperazine), the active metabolite of trazodone, is a CYP 2D6 substrate; observe for unwanted effects when trazodone is co-administered with the 2D6 inhibitors fluoxetine or paroxetine.
Several of these drugs produce active metabolites that prolong their action (e.g. fluoxetine is metabolised to norfluoxetine, t½ 200 h). The metabolic products of certain TCAs are antidepressants in their own right, e.g. nortriptyline (from amitriptyline), desipramine (from lofepramine and imipramine) and imipramine (from clomipramine). Half-lives of TCAs lie generally in a range from 15 h (imipramine) to 100 h (protriptyline), and those for SSRIs from 15 h (fluvoxamine) to 72 h (fluoxetine).
Around 7% of the Caucasian population have very limited CYP 2D6 enzyme activity. Such ‘poor metabolisers’ may find standard doses of TCAs intolerable, and it is often worth prescribing them at a very low dose. If the drug is then tolerated, plasma concentration assay may confirm the suspicion that the patient is a poor metaboliser. There is also a genetic polymorphism influencing CYP 2 C19 activity which has a clinically important effect on metabolism of escitalopram.
Therapeutic efficacy
Provided antidepressant drugs are prescribed at an adequate dose and taken regularly, 60–70% of patients with depression should respond within 3–4 weeks. Conventional meta-analyses have shown little evidence that any particular drug or class of antidepressant is more efficacious than others, but there are some possible exceptions to this general statement:
• Venlafaxine, in high dose (> 150 mg/day) and Escitalopram may have greater efficacy than other antidepressants.
• Amitriptyline appears to be slightly more effective than other TCAs and also SSRIs for severe depression, but this advantage is compromised by its poor tolerability and lack of safety in overdose relative to more modern agents.
• The older MAOIs (e.g. phenelzine) may be more effective than other classes in ‘atypical’ depression, a form of depressive illness where mood reactivity is preserved, lack of energy may be extreme and biological features are the opposite of the normal syndrome, i.e. excess sleep and appetite with weight gain.
Selection
An antidepressant should be selected to match individual patients’ requirements, such as the need or otherwise for a sedative effect, or the avoidance of antimuscarinic effects (especially in the elderly). In the absence of special factors, the choice rests on the weight of evidence of efficacy, the tolerability, the safety in overdose and the likelihood of an effective dose being reached. SSRIs and other newer drugs (e.g. mirtazapine and venlafaxine) are highlighted as best meeting these needs.
Mode of use
Antidepressants usually require 3–4 weeks for the full therapeutic effect to be achieved. When a minimal response is seen, an antidepressant can usefully be extended to 6 weeks to see whether further benefit is achieved. By contrast, patients may experience unwanted effects, especially ‘jitteriness’ or ‘activation’ symptoms such as increased anxiety and irritability, soon after starting treatment (they should be warned about this possibility), but such symptoms usually diminish with time. Some drugs have the advantage that they can be started at a dose which would be considered adequate for the therapeutic effect (e.g. most SSRIs) but in contrast many others, including all tricylic antidepressants, need to be started at a low and generally tolerable starting dose to the therapeutic dose. For example, imipramine should be started at 25–50 mg/day, with gradual increments to a recognised ‘minimum therapeutic’ dose, around 125 mg/day (140 mg/day for lofepramine). Low starting doses are particularly important for elderly patients. Only when the drug has reached the minimum therapeutic dose and been taken for at least 4 weeks can response or non-response be adequately established. However, some patients do achieve response or remission at subtherapeutic doses, for reasons of drug kinetics and limited capacity to metabolise, the self-limiting nature of depression, or by a placebo effect (reinforced by the experience of side-effects suggesting that the drug must be having some action).
For SSRIs dose titration is often unnecessary as the minimum therapeutic dose can usually be tolerated as a starting dose. Divided doses are not usually required, and administration is by a single morning or evening dose. Evidence suggests that patients commencing treatment on SSRIs are more likely to reach an effective dose than those starting on TCAs. Of the novel compounds, trazodone usually requires titration to a minimum therapeutic dose of at least 200 mg/day. Response to reboxetine, venlafaxine and mirtazapine may occur at the starting dose, but some dose titration is commonly required. Venlafaxine is licensed for treatment-resistant depression by gradual titration from 75 to 375 mg/day. There is some need for dose titration when using MAOIs. Unlike other drug classes, reduction to a lower maintenance dose is recommended after a response is achieved if unwanted effects are problematical.
Changing and stopping antidepressants
When an antidepressant fails through lack of efficacy despite an adequate trial or due to unacceptable adverse effects, a change to a drug of a different class is generally advisable. For a patient who has not responded to an SSRI it is logical to try a novel compound such as venlafaxine, mirtazapine or reboxetine, or sometimes a tricylic antidepressant. Any of these options may offer a greater increase in synaptic noradrenaline/norepinephrine than the ineffective SSRI.
Evidence also suggests that patients failing on one SSRI may respond to a different drug within the class, an approach that is particularly useful where other antidepressant classes have been unsuccessful previously, are contraindicated, or have characteristics that the patient or doctor feels are undesirable. Awareness of biological differences between drugs within a class may also be helpful when patients cannot tolerate other drug classes. For instance, among SSRIs, paroxetine has the most affinity for the serotonin transporter and fluoxetine the least, while among TCAs, clomipramine has more important serotonergic enhancing effects than the others.
When changing between antidepressant doses, a conservative approach would be to reduce the first antidepressant progressively over 2 or more weeks before starting the new drug. The gradual reduction is particularly important with paroxetine and venlafaxine which are known to cause ‘discontinuation syndromes’ if stopped abruptly, and less important with fluoxetine due to its long half-life active metabolite which offers ‘built-in’ protection against withdrawal problems. A more proactive approach would involve ‘cross-tapering’ the second antidepressant – i.e. starting it while the first antidepressant is being reduced and gradually titrating the dose up. However, an important exception concerns changes to or from MAOIs, which must be handled with great caution due to the dangers of interactions between antidepressants (see below). Therefore MAOIs cannot safely be introduced within 2 weeks of stopping most antidepressants (3 weeks for imipramine and clomipramine; combination of the latter with tranylcypromine is particularly dangerous), and not until 5 weeks after stopping fluoxetine, due to its long half-life active metabolite. Similarly, other antidepressants should not be introduced until 2–3 weeks have elapsed from discontinuation of MAOI (as these are irreversible inhibitors; see p. 313). No washout period is required when using the reversible MAOI, moclobemide.
When a patient achieves remission, the antidepressant should be continued for at least 9 months at the dose that returned mood to normal. Premature dose reduction or withdrawal is associated with increased risk of relapse. In cases where three or more depressive episodes have occurred, evidence suggests that long-term continuation of an antidepressant offers protection, as further relapse is almost inevitable in the next 3 years.
When ceasing use of an antidepressant, the dose should be reduced gradually to avoid discontinuation syndromes (symptoms include anxiety, agitation, nausea and mood swings). Discontinuation of SSRIs and venlafaxine are associated additionally with dizziness, electric shock-like sensations and paraesthesia. Short t½ drugs that do not produce active metabolites (e.g. paroxetine, venlafaxine) and TCAs are most likely to cause such problems.
Augmentation
The development of many new antidepressants in recent years has reduced the need to use augmentation strategies. Nevertheless augmentation, i.e. the addition of a second drug to an existing antidepressant, can be used when two or more standard antidepressants have successively failed to alleviate depressive symptoms despite treatment at an adequate dose for an adequate time. Some of the augmentations discussed may even be used earlier than this if there is an indication or justification for the augmenting drug specific to the individual patient.
One strategy which has come to prominence is to augment (or combine) an SSRI or SNRI antidepressant with the novel antidepressant mirtazapine. The initial justification for this combination stems from mirtazapine's unorthodox mechanism of action – the idea being that the presynaptic adjustments effected by mirtazapine could act additively or even synergistically with the monoamine reuptake inhibition of SSRIs and SNRIs. A second justification is more practical – mirtazapine is known to improve the quality of sleep and serotonin reuptake inhibitors may initially disrupt this, thus mirtazapine can be added both to boost the antidepressant effect and to address an unresolved problem with sleep. An evidence base does exist both for mirtazapine–venlafaxine and mirtazapine–fluoxetine co-prescription in depression, with both combinations reported as providing significantly higher remission rates than fluoxetine alone. Ease of initiation of these combinations, along with the evidence of enhanced effectiveness, means that these are currently the most commonly used augmentation strategies for treatment of depression in psychiatry inpatients in the UK.
Another important augmentation strategy employs the mood stabiliser lithium carbonate. Controlled trials suggest that up to 50% of patients who have not responded to standard antidepressants can respond after lithium augmentation but the evidence is stronger for augmenting tricyclics than for augmenting SSRIs. Addition of lithium requires careful titration of the plasma concentration up to the therapeutic range, with periodic checks thereafter and monitoring for toxicity (see p. 331).
More recently, augmentation of SSRIs with atypical antipsychotics has been effective in clinical trials. Trial evidence is strongest using olanzapine, and also exists for quetiapine, risperidone and aripiprazole. Antipsychotics also have important potential for side-effects which must be taken into account before their introduction (see p. 322).
Tri-iodothyronine (T3) also aids antidepressant action, and most evidence points to added benefit with TCAs. When co-prescribing TCAs with thyroid hormone derivatives, be aware that the combination of lofepramine with the levo isomer of thyroxine is contraindicated. The amino acid L-tryptophan and the β-adrenoceptor blocker pindolol may also be used to augment. Tryptophan increases 5-hydroxytryptamine (5HT) production, and pindolol may act by blocking negative feedback of 5HT on to 5HT1A-autoreceptors.
Other indications for antidepressants
Antidepressants may benefit most forms of anxiety disorder, including panic disorder, generalised anxiety disorder, post-traumatic stress disorder, obsessive–compulsive disorder and social phobia (see p. 331). SSRIs are recognised as first-line drug treatment for all five of these anxiety disorders.
Fluoxetine is effective in milder cases of the eating disorder bulimia nervosa, in higher doses (60 mg/day) than are required for depression. This effect is independent of that on depression (which may coexist), and may therefore involve a different mode of action. Antidepressants appear to be ineffective in anorexia nervosa. Antidepressants also have a role in pain control. The SNRI drug duloxetine is licensed for diabetic neuropathy while considerable trial evidence exists for use of the original tricyclic antidepressants imipramine and amitriptyline for the control of chronic pain.
Adverse effects
As most antidepressants have similar therapeutic efficacy, the decision regarding which drug to select often rests on adverse effect profiles and potential to cause toxicity.
Selective serotonin reuptake inhibitors
SSRIs have a range of unwanted effects including nausea, anorexia, dizziness, gastrointestinal disturbance, agitation, akathisia (motor restlessness) and anorgasmia (failure to experience an orgasm). They lack direct sedative effect, an advantage over older drugs in patients who need to drive motor vehicles or need to work or study. SSRIs can disrupt the pattern of sleep with increased awakenings, transient reduction in the amount of rapid eye movement (REM) and increased REM latency, but eventually sleep improves due to improved mood. SSRIs lack the side-effects of postural hypotension, antimuscarinic and antihistaminergic effects seen with TCAs. In contrast to both TCAs and mirtazapine, SSRIs may induce weight loss through their anorectic effects, at least in the short term. SSRIs are relatively safe in overdose.
The serotonin syndrome
is a rare but dangerous complication of SSRI use and features restlessness, tremor, shivering and myoclonus, possibly leading on to hyperpyrexia, convulsions and delirium. The risk is increased by co-administration with drugs that enhance serotonin transmission, especially MAOIs, the antimigraine triptan drugs and St John's wort. The combination of fluoxetine or paroxetine with tramadol can also cause serotonin syndrome. These SSRIs inhibit the metabolism of tramadol to its active metabolite (which is responsible for the pain relief), leaving a build-up of unmetabolised tramadol which has sufficient serotonergic activity itself to interact with the SSRIs and enhance the risk of serotonin syndrome.
Novel compounds
Venlafaxine
produces unwanted effects that resemble those of SSRIs with a higher incidence of nausea. Sustained hypertension (due to blockade of noradrenaline/norepinephrine reuptake) is a problem in a small proportion of patients at high dose, and blood pressure should be monitored when more than 200 mg/day is taken. Venlafaxine appears to have some association with cardiac arrhythmias but whether this is to a degree that is clinically significant is unclear.
Duloxetine
may cause early nausea, which tends to subside quickly. Other unwanted effects are somnolence, dizziness and constipation.
Mirtazapine
has benefits in rarely being associated with sexual dysfunction and in improving sleep independent of mood but it may cause unwanted sedation and weight gain.
Trazodone
is an option for depressed patients where heavy sedation is required. It also has the advantages of lacking antimuscarinic effects and of being relatively safe in overdose. Males should be warned of the possibility of priapism (painful penile erections), attributable to the drug's blockade of α1-adrenoceptors.
Agomelatine
is given at night when it appears to resynchronise circadian rhythms and therefore promotes improved sleep. Like mirtazapine it is rarely associated with sexual dysfunction, but its use necessitates early liver function tests.
Tricyclic antidepressants
The commonest unwanted effects are those of antimuscarinic action, i.e. dry mouth, constipation, blurred vision and difficulty with accommodation, raised intraocular pressure (glaucoma may be precipitated) and bladder neck obstruction (may lead to urinary retention in older males).
Patients may also experience: postural hypotension (through inhibition of α-adrenoceptors), which is often a limiting factor in the elderly; interference with sexual function; weight gain (through blockade of histamine H1receptors); prolongation of the QTc interval of the ECG, which predisposes to cardiac arrhythmias especially in overdose (use after myocardial infarction is contraindicated).
Some TCAs (especially trimipramine and amitriptyline) are heavily sedating through a combination of antihistaminergic and α1-adrenergic blocking actions, and this presents special problems to those whose lives involve driving vehicles or performing skilled tasks. In selected patients, sedation may be beneficial, e.g. a severely depressed person who has a disrupted sleep pattern or marked agitation.
There is great heterogeneity in adverse-effect profiles between TCAs. Imipramine and lofepramine cause relatively little sedation, and lofepramine is associated with milder antimuscarinic effects (but is contraindicated in patients with severe liver disease). When comparing SSRIs and TCAs for dropouts (a surrogate endpoint for tolerability), most meta-analyses show a small benefit in favour of SSRIs, although the older tricyclics imipramine and amitripyline are overrepresented in these meta-analyses.
Overdose
Depression is a risk factor for both parasuicide and completed suicide, and TCAs are commonly taken by those who deliberately self-harm. Dosulepin and amitriptyline are particularly toxic in overdose. Lofepramine is at least 15 times less likely to cause death from overdose; clomipramine and imipramine occupy intermediate positions.
Clinical features of overdose reflect the pharmacology of TCAs. Antimuscarinic effects result in warm, dry skin from vasodilatation and inhibition of sweating, blurred vision from paralysis of accommodation, papillary dilatation and urinary retention.
Consciousness is commonly dulled, and respiration depression and hypothermia may develop. Neurological signs including hyperreflexia, myoclonus, divergent strabismus and extensor plantar responses may accompany lesser degrees of impaired consciousness and provide scope for diagnostic confusion, e.g. with structural brain damage. Convulsions occur in a proportion of patients. Hallucinations and delirium occur during recovery of consciousness, often accompanied by a characteristic plucking at bedclothes.
Sinus tachycardia (due to vagal blockade) is a common feature but abnormalities of cardiac conduction accompany moderate to severe intoxication and may proceed to dangerous tachyarrhythmias or bradyarrhythmias. Hypotension may result from a combination of cardiac arrhythmia, reduced myocardial contractility and dilatation of venous capacitance vessels.
Supportive treatment suffices for the majority of cases. Activated charcoal by mouth is indicated to prevent further absorption from the alimentary tract and may be given to the conscious patient in the home prior to transfer to hospital. Convulsions are less likely if unnecessary stimuli are avoided, but severe or frequent seizures often precede cardiac arrhythmias and arrest, and their suppression with diazepam is important. Cardiac arrhythmias do not need intervention if cardiac output and tissue perfusion are adequate. Correction of hypoxia with oxygen, and acidosis by intravenous infusion of sodium bicarbonate are reasonable first measures and usually suffice.
Reboxetine
is not structurally related to tricyclic agents but like lofepramine and desipramine acts predominantly by noradrenergic reuptake inhibition. Pseudo-antimuscarinic effects, particularly urinary hesistancy and dry mouth, trouble a minority of patients, postural hypotension may occur, as may impotence in males. It is relatively safe in overdose.
Monoamine oxidase inhibitors
Adverse effects include postural hypotension (especially in the elderly) and dizziness. Less common are headache, irritability, apathy, insomnia, fatigue, ataxia, gastrointestinal disturbances including dry mouth and constipation, sexual dysfunction (especially anorgasmia), blurred vision, difficult micturition, sweating, peripheral oedema, tremulousness, restlessness and hyperthermia. Appetite may increase inappropriately, causing weight gain.
Interactions
Antidepressant use offers considerable scope for adverse interaction with other drugs and it is prudent always to check specific sources for unwanted outcomes whenever a new drug is added or removed to a prescription list that includes an antidepressant.
Pharmacodynamic interactions
• Most antidepressants (including SSRIs and tricylics) may cause central nervous system (CNS) toxicity if co-prescribed with the dopaminergic drugs entacapone and selegiline (for Parkinson's disease). SSRIs increase the risk of the serotonin syndrome when combined with drugs that enhance serotonin transmission, e.g. the antimigraine triptan drugs which are 5HT1-receptor antagonists, and the antiobesity drug sibutramine.
• Most antidepressants lower the convulsion threshold, complicate the drug control of epilepsy and lengthen seizure time in electroconvulsive therapy (ECT). The situation is made more complex by the capacity of carbamazepine to induce the metabolism of antidepressants and of certain antidepressants to inhibit carbamazepine metabolism (see below).
• SSRIs are known to interfere with platelet aggregation and may increase the risk of gastrointestinal bleeding, especially in those with existing risk factors.
• Trazodone and many tricyclics cause sedation and therefore co-prescription with other sedative agents such as opioid analgesics, H1-receptor antihistamines, anxiolytics, hypnotics and alcohol may lead to excessive drowsiness and daytime somnolence.
• The majority of tricyclics have undesirable cardiovascular effects, in particular prolongation of the QTc interval. Numerous other drugs also prolong the QTc interval, e.g. amiodarone, disopyramide, procainamide, propafenone, quinidine, terfenadine, and psychotropic agents such as pimozide and sertindole. Their use in combination with TCAs that prolong QTc enhances the risk of ventricular arrhythmias.
• Tricylics potentiate the effects of catecholamines and other sympathomimetics, but not those of β2-receptor agonists used in asthma. Even the small amounts of adrenaline/epinephrine or noradrenaline/norepinephrine in dental local anaesthetics may produce a serious rise in blood pressure.
Pharmacokinetic interactions
Metabolism by cytochrome P450 enzymes provides ample opportunity for interaction of antidepressants with other drugs by inhibition of, competition for, or induction of enzymes. Tables 20.2A and 20.2Bindicate examples of mechanisms by which interaction that may occur when relevant drugs are added to, altered in dose or discontinued from regimens that include antidepressants.
Enzyme inhibition
In depressive psychosis, antidepressants are commonly prescribed with antipsychotics and there is potential for enhanced drug effects with paroxetine + perphenazine (CYP 2D6), fluoxetine + sertindole (3A4) and fluvoxamine + olanzapine (1A2). Rapid tranquillisation with zuclopenthixol acetate (see p. 325) of an agitated patient who is also taking fluoxetine or paroxetine can result in toxic plasma concentrations with excessive sedation and respiratory depression due to inhibition of zuclopenthixol metabolism by CYP 2D6 and CYP 3A4. P450 enzyme inhibition by fluoxetine or paroxetine may also augment effects of alcohol, tramadol (danger of serotonin syndrome) methadone, terfenadine (danger of cardiac arrhythmia), -caine anaesthetics and theophylline.
Enzyme-inducing drugs
e.g. carbamazepine and several other antiepilepsy drugs, accelerate the metabolism of antidepressants, reducing their therapeutic efficacy and requiring adjustment of dose. Epilepsy is a particularly common co-morbid illness in patients who have both psychiatric illness and learning disabilities, and the combination of an anticonvulsant and an antidepressant or major psychotropic drug is to be anticipated. Depression and hypertension are both such common conditions that some co-morbidity is inevitable. Panic disorder (an indication for an antidepressant drug) is associated with hypertension.1 An antidepressant that is an enzyme inhibitor may exaggerate antihypertensive effects of metoprolol (metabolised by CYP 2D6), or diltiazem or amlodipine (3A4).
Monoamine oxidase inhibitors
Hypertensive reactions
Patients taking MAOIs are vulnerable to highly dangerous hypertensive reactions. Firstly, as MAOIs increase catecholamine stores in adrenergic and dopaminergic nerve endings, the action of sympathomimetics that act indirectly by releasing stored noradrenaline/norepinephrine is augmented. Secondly, patients taking a MAOI are deprived of the protection of the MAO enzyme present in large quantities in the gut wall and liver. Thus orally administered sympathomimetics that would normally be inactivated by MAO are absorbed intact. (Note that enhanced effects are not as great as might be expected from adrenaline/epinephrine, noradrenaline/norepinephrine and isoprenaline, which are chiefly destroyed by another enzyme, catechol-O-methyltransferase, in the blood and liver.)
Symptoms
include severe, sudden throbbing headache with slow palpitation, flushing, visual disturbance, nausea, vomiting and severe hypertension. If headache occurs without hypertension it may be due to histamine release. The hypertension is due both to vasoconstriction from activation of α-adrenoceptors and to increased cardiac output consequent on activation of cardiac β-adrenoceptors. The mechanism is thus similar to that of the episodic hypertension in a patient with phaeochromocytoma.
The rational and effective treatment
is an α-adrenoceptor blocker (phentolamine 5 mg i.v.), with a β-blocker later added in case of excessive tachycardia.
Patient education
It is essential to warn patients taking MAOIs of possible sources of the hypertensive reaction.
Many simple remedies
sold direct to the public, e.g. for nasal congestion, coughs and colds, contain sympathomimetics (ephedrine, phenylpropanolamine).
Foods likely to produce hypertensive effects in patients taking MAOIs include:
• Cheese, especially if well matured.
• Red wines (especially Chianti) and some white wines; some beers (non- or low-alcohol varieties contain variable but generally low amounts of tyramine).
• Yeast extracts (Marmite, Oxo, Bovril).
• Some pickled herrings.
• Broad bean pods (contain dopa, a precursor of adrenaline/epinephrine).
• Over-ripe bananas, avocados, figs.
• Game.
• Stale foods.
• Fermented bean curds including soy sauce.
• Fermented sausage, e.g. salami, shrimp paste.
• Flavoured textured vegetable protein (Vegemite).
This list may be incomplete and any partially decomposed food may cause a reaction. Milk and yoghurt appear safe.
Foods
to avoid are those that contain sympathomimetics, most commonly tyramine, which acts by releasing noradrenaline/norepinephrine from nerve vesicles. Degradation of the protein, casein, by resident bacteria in well matured cheese can produce tyramine from the amino acid tyrosine (hence the general term ‘cheese reaction’ to describe provocation of a hypertensive crisis).
Stale foods present a particular danger, as any food subjected to autolysis or microbial decomposition during preparation or storage may contain pressor amines resulting from decarboxylation of amino acids.
The newer drug moclobemide offers the dual advantages of selective MAO-A inhibition; in theory, this should avoid the ‘cheese’ reaction by sparing the intestinal MAO, which is mainly MAO-B, and of being a competitive, reversible inhibitor. Whereas the irreversible inhibitors inactivate the MAO enzyme and can therefore continue to cause dangerous interactions in the 2–3 weeks after withdrawal, until more enzyme can be synthesised, the reversible nature of MAO inhibition means it is incomplete except during peak plasma concentrations. As the inhibition is competitive, tyramine can then displace the inhibitor from the active site of the MAO enzyme. Consequently there are fewer dietary restrictions for patients using moclobemide, although hypertensive reactions have been reported.
MAOI interactions with other drugs
The mechanisms of many of the following interactions are obscure, and some are probably due to inhibition of drug-metabolising enzymes other than MAO enzyme, as MAOIs are not entirely selective in their action. Effects last for up to 2–3 weeks after discontinuing the MAOI.
Antidepressants. Combination with tricyclic antidepressants has the potential to precipitate a hypertensive crisis complicated by CNS excitation with hyperreflexia, rigidity and hyperpyrexia.
MAOI–SSRI combinations may provoke the life-threatening ‘serotonin syndrome’ (see above). Strict rules apply regarding washout periods when switching between MAOIs and other drugs (see above, Changing antidepressants, p. 316). Very occasionally, MAOIs are co-prescribed with other antidepressants, but as many combinations are highly dangerous such practice should be reserved for specialists only and then as a last resort.
Narcotic analgesics. With co-prescribed pethidine, respiratory depression, restlessness, even coma, and hypotension or hypertension may result (probably due to inhibition of its hepatic demethylation). Interaction with other opioids occurs but is milder.
Other drugs that cause minor interactions with MAOIs include antiepileptics (convulsion threshold lowered), dopaminergic drugs, e.g. selegiline (MAO-B inhibitor) may cause dyskinesias, antihypertensives and antidiabetes drugs (metformin and sulphonylureas potentiated). Concomitant use with bupropion/amfebutamone (smoking cessation), sibutramine (weight reduction) and 5HT1-agonists (migraine) should be avoided. Because of the use of numerous drugs during and around surgery, an MAOI is best withdrawn 2 weeks before, if practicable.
Overdose
with MAOIs can cause hypomania, coma and hypotension or hypertension. General measures are used as appropriate with minimal administration of drugs: chlorpromazine for restlessness and excitement; phentolamine for hypertension; no vasopressor drugs for hypotension, because of risk of hypertension (use posture and plasma volume expansion).
St John's wort
The herbal remedy St John's wort (Hypericum perforatum) has found favour in some patients with mild to moderate depression. The active ingredients in the hypericum extract have yet to be identified, and their mode of action is unclear. Several of the known mechanisms of action of existing antidepressants are postulated, including inhibition of monoamine reuptake and the MAO enzyme, as well as a stimulation of GABA receptors. Much of the original research into the efficacy of St John's wort was performed in Germany, where its use is well established. Several direct comparisons with tricyclic antidepressants have shown equivalent rates of response, but the interpretation of these studies is complicated by the fact that many failed to use standardised ratings for depressive symptoms, patients tended to receive TCAs below the minimum therapeutic dose, and sometimes received St John's wort in doses above the maximum recommended in commercially available preparations. Use of St John's wort is further complicated by the lack of standardisation of the ingredients. A large multi-centre trial found only limited evidence of benefit for St John's wort over placebo in significant major depression.2
Despite these reservations, there is certainly a small proportion of patients who, when presented with all the available facts, express a strong desire to take only St John's wort, perhaps from a preference for herbally derived compounds over conventional medicine. For patients with mild depression, it seems reasonable on existing evidence to accede to this preference rather than impair the therapeutic alliance and risk prescribing a conventional antidepressant that will not be taken.
Adverse effects
Those who wish to take St John's wort should be made aware that it may cause dry mouth, dizziness, sedation, gastrointestinal disturbance and confusion. Importantly also, it induces hepatic P450 enzymes (CYP 1A2 and CYP 3A4) with the result that the plasma concentration and therapeutic efficacy of warfarin, oral contraceptives, some anticonvulsants, antipsychotics and HIV protease/reverse transcriptase inhibitors are reduced. Concomitant use of tryptophan and St John's wort may cause serotonergic effects including nausea and agitation.
Electroconvulsive therapy
ECT involves the passage of a small electrical charge across the brain by electrodes applied to the frontotemporal aspects of the scalp with the aim of inducing a tonic–clonic seizure. Reference to it is made here principally to indicate its place in therapy.
ECT requires the patient to be under a general anaesthetic, so carrying the small risks associated with general anaesthesia in minor surgical operations. It may cause memory problems, although these are generally transient. For these reasons, as well as the relative ease of use of antidepressant drugs, ECT is usually reserved for psychiatric illness where pharmacological treatments have been unsuccessful or where the potential for rapid improvement characteristic of ECT treatment is important. This may arise where patients are in acute danger from their mental state, for instance the severely depressed patient who has stopped eating or drinking, or those with florid psychotic symptoms. Modern-day ECT is a safe and effective alternative to antidepressant treatment and remains a first-line option in clinical circumstances where a rapid response is desired, when it can be life saving.
Antipsychotics
Classification
Originally tested as an antihistamine, chlorpromazine serendipitously emerged as an effective treatment for psychotic illness in the 1950s. Chlorpromazine-like drugs were originally termed ‘neuroleptics’ or ‘major tranquillisers’, but the preferred usage now is ‘antipsychotics’. Classification is by chemical structure, e.g. phenothiazines, butyrophenones. Within the large phenothiazine group, compounds are divided into three types on the basis of the side-chain, as this tends to predict adverse effect profiles (Table 20.3). The continuing search for greater efficacy and better tolerability led researchers and clinicians to reinvestigate clozapine, a drug that was originally licensed in the 1960s but subsequently withdrawn because of toxic haematological effects. Clozapine appeared to offer greater effectiveness in treatment-resistant schizophrenia, to have efficacy against ‘negative’ in addition to ‘positive’ psychiatric symptoms (see Table 20.4), and to be less likely to cause extrapyramidal motor symptoms. It regained its licence in the early 1990s with strict requirements on dose titration and haematological monitoring. The renewed interest in clozapine and its unusual efficacy and tolerability stimulated researchers to examine other ‘atypical’ antipsychotic drugs.
Table 20.3 Antipsychotic drugs
|
Atypical antipsychoticsa |
Classical antipsychotics |
|
|
Clozapine |
Phenothiazines |
|
|
Olanzapine |
Type 1 |
Chlorpromazine |
|
Quetiapine |
Promazine |
|
|
Risperidone |
Type 2 |
Pericyazine |
|
Ziprasidone |
Type 3 |
Trifluoperazine |
|
Amisulprideb |
Prochlorperazine |
|
|
Zotepine |
Fluphenazine |
|
|
Sertindolec |
Butyrophenones |
Haloperidol |
|
Aripiprazole |
Benperidol |
|
|
Paliperidone |
Substituted benzamide |
Sulpirideb,c |
|
Thioxanthines |
Flupentixol |
|
|
Other |
Pimozide |
a No recognised classification system exists for atypical antipsychotics. Tentative terms based on receptor binding profiles have been applied to certain drug groupings, e.g. ‘broad-spectrum atypicals’ for clozapine, olanzapine and quetiapine, whereas risperidone and ziprasidone have been described as ‘high-affinity serotonin–dopamine antagonists’.
b Amisulpride and sulpiride are structurally related.
c Sertindole is available only on a named-patient basis when at least one previous antipsychotic has failed owing to lack of efficacy or adverse effects.
Table 20.4 Symptoms of schizophrenia
|
Positive symptoms |
Negative symptoms |
|
Hallucinations: most commonly auditory (i.e. voices) in the third person, which patients may find threatening. The voices may also give commands. Visual hallucinations are rare |
Affective flattening manifest by unchanging facial expression with lack of communication through expression, poor eye contact, lack of responsiveness, psychomotor slowing |
|
Delusions: most commonly persecutory. ‘Passivity phenomena’ include delusions of thought broadcasting, thought insertion or thought withdrawal, made actions, impulses or feelings |
Alogia (literally‘absence of words’), manifesting clinically as a lack of spontaneous speech (poverty of speech) |
|
Bizarre behaviours including agitation, sexual disinhibition, repetitive behaviour, wearing of striking but inappropriate clothing |
Anhedonia (inability to derive pleasure from any activity) and associality (narrowing of repertoire of interests and impaired relationships) |
|
Thought disorder manifest by failure in the organisation of speech such that it drifts away from the point (tangentiality), never reaches the point (circumstantiality), moves from one topic to the next illogically (loosened associations, knight's move thinking), breaks off abruptly only to continue on an unrelated topic (derailment) or moves from one topic to the next on the basis of a pun or words that sound similar (clang association) |
Apathy/avolution involving lack of energy, lack of motivation to work, participate in activities or initiate any goal-directed behaviour, and poor personal hygiene |
Thus the most important distinction in modern-day classification of antipsychotic drugs is between the classical (typical) agents, such as chlorpromazine, haloperidol and zuclopenthixol, and the so-called atypical antipsychotics, which include clozapine and now risperidone, olanzapine, quetiapine, amisulpride, aripiprazole and others. These latter are ‘atypical’ in their mode of action, their lack of extrapyramidal motor symptoms and adverse effect profiles. Categorisation of atypical agents by their chemical structure is of limited value clinically as they are very heterogeneous. Similarly classification through a shared affinity for a particular receptor system has not been possible; as discussed below, the atypical antipsychotics are very heterogeneous in their receptor-binding profiles.
Indications
Antipsychotic drugs are used for the prophylaxis and acute treatment of psychotic illnesses including schizophrenia and psychoses associated with depression and mania. They also have an important role as an alternative or adjunct to benzodiazepines in the management of the acutely disturbed patient, for both tranquillisation and sedation. There is some evidence that atypical antipsychotics may be used for treatment-resistant anxiety disorders after other treatments (e.g. SSRIs, SNRIs, pregabalin) have failed to produce an adequate response. Certain antipsychotics have an antidepressant effect that is distinct from their ability to alleviate the psychosis associated with depression, and as such can be used to augment the effect of antidepressants. Antipsychotics have also proved useful in the tic disorder Tourette's syndrome, and for recurrent self-harming behaviour.
Mechanism of action
The common action of conventional antipsychotics is to decrease brain dopamine function by blocking the dopamine D2 receptors (Fig. 20.3). However, the atypical drugs act on numerous receptors and modulate several interacting transmitter systems. All atypicals (except amisulpride) exhibit greater affinity for 5HT2 receptors than D2 receptors, unlike the classical agents. Atypical drugs that do antagonise dopamine D2 receptors appear to have some selectivity of effect for those in the mesolimbic system (producing antipsychotic effect) rather than the nigrostriatal system (associated with unwanted motor effects). Clozapine and risperidone exert substantial antagonism of α2-adrenoceptors, a property that may explain their benefits against negative symptoms. Blockade of muscarinic acetylcholine receptors as with chlorpromazine and clozapine reduces the occurrence of extrapyramidal effects. Aripiprazole is a unique drug because it is a partial dopamine D2-receptor agonist that acts conversely as an antagonist in regions where dopamine is overactive, such as the limbic system. It increases dopamine function where this is low (such as in the frontal cortex) and has little motor effect.
Fig. 20.3 Sagittal brain section illustrating dopaminergic pathways. (1) Mesolimbic pathway (thought to be overactive in psychotic illness according to the dopamine hypothesis of schizophrenia). (2) Nigrostriatal pathway(involved in motor control, underactive in Parkinson's disease and associated with extrapyramidal motor symptoms). (3) Tuberoinfundibular pathway (moderates prolactin release from the hypothalamus). VTA, ventrotegmental area.
Pharmacokinetics
Antipsychotics are well absorbed after oral administration and distribute widely. They are metabolised mainly by hepatic cytochrome P450 isoenzymes, e.g. CYP 2D6 (risperidone, perphenazine; see Table 20.2A), CYP 3A4 (sertindole; see Table 20.2B), CYP 1A2 (olanzapine, clozapine). Metabolism of some compounds is complex, e.g. zuclopenthixol and haloperidol are metabolised by both CYP 2D6 and CYP 3A4, which means that co-prescription of inhibitors of either enzyme can cause raised plasma concentrations of these antipsychotics. Amisulpride is an exception to the general rule as it is mainly eliminated unchanged by the kidneys with little hepatic metabolism. Elimination t½ values range from quetiapine 7 h, clozapine 12 h, haloperidol 18 h to olazapine 33 h. Depot preparations usefully release drug over 2–4 weeks after intramuscular injection (see below).
Efficacy
Symptoms in schizophrenia are defined as positive and negative (Table 20.4). Although a classical antipsychotic drug should provide adequate treatment of positive symptoms including hallucinations and delusions, at least 60% of patients may have unresolved negative symptoms such as apathy, flattening of affect and alogia. Evidence suggests that clozapine may have a significant advantage against negative symptoms. This drug has a further advantage over all other antipsychotics, whether classical or atypical, in that it is the most effective agent for ‘resistant’ schizophrenia, i.e. where other antipsychotics prescribed at adequate doses fail to produce improvement or are not tolerated.
Schizophrenia often runs a chronic relapsing and remitting course. Less than a quarter of patients avoid further episodes, with the most common reason for relapse being the stopping of medication against medical advice.
Mode of use
Atypical antipsychotics are all licensed for use in schizophrenia and are now recommended as the first-line treatment for newly diagnosed cases. Some also have licences for psychosis in mania and for control of agitated or disturbed behaviour in the context of a psychotic illness.
The longer a psychosis is left untreated, the less favourable is the outcome, and drug treatment should be instigated as soon as an adequate period of assessment has allowed a provisional diagnosis to be established. Patients who are ‘neuroleptic naïve’, i.e. have never previously taken any antipsychotic agent, should start at the lowest available dose (see Table 20.5, below). For most atypical agents a period of dose titration by protocol from the starting dose up to a stated lowest therapeutic dose is usual, e.g. risperidone 4 mg/day, quetiapine 300 mg/day. Dose increases are indicated when there is no response until the desired effect on psychotic symptoms or calming of disturbed behaviour is achieved, the urgency of the situation determining the interval between increments until the maximum licensed dose is achieved. Conservative dose titration is advisable for the elderly and patients with learning disabilities (who may require antipsychotics for psychosis or severe behavioural disturbance).
Table 20.5 Relative frequency of selected adverse effects of antipsychotic drugs
Prescription of conventional antipsychotics follows similar rules to those for atypical drugs, starting at low doses in neuroleptic-naïve patients, e.g. haloperidol 0.5 mg/day in case the patient is particularly susceptible to adverse, especially extrapyramidal, motor side-effects. There is a wide range of effective doses for many classical agents (e.g. chlorpromazine, once the most prescribed antipsychotic but now rarely used, has a dose range from 25 to 1000 mg/day). As the potency (therapeutic efficacy in relation to dose) of antipsychotic agents varies markedly between compounds, it is useful to think of the effective antipsychotic dose of classical agents in terms of ‘chlorpromazine equivalents’ (see Table 20.5). For example, haloperidol has a relatively high antipsychotic potency, such that 2–3 mg is equivalent to chlorpromazine 100 mg, whereas 200 mg sulpiride (low potency) is required for equivalent antipsychotic effect. Prescribing in excess of this requires specialist involvement. With co-prescribed antipsychotics, their total maximum antipsychotic dose should not exceed 1000 mg chlorpromazine equivalents per day, except under specialist supervision.
Clozapine may be initiated only under specialist supervision and usually after at least one other antipsychotic has failed through lack of efficacy or unacceptable adverse effects. Additionally, monitoring of leucocyte count is mandatory (danger of agranulocytosis) and blood pressure checking is required (for hypotensive effect). Patients are most vulnerable to agranulocytosis on initiation of therapy, with 75% of cases occurring in the first 18 weeks. The dose titration schedule must be followed strictly, starting with clozapine 12.5 mg at night and working up over a period of 4 weeks to a target therapeutic dose of 450 mg/day.
Alternative administration strategies in acute antipsychotic use
Preparations of antipsychotics for intramuscular injection are advantageous in patients who are unable or unwilling to swallow tablets, a common situation in psychosis or severe behavioural disturbance. Intramuscular preparations of the atypical antipsychotics olanzapine and aripiprazole are suitable for acute behavioural disturbance in schizophrenia but the conventional agent haloperidol is widely used. Formulations of risperidone and olanzapine that dissolve rapidly on contact with the tongue are available. These can be rapidly absorbed even by a disturbed and uncooperative patient.
Long-acting depot injections
Haloperidol, zuclopenthixol, fluphenazine, flupentixol, risperidone and pipothiazine are available as long-acting (2–4 weeks) depot intramuscular injections for maintenance treatment of patients with schizophrenia and other chronic psychotic disorders. Compliance is improved and there is less risk of relapse from ceasing to take medication. In view of the prolonged effect, it is prudent to administer a small initial test dose and review 5–10 days later for unwanted effects.
Rapid tranquillisation
Rapid tranquillisation protocols address the problem of severely disturbed and violent patients who have not responded to non-pharmacological approaches. The risks of administering psychotropic drugs (notably cardiac arrhythmia with high-dose antipsychotics) then greatly outweigh those of non-treatment.
A first step is to offer oral medication, usually haloperidol, olanzapine or risperidone with or without the benzodiazepine, lorazepam. If this is not accepted or fails to achieve control despite repeated doses, the intramuscular route is used to administer a benzodiazepine (e.g. lorazepam or midazolam) or an antipsychotic (e.g. haloperidol or olanzapine), or both (but intramuscular olanzapine should not be given with a benzodiazepine as excess sedation may ensue). After emergency use of an intramuscular antipsychotic or benzodiazepine, pulse, blood pressure, temperature and respiration are monitored, and pulse oximetry (for oxygen saturation) if consciousness is lost.
Zuclopenthixol acetate i.m. was previously used for patients who do not respond to two doses of haloperidol i.m. This usually induces a calming effect within 2 h, persisting for 2–3 days. Clinicians are now becoming reluctant to use this heavily sedating preparation other than for patients who have previously responded well to it, and never use it for neuroleptic-naïve patients. Patients must be observed with care following administration. Some will require a second dose within 1–2 days.
Amobarbital and paraldehyde have a role in emergencies only when antipsychotic and benzodiazepine options have been exhausted.
Adverse effects (Table 20.5)
Active psychotic illnesses often cause patients to have poor insight into their condition. Adverse drug effects can be the final straw in compromising already fragile compliance, leading to relapse. When atypical antipsychotics first came to prominence in the mid-1990s much was made of their lower propensity to cause several of the most troublesome side-effects of classical antipsychotics, especially extrapyramidal motor effects. However, while these problems are encountered less frequently, atypical drugs have a range of troublesome metabolic side-effects which had not been reported in the previous era of classic antipsychotics. Thus, to understand the current position relating to the pros and cons of atypical antipsychotics, it is necessary first to describe the side-effect profile of classical antipsychotic drugs.
Classical antipsychotics
It is rare for any patient taking classical antipsychotic agents to escape their adverse effects completely. Thus it is essential to discuss with patients the possibility of unwanted effects and regularly to review this aspect of their care.
Extrapyramidal symptoms
All classical antipsychotics produce these effects because they act by blocking dopamine receptors in the nigrostriatal pathway. Consequently some 75% of patients experience extrapyramidal symptoms shortly after starting the drug or increasing its dose (acute effects), or some time after a particular dose level has been established (tardive effects).
Acute extrapyramidal symptoms. Dystonias are manifest as abnormal movements of the tongue and facial muscles with fixed postures and spasm, including torticollis and bizarre eye movements (‘oculogyric crisis’). Parkinsonian symptoms result in the classical triad of bradykinesia, rigidity and tremor. Both dystonias and parkinsonian symptoms are believed to result from a shift in favour of cholinergic rather than dopaminergic neurotransmission in the nigrostriatal pathway (see p. 323). Anticholinergic (antimuscarinic) agents, e.g. procyclidine, orphenadrine or benztropine, act to restore the balance in favour of dopaminergic transmission but are liable to provoke antimuscarinic effects (dry mouth, urinary retention, constipation, exacerbation of glaucoma and confusion) and they offer no relief for tardive dyskinesia, which may even worsen. They should be used only to treat established symptoms and not for prophylaxis. Benzodiazepines are an alternative.
Akathisia
is a state of motor and psychological restlessness, in which patients exhibit persistent foot tapping, moving of legs repetitively and being unable to settle or relax. A strong association has been noted between its presence in treated schizophrenics and subsequent suicide. A β-adrenoceptor blocker, e.g. nadolol, is the best treatment, although anticholinergic agents may be effective where akathisia coexists with dystonias and parkinsonian symptoms. Differentiating symptoms of psychotic illness from adverse drug effects is often difficult: drug-induced akathisia may be mistaken for agitation induced by psychosis.
Tardive dyskinesia
affects about 25% of patients taking classical antipsychotic drugs, the risk increasing with length of exposure. It was originally thought to be a consequence of up-regulation or supersensitivity of dopamine receptors, but a more recent view is that oxidative damage leads to increases in glutamate transmission. Patients display a spectrum of abnormal movements from minor tongue protrusion, lip-smacking, rotational tongue movements and facial grimacing, choreoathetoid movements of the head and neck, and even to twisting and gyrating of the whole body. Remission on discontinuing the causative agent is less likely than are simple dystonias and parkinsonian symptoms. Any anticholinergic agent should be withdrawn immediately. Reduction of the dose of classical antipsychotic is an option, but psychotic symptoms may then worsen or be ‘unmasked’. Alternatively, an atypical antipsychotic can provide rapid improvement while retaining control of psychotic symptoms. Atypicals, particularly at high doses, can cause extrapyramidal effects, so this strategy is not always helpful. Clozapine, which does not appear to cause tardive dyskinesia, may be used in severe cases where continuing antipsychotic treatment is required and symptoms have not responded to other medication strategies.
If the classical antipsychotic is continued, tardive dyskinesia remits spontaneously in around 30% of patients within 1 year, but the condition is difficult to tolerate and patients may be keen to try other medications even where evidence suggests that the success rates for remission are limited. These include vitamin E, benzodiazepines, β-blockers, bromocriptine and tetrabenazine.
Cardiovascular effects
Postural hypotension may result from blockade of α1-adrenoceptors; it is dose related. Prolongation of the QTc interval in the cardiac cycle may rarely lead to ventricular arrhythmias and sudden death. This observation led to the withdrawal from the market of thioridazine and droperidol, restrictions on the use of pimozide and general warnings regarding the use of several other antipsychotics including haloperidol.
Prolactin increase
Classical antipsychotics raise plasma prolactin concentration by blocking dopamine receptors in the tuberoinfundibular pathway, causing gynaecomastia and galactorrhoea in both sexes, and menstrual disturbances in women. A change to an atypical agent such as aripiprazole, quetiapine or olanzapine (but not risperidone or amisulpride) should minimise the effects. If continuation of the existing classical antipsychotic is obligatory, dopamine agonists such as bromocriptine and amantadine that reduce prolactin secretion may help.
Sedation
In the acute treatment of psychotic illness this may be a highly desirable property, but it may be undesirable as the patient seeks to resume work, study or relationships.
Classical antipsychotics may also be associated with:
• Weight gain (a problem with almost all classical antipsychotics with the exception of loxapine; most pronounced with fluphenazine and flupentixol).
• Seizures (chlorpromazine is especially likely to lower the convulsion threshold).
• Interference with temperature regulation (hypothermia or hyperthermia, especially in the elderly).
• Skin problems (phenothiazines, particularly chlorpromazine, may provoke photosensitivity necessitating advice about limiting exposure to sunlight); rashes and urticaria may also occur.
• Sexual dysfunction (ejaculatory problems through α-adrenoceptor blockade).
• Retinal pigmentation (chlorpromazine can cause visual impairment if the dose is prolonged and high).
• Corneal and lens opacities.
• Blood dyscrasias (agranulocytosis and leucopenia).
• Osteoporosis (associated with increased prolactin levels).
• Jaundice (including cholestatic).
Atypical antipsychotics
Having considered the side-effect profile of classical antipsychotic agents, the adverse effects of atypical antipsychotics can be viewed as those shared with classical agents and those unique to one or more atypical agents.
Extrapyramidal effects occur less frequently than with classical agents (there is less blockade of dopamine D2 receptors in the nigrostriatal pathway) but do occur with high doses of risperidone and olanzapine. Tardive dyskinesia is much less common with all of the atypical agents than with classical drugs. Anticholinergic (antimuscarinic) effects are most likely with clozapine and olanzapine. Sexual dysfunction and skin problems are rare with atypical antipsychotics. Adverse effects relating to prolactin stimulation are also rare, with the exception of risperidone and amisulpride (for which galactorrhea is as common as with classical drugs).
One of the most problematic side-effects with atypical antipsychotics, especially with olanzapine and clozapine, is these drugs’ propensity to cause weight gain. The effect appears to be dose dependent for olanzapine but is often greater than 10 kg after 1 year's treatment with the 15 mg/day dose. Atypicals have also been implicated as causing metabolic disorders especially diabetes mellitus and hyperlipidaemia. Olanzapine, clozapine and quetiapine appear to be the most problematic. Obesity, impaired glucose tolerance and hyperlipidaemia, along with hypertension, are all features of metabolic syndrome. Hypertension can occur gradually with antipsychotics, most frequently as a consequence of weight gain. In a small number of cases hypertension may result from α2-adrenoceptor blockade. However, hypertension is less commonly an antipsychotic side-effect than the other manifestations of metabolic syndrome and some atypical antipsychotics (notably clozapine and sertindole) are associated with postural hypotension.
Atypical antipsychotics are associated with other important cardiovascualr effects. QTc prolongation is most likely to occur with sertindole (which is restricted for this reason), with quetiapine and zotepine associated with a lower level of risk (below that of the conventional antipsychotics haloperidol and pimozide). Olanzapine and risperidone are also associated with a greater risk of stroke in elderly patients with dementia.
Atypicals can also cause sedation. Clozapine is the most sedative followed by zotepine, quetiapine and olanzapine.
Clozapine warrants separate mention, given its value for patients with treatment-resistant schizophrenia or severe treatment-related extrapyramidal symptoms. Most important is the risk of agranulocytosis in up to 2% of patients (compared with 0.2% for classical antipsychotics). When clozapine was first licensed without requirement for regular blood counts, this problem caused appreciable mortality. With the introduction of strict monitoring, there have been no recorded deaths in the UK from agranulocytosis since clozapine was reintroduced, and internationally the death rate from agranulocytosis is now considerably less than 1 in 1000. In addition to postural hypotension clozapine may cause tachycardia and provoke seizures in 3–5% of patients at doses above 600 mg/day. Finally there are reported assciations between clozapine use and cardiomyopathy and myocarditis, although both are very rare outcomes.
Neuroleptic malignant syndrome
The syndrome may develop in up to 1% of patients using antipsychotics, both classical and atypical (although rarely with the latter); it is more prevalent with high doses. The elderly and those with organic brain disease, hyperthyroidism or dehydration are thought to be most susceptible. Clinical features include fever, confusion or fluctuating consciousness, rigidity of muscles which may become severe, autonomic instability manifest by labile blood pressure, tachycardia and urinary incontinence or retention.
Raised plasma creatine kinase concentration and white cell count are suggestive (but not conclusive) of neuroleptic malignant syndrome. There is some clinical overlap with the ‘serotonin syndrome’ (see p. 318) and concomitant use of SSRI antidepressants (or possibly TCAs) with antipsychotics may increase the risk.
When the syndrome is suspected, it is essential to discontinue the antipsychotic, and to be ready to undertake rehydration and body cooling. A benzodiazepine is indicated for sedation, tranquillising effect and may be beneficial where active psychosis remains untreated. Dopamine agonists (bromocriptine, dantrolene) are helpful in some cases. Even when recognised and treated, the condition carries a mortality rate of 12–15%, through cardiac arrhythmia, rhabdomyolysis or respiratory failure. The condition usually lasts for 5–7 days after the antipsychotic is stopped but may continue longer when a depot preparation has been used. Fortunately those who survive tend to have no long-lasting physical effects from their ordeal though care is required if, as is usual, they need further antipsychotic treatment.
Comparison of conventional and atypical antipsychotics
Atypical antipsychotics may have advantages in two areas:
1. Tolerability, and thus compliance, appears to be better, in particular with less likelihood of inducing extrapyramidal effects and hyperprolactinaemia (although the latter remains common with risperidone and amisulpride).
2. Regarding efficacy it was originally thought that all atypicals had an advantage over conventional agents at least for negative symptoms. More recently, evidence has emerged that for overall efficacy in schizophrenia, olanzapine, risperidone and amisulpride, in addition to clozapine, have an advantage over the other atypicals and the conventional antipsychotics. Note that clozapine is normally only used when at least two atypical antipsychotics have been tried without adequate response.
In some countries finance may be the overriding factor in favour of retaining classical agents rather than atypicals as first choice in schizophrenia. The basis for any such decision must extend beyond crude drug costs and take account of the capacity of atypicals to lessen extrapyramidal symptoms, improve compliance, and thus prevent relapse of psychotic illness and protect patients from the lasting damage of periods of untreated psychosis. Additionally, greater efficacy in relation to negative symptoms affords schizophrenic patients the opportunity to reintegrate into the community and make positive contributions to society, when the alternative is long-term residence in hospital. Recognising drugs as therapeutic entities as well as units of cost is an important element in deciding between classical and atypical drugs, and indeed about decision-making in the purchase of all drugs by institutions or countries.
Mood stabilisers
In bipolar affective disorder patients suffer episodes of mania, hypomania and depression, classically with periods of normal mood in between. Manic episodes involve greatly elevated mood, often associated with irritability, loss of social inhibitions, irresponsible behaviour and grandiosity accompanied by biological symptoms (increased energy, restlessness, decreased need for sleep, and increased sex drive). Psychotic features may be present, particularly disordered thinking manifested by grandiose delusions and ‘flight of ideas’ (acceleration of the pattern of thought with rapid speech). Hypomania is a less dramatic and less dangerous presentation, but retains the features of elation or irritability and the biological symptoms, abnormalities in speech being limited to increased talkativeness and in social conduct to over-familiarity and mild recklessness. Depressive episodes may include any of the depressive symptoms described above, and may include psychotic features.
Lithium
Lithium salts were known anecdotally to have beneficial psychotropic effects as long ago as the middle of the 19th century, but scientific evidence of their efficacy was not obtained until 1949, when lithium carbonate was tried in manic patients; it was found to be effective in the acute state and, later, to prevent recurrent attacks.3
The mode of action
is not fully understood. Its main effect is probably to inhibit hydrolysis of inositol phosphate, so reducing the recycling of free inositol for synthesis of phosphatidylinositides, which if present in excess may interfere with cell homeostasis by promoting uncontrolled cell signalling. Other putative mechanisms involve the cyclic AMP ‘second messenger’ system, and monoaminergic and cholinergic neurotransmitters.
Pharmacokinetics
The therapeutic and toxic plasma concentrations are close (low therapeutic index). Lithium is a small cation and, given orally, is rapidly absorbed throughout the gut. High peak plasma concentrations are avoided by using sustained-release formulations which deliver the peak plasma lithium concentrations in about 5 h. At first lithium is distributed throughout the extracellular water, but with continued administration it enters the cells and is eventually distributed throughout the total body water with a somewhat higher concentration in brain, bones and thyroid gland. Lithium is easily dialysable from the blood but the concentration gradient from cell to blood is relatively small and the intracellular concentration (which determines toxicity) falls slowly. Being a metallic ion it is not metabolised, nor is it bound to plasma proteins.
The kidneys eliminate lithium. Like sodium, it is filtered by the glomerulus and 80% is reabsorbed by the proximal tubule, but it is not reabsorbed by the distal tubule. Intake of sodium and water are the principal determinants of its elimination. In sodium deficiency lithium is retained in the body, and thus concomitant use of a diuretic can reduce lithium clearance by as much as 50%, and precipitate toxicity. Sodium chloride and water are used to treat lithium toxicity.
With chronic use the plasma t½ of lithium is 15–30 h. It is usually given 12–24-hourly to avoid unnecessary fluctuation (peak and trough) and maintain plasma concentrations just below the toxic level. A steady-state plasma concentration will be attained after about 5–6 days (i.e. 5 × t½) in patients with normal renal function. Old people and patients with impaired renal function will have a longer t½ so that steady state will be reached later and dose increments must be adjusted accordingly.
Indications and use
Lithium carbonate is effective treatment in more than 75% of episodes of acute mania or hypomania. Because its therapeutic action takes 2–3 weeks to develop, lithium is generally used in combination with a benzodiazepine such as lorazepam or diazepam (or with an antipsychotic agent where there are also psychotic features).
For prophylaxis, lithium is indicated when there have been two episodes of mood disturbance in 2 years, although in severe cases prophylactic use is indicated after one episode. When an adequate dose of lithium is taken consistently, around 65% of patients achieve improved mood control.
Patients who start lithium only to discontinue it within 2 years have a significantly poorer outcome than matched patients who are not given any pharmacological prophylaxis. The existence of a ‘rebound effect’ (recurrence of manic symptoms) during withdrawal dictates that long-term treatment with the drug is of great importance.
Lithium salts are ineffective for prophylaxis of bipolar affective disorder in around 35% of patients. The search for alternatives has centred on anticonvulsants, notably carbamazepine and sodium valproate and lamotrigine, and more recently the atypical antipsychotics.
Lithium is also used to augment the action of antidepressants in treatment-resistant depression (see p. 318).
Pharmaceutics
The dose of lithium ions (Li+) delivered varies with the pharmaceutical preparation; thus it is vital for patients to adhere to the same pharmaceutical brand. For example, Camcolit 250-mg tablets each contain 6.8 mmol Li+, Liskonum450-mg tablets contain 12.2 mmol Li+ and Priadel 200-mg tablets contain 5.4 mmol Li+. The proprietary name must be stated on the prescription.
Some patients cannot tolerate slow-release preparations because release of lithium distally in the intestine causes diarrhoea; they may be better served by the liquid preparation, lithium citrate, which is absorbed proximally. Patients who are naive to lithium should be started at the lowest dose of the preparation selected. Any change in preparation demands the same precautions as does initiation of therapy.
Monitoring
Dose is guided by monitoring the plasma concentration once steady state has been reached. Increments are made at weekly intervals until the concentration lies within the range 0.4–1 mmol/L (maintenance at the lower level is preferred for elderly patients). The timing of blood sampling is important, and by convention a blood sample is taken prior to the morning dose, as close as possible to 12 h after the evening dose. Once the plasma concentration is at steady state and in the therapeutic range, it should be measured every 3 months. For toxicity monitoring, thyroid function (especially in women) and renal function (plasma creatinine and electrolytes) should be measured before initiation and every 3–6 months during therapy.
Patient education about the role of lithium in the prophylaxis of bipolar affective disorder is particularly important to achieve compliance with therapy; treatment cards, information leaflets and, where appropriate, video material are used.
Adverse effects
are encountered in three general categories:
• Those occurring at plasma concentrations within the therapeutic range (0.4–1 mmol/L), which include fine tremor (especially involving the fingers; a β-blocker may benefit), constipation, polyuria, polydipsia, metallic taste in the mouth, weight gain, oedema, goitre, hypothyroidism, acne, rash, diabetes insipidus and cardiac arrhythmias. Mild cognitive and memory impairment also occur.
• Signs of intoxication, associated with plasma concentrations greater than 1.5 mmol/L, are mainly gastrointestinal (diarrhoea, anorexia, vomiting) and neurological (blurred vision, muscle weakness, drowsiness, sluggishness and coarse tremor, leading on to giddiness, ataxia and dysarthria).
• Frank toxicity, due to severe overdosage or rapid reduction in renal clearance, usually associated with plasma concentrations over 2 mmol/L, constitutes a medical emergency. Hyperreflexia, hyperextension of limbs, convulsions, hyperthermia, toxic psychoses, syncope, oliguria, coma and even death may result if treatment is not instigated urgently.
Overdose
Acute overdose may present without signs of toxicity but with plasma concentrations well exceeding 2 mmol/L. This requires only measures to increase urine production, e.g. by ensuring adequate intravenous and oral fluid intake while avoiding sodium depletion (and a diuretic is contraindicated; see above). Treatment is otherwise supportive, with special attention to electrolyte balance, renal function and control of convulsions. Where toxicity is chronic, haemodialysis may be needed, especially if renal function is impaired. Plasma concentration may rise again after acute reduction, because lithium leaves cells slowly, and also due to continued absorption from sustained-release formulations. Whole bowel irrigation may be an option for significant ingestion, but specialist advice should be sought.
Interactions
Drugs that interfere with lithium excretion by the renal tubules cause the plasma concentration to rise. They include diuretics (thiazides more than loop type), angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II antagonists, and non-steroidal anti-inflammatory analgesics. Theophylline and sodium-containing antacids reduce plasma lithium concentration. These effects can be important because lithium has a low therapeutic ratio. Diltiazem, verapamil, carbamazepine and phenytoin may cause neurotoxicity without affecting the plasma lithium level.
Carbamazepine
Carbamazepine is licensed as an alternative to lithium for prophylaxis of bipolar affective disorder, although clinical trial evidence is actually stronger to support its use in the treatment of acute mania. While lithium monotherapy is more effective than carbamazepine for prophylaxis of classical bipolar affective disorder, carbamazepine appears to be more effective than lithium for rapidly cycling bipolar disorders, i.e. with recurrent swift transitions from mania to depression. It is also effective in combination with lithium. (See also Epilepsy, p. 349.)
Valproate
Three forms of valproate are available: valproic acid, sodium valproate and semisodium valproate. The latter two are metabolised to valproic acid which exerts the pharmacological effect. It is the semisodium valproate preparation (Depakote) which is licensed in the UK for acute treatment of mania, underpinned by a reasonably strong evidence base. Valproate has become the drug of first choice for prophylaxis of bipolar affective disorder in the USA, despite the lack of robust supporting clinical trial evidence. Treatment with valproic acid is easy to initiate (especially compared to lithium) with no requirement for plasma concentration monitoring needed, although baseline and periodic checks of full blood count and liver function are recommended following reports of occasional blood dyscrasias or hepatic failure. It is generally well tolerated but weight gain can be a problem, so body mass index should be recorded and evaluated at intervals. Other potential side-effects include gastric irritation, lethargy, confusion, tremor and hair loss.
Treatment with carbamazepine or valproic acid appears not to be associated with the ‘rebound effect’ of relapse into manic symptoms that may accompany early withdrawal of lithium therapy.
Other drugs
Evidence is emerging for the efficacy of lamotrigine in prophylaxis of bipolar affective disorder, especially when depressive episodes predominate. Another drug class which is developing increasing importance in bipolar affective disorder is the atypical antipsychotics. Antipsychotic agents (both conventional and atypical) have long been used for control of acute manic symptoms, including both the grandiose delusions and thought disorder associated with manic psychosis and the acute behavioural disturbance which can occur in an extremely agitated patient. However, atypical antipsychotics such as olanzapine, quetiapine and aripiprazole are now known to be useful alternatives to conventional mood stabilisers in long-term prevention of manic relapse. Quetiapine appears to be particularly useful in preventing depressive relapse.
Other drugs that have been used in augmentation of existing agents include the anticonvulsants oxcarbazepine and gabapentin, the benzodiazepine clonazepam, and the calcium channel blocking agents verapamil and nimodipine.
Drugs used in anxiety and sleep disorders
The disability and health costs caused by anxiety are high and comparable with those of other common medical conditions such as diabetes, arthritis or hypertension. People with anxiety disorders experience impaired physical and role functioning, more work days lost due to illness, increased impairment at work and high use of health services. Our understanding of the nature of anxiety has increased greatly from advances in research in psychology and neuroscience. It is now possible to distinguish different types of anxiety with distinct biological and cognitive symptoms, and clear criteria have been accepted for the diagnosis of various anxiety disorders. The last decade has seen developments in both drug and psychological therapies such that a range of treatment options can be tailored to individual patients and their condition.
Anxiety does not manifest itself only as a psychic or mental state: there are also somatic or physical concomitants, e.g. consciousness of the action of the heart (palpitations), tremor, diarrhoea, which are associated with increased activity of the sympathetic autonomic system. These symptoms are not only caused by anxiety, they also add to the feeling of anxiety (positive feedback loop). Anxiety symptoms exist on a continuum and many people with a mild anxiety, perhaps of recent onset and associated with stressful life events but without much disability, tend to improve without specific intervention. The chronic nature and associated disability of many anxiety disorders means that most patients who fulfil diagnostic criteria for a disorder are likely to benefit from some form of treatment.
Classification of anxiety disorders
The diagnostic criteria of DSM-IV (Diagnostic and Statistical Manual) or ICD-10 (International Classification of Disease) are generally used. Both divide anxiety into a series of subsyndromes with clear operational criteria to assist in distinguishing them. At any one time many patients may have symptoms of more than one syndrome, but making the primary diagnosis is important as this can markedly influence the choice of treatment (Table 20.6).
Table 20.6 Evidence-based treatments for anxiety disorders
The key features of each anxiety disorder follow, with a practical description of the preferred choice of medication, its dose and duration.
Panic disorder (PD)
The main feature is recurrent, unexpected panic attacks. These are discrete periods of intense fear accompanied by characteristic physical symptoms such as skipping or pounding heart, sweating, hot flushes or chills, trembling/shaking, breathing difficulties, chest pain, nausea, diarrhoea and other gastrointestinal symptoms, dizziness or light-headedness. The first panic attack often occurs without warning but may subsequently become associated with specific situations, e.g. in a crowded shop, driving. Anticipatory anxiety and avoidance behaviour develop in response to this chain of events. The condition must be distinguished from alcohol withdrawal, caffeinism, hyperthyroidism and (rarely) phaeochromocytoma.
Patients experiencing panic attacks often do not know what is happening to them, and because the symptoms are similar to those of cardiovascular, respiratory or neurological conditions, often present to non-psychiatric services, e.g. casualty departments, family doctors, medical specialists, where they may either be extensively investigated or given reassurance that there is nothing wrong. A carefully taken history reduces the likelihood of this occurrence.
Treatment
The choice lies between a fast-acting benzodiazepine, such as lorazepam or alprazolam, and one with delayed efficacy but fewer problems of withdrawal, such as a tricyclic antidepressant (TCA), e.g. clomipramine or imipramine, or an SSRI, e.g. paroxetine. The different time course of these two classes of agent in panic disorder is depicted in Figure 20.4 (see also Table 20.6).
Fig. 20.4 Schematic representation of the time course of panic treatments.
Benzodiazepines rapidly reduce panic frequency and severity and continue to be effective for months; significant tolerance to the therapeutic action is uncommon. On withdrawal of the benzodiazepine, even when it is gradual, increased symptoms of anxiety and panic attacks may occur, reaching a maximum when the final dose is stopped. Indeed, some patients find they are unable to withdraw and remain long-term on a benzodiazepine.
Antidepressants (both SSRIs and TCAs) have a slower onset of action and may cause an initial increase in both anxiety and panic frequency, such that a patient may discontinue medication, even after a single dose. This provoking reaction usually lasts for no more than 2–3 weeks after which panic frequency and severity improve quickly, but patients need help to stay on treatment in the first weeks. The doctor needs to give a clear explanation of the likely course of events and the antidepressant should be started at half the usual initial dose to reduce the likelihood of exacerbation. The dose of antidepressant required to treat panic disorder is generally as high as, or higher than, that for depression and maximal benefit may not emerge for 8–12 weeks. Patients should therefore receive as large a dose as can be tolerated for this length of time.
Social anxiety disorder
The essential feature of social phobia is a marked and persistent fear of performance situations when patients feel they will be the centre of attention and will do something humiliating or embarrassing. The situations that provoke this fear can be quite specific, for example public speaking, or be of a much more generalised nature involving fear of most social interactions, for example initiating or maintaining conversations, participating in small groups, dating, speaking to anyone in authority. Exposure to the feared situation almost invariably provokes anxiety with similar symptoms to those experienced by patients with panic attacks, but some seem to be particularly prominent and difficult, i.e. blushing, tremor, sweating and a feeling of ‘drying up’ when speaking.
Treatment
The drugs with established efficacy are the SSRIs (especially sertraline, paroxetine and escitalopram) the MAOI phenelzine and the RIMA moclobemide in the same doses as for depression. These achieve equivalent degrees of improvement; phenelzine has a slightly faster onset of action but produces more adverse effects. Some benzodiazepines are reported to provide benefit but evidence for their therapeutic efficacy is less conclusive. Pregabalin has been shown to be effective in a recent trial in social anxiety disorder although higher doses are required than for generalised anxiety disorder. β-Adrenoceptor blockers continue to be widely used despite their having no proven efficacy in social phobia. But they have a place in the treatment of specific performance anxiety in, e.g., musicians, when management of the tremor is crucial.
The duration of treatment is as for depression or longer, for this can be a life-long condition.
Post-traumatic stress disorder (PTSD)
Symptoms characteristically follow exposure to an extreme traumatic stressor event. These include persistent re-experiencing of the traumatic event, persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness, and persistent symptoms of increased arousal. In taking a history the association with the event is usually obvious. PTSD is differentiated from acute stress disorder (below) by its persistence – the symptoms of the latter resolve within about 4 weeks. Depression quite commonly coexists with PTSD and should be enquired for in the history.
Treatment
is poorly researched; there have been no properly controlled trials and almost all open trials have been conducted on small numbers of patients long after the causative incident. The wide range of drugs that has been reported to provide benefit includes benzodiazepines, TCAs and MAOIs; paroxetine (SSRI) is now licensed for this indication in the UK. The preferred treatment immediately following the incident should probably be a short course of a hypnotic (or sedating antidepressant, e.g. mirtazapine) to promote sleep and help minimise mental rehearsal of the trauma that may lead to its perpetuation. Long-term therapy with antidepressants appears to be indicated at doses in the same range as for other anxiety disorders.
Acute stress disorder/adjustment disorder
Acute stress disorder is anxiety in response to a recent extreme stress. Although in some respects it is a normal and understandable reaction to an event, the problems associated with it are not only the severe distress the anxiety causes but also the risk that it may evolve into a more persistent state.
Treatment
A benzodiazepine used for a short time is the preferred approach for treating overwhelming anxiety that needs to be brought rapidly under control. It particularly relieves the accompanying anxiety and sleep disturbance. A drug with a slow onset of action such as oxazepam (60–120 mg/day) causes less dependence and withdrawal, and is preferred to those that enter the brain rapidly, e.g. diazepam, lorazepam. Some patients find it hard to discontinue the benzodiazepine, so its use should be reserved for those in whom extreme distress disrupts normal coping strategies.
Generalised anxiety disorder (GAD)
The essential feature of this condition is chronic anxiety and worry. To the non-sufferer the focus of the worry often seems to be trivial, e.g. getting the housework done or being late for appointments, but to the patient it is insurmountable. The anxiety is often associated with other symptoms, which include restlessness, difficulty in concentrating, irritability, muscle tension and sleep disturbance. The course of the disorder is typically chronic with exacerbations at times of stress, and is often associated with depression. Its chronic nature with worsening at times of stress helps to distinguish GAD from anxiety in the form of episodic panic attacks with associated anticipatory anxiety (panic disorder). Hyperthyroidism and caffeinism should also be excluded.
Treatment
Historically benzodiazepines have been seen as the most effective treatment for GAD for they rapidly reduce anxiety and improve sleep and somatic symptoms. Consequently patients like taking them, but the chronic nature of GAD raises issues of duration of treatment, tolerance, dependence and withdrawal reactions. Another sedative drug, the antihistamine hydrozyzine, is also used in GAD but excessive sedation can be an issue.
Buspirone is structurally unrelated to other anxiolytics and was the first non-benzodiazepine to demonstrate efficacy in GAD. While its mode of action is not well understood, it is a 5HT1A-receptor partial agonist and over time produces anxiolysis without undue sedation. Buspirone is generally less effective and slower in action than benzodiazepines and does not improve sleep; it does not benefit benzodiazepine withdrawal symptoms but has the advantages that it does not seem to cause dependence or withdrawal reactions and does not interact with alcohol. It is less effective in patients who have previously received benzodiazepines and is therefore probably best reserved for benzodiazepine-naïve patients. A disadvantage is that useful anxiolytic effect is delayed for 2 or more weeks.
Paroxetine, escitalopram and sertraline (SSRIs) and venlafaxine and duloxetine (SNRI) are effective (and are licensed for GAD in the UK), and some TCAs have also been shown to give benefit, and are more efficacious than buspirone or benzodiazepines. These drugs have a slower onset of action than benzodiazepines, are less well tolerated but cause fewer problems of dependence and on withdrawal. Recently pregabalin (an analogue of gabapentin), which is known to block a certain type of calcium channel, has received a licence for GAD. It is thought to reduce overactive synaptic activity in the brain possibly involving the transmitter glutamate. It works more slowly than the benzodiazepines, though faster than SSRIs. Despite its name it does not have any effect on the neurotransmitter GABA.
A delayed response in GAD is not as problematic as with acute situational anxiety. A sensible approach is to start with an antidepressant (SSRI or venlafaxine) for 6–8 weeks at least, increasing over 2–3 weeks to minimise unwanted actions; patients should be warned not to expect an immediate benefit. Those who do not respond should receive either buspirone for 6–8 weeks at full therapeutic dose (possibly as an add-on) or pregabalin. There remain some patients, including those with a long history of benzodiazepine use, who yet fail to respond. A benzodiazepine may be the only medication that provides relief for such resistant cases, and can be used as the sole treatment.
The duration of therapy depends on the nature of the underlying illness. If symptoms are intermittent, i.e. triggered by anxiety-provoking situations, then intermittent use of a benzodiazepine (for a few weeks) may be sufficient. More typically GAD requires treatment over 6–8 months with gradual withdrawal of medication thereafter. This may suffice but some patients experience severe, unremitting anxiety and the best resort is to chronic maintenance treatment with a benzodiazepine (analogous to long-term drug use in epilepsy). Such clinically supervised benzodiazepine use is justified because, without treatment, patients often resort to alcohol.
Simple phobia
A specific phobia is a fear of a circumscribed object or situation, for instance fear of spiders, of flying, of heights. The diagnosis is not usually in doubt. A course of treatment by a trained therapist, involving graded exposure to the feared stimulus is the treatment of choice and can be very effective. By its nature such therapy generates severe anxiety and a benzodiazepine (or prior treatment with an SSRI, e.g. paroxetine) may be necessary to allow patients to engage in therapy.
Obsessive–compulsive disorder (OCD)
Obsessive–compulsive disorder has two main components:
• The repetition of acts or thoughts which are involuntary, recognised by the sufferer to be generated by their own brain but unwanted, irrational, and out of keeping with their morals or values, and so very distressing.
• Anxiety provoked by the occurrence of such thoughts, or by prevention of the compulsive acts.
OCD on its own often starts in adolescence and has a chronic and pervasive course unless treated. OCD starting later on in life is often associated with affective or anxiety disorders. Symptoms often abate briefly if the individual is taken to a new environment.
Treatments
are cognitive behavioural therapy and an SSRI or clomipramine (i.e. antidepressants that enhance serotonergic function), used at higher doses and for much longer periods than for depressive disorders. Atypical antipsychotics or haloperidol in low dose and benzodiazepines can be used successfully to augment the SSRIs if they are not wholly effective, especially in patients with tics. Psychosurgery is still occasionally used for severe and treatment-resistant cases, though deep brain stimulation techniques are superseding it. Interestingly the brain pathway targeted is one that recent neuroimaging studies of OCD have revealed as overactive, namely the basal ganglia/orbitofrontal pathway.
General comments about treating anxiety disorders (Table 20.7)
• There is need to discuss the benefits and risks of specific treatments with patients before treatment and take account of their clinical features, needs, preferences and availability of local services when choosing treatments.
• SSRIs are usually effective in anxiety disorders and are generally suitable for first-line treatment.
• Benzodiazepines are effective in many anxiety disorders but their use should be short term except in treatment-resistant cases.
• SNRIs, TCAs, MAOIs, pregabalin and antipsychotics need to be considered in relation to their evidence base for specific conditions and their individual risks and benefits.
• With all antidepressants, especially SSRIs and SNRIs, there should be specific discussion and monitoring of possible adverse effects early in treatment, and also on stopping the drugs after a week of treatment; this latter also applies to benzodiazepines.
• SSRI/SNRI treatment is often slow to produce the therapeutic effect, and it is advisable to wait 12 weeks to assess efficacy.
• In a first episode, patients may need medication for at least 6 months, withdrawing over a further 4–8 weeks if they are well. Those with recurrent illness may need treatment for 1–2 years to enable them to learn and put into place psychological approaches to their problems. In many cases the illness is life-long and chronic maintenance treatment is justified if it significantly improves their well-being and function.
• Specific psychological treatments are also effective in treatment.
• When initial treatments fail, consider switching to another evidence-based treatment, combining evidence-based treatments (only when there are no contraindications), and referring to regional or national specialist services in refractory patients.
Table 20.7 Properties of anti-anxiety drugs
Sleep disorders
Normal sleep
Humans spend about a third of their lives asleep, but why we sleep is not yet fully understood. Sleep is a state of inactivity accompanied by loss of awareness and a markedly reduced responsiveness to environmental stimuli. The time of falling asleep is determined by three factors, which in normal sleepers occur at bedtime. These are: (1) circadian rhythm, i.e. the body's natural clock in the hypothalamus triggers the rest/sleep part of the sleep–wake cycle; (2) ‘tiredness’, i.e. time since last sleep, usually about 16 h, which is in part mediated by the build-up of sleep-promoting chemicals in the brain; and (3) lowered mental and physical arousal. If one of these processes is disrupted then sleep initiation is difficult, and it is these three factors that are addressed by standard teaching of good sleep habits (see below).
Types of sleep disorder
Several types of sleep disorder are recognised, and their differentiation is important; a simplified summary is given below but reference to DSM-IV, ICD-10 and ICSD4 will clarify the exact diagnostic criteria:
• Insomnia: not enough sleep or sleep of poor quality; problems of falling asleep (initial insomnia) or staying asleep (maintenance insomnia), or waking too early.
• Hypersomnia: excessive daytime sleepiness.
• Parasomnia: unusual happenings in the night:
nightmares
night terrors
sleep walking
REM behaviour disorder.
• Other, e.g.:
sleep scheduling disorders (circadian rhythm disorder)
restless legs syndrome
periodic leg movements of sleep.
Insomnia
Insomnia is the complaint of poor sleep, with difficulty either in initiating sleep or maintaining sleep throughout the night, and causing significant distress and impairment in social, occupational or other important areas of functioning. It is by far the most common sleep disorder, with 7–10% of adults fulfilling these diagnostic criteria in surveys. It can occur exclusively in the course of a physical disorder such as pain, a mental disorder such as depression, or a sleep disorder such as restless legs syndrome, or it can be a primary sleep disorder. One survey showed similar deficits in quality of life in insomniacs as in patients with long-term disorders such as diabetes.
Insomnia may or may not be accompanied by daytime fatigue, but is not usually accompanied by subjective sleepiness during the day. If sleep propensity in the daytime is measured by objective means (time to EEG sleep), these patients are in fact less sleepy (take longer to fall asleep) than normal subjects.
A summary of precipitating factors for insomnia is shown in Box 20.1.
Box 20.1 Precipitating factors for insomnia
Psychological
• Hyperarousal due to: stress
• The need to be vigilant at night because of sick relatives or young children
• Being ‘on call’.
Psychiatric
• Patients with depressive illnesses often have difficulty falling asleep at night and complain of restless, disturbed and unrefreshing sleep, and early morning waking. When their sleep is analysed by polysomnography, time to sleep onset is indeed prolonged, and there is a tendency for more REM sleep to occur in the first part of the night, with reduced deep quiet sleep in the first hour or so after sleep onset, and increased awakenings during the night. They may wake early in the morning and fail to get back to sleep again.
• Anxiety disorders may cause patients to complain about their sleep, either because there is a reduction in sleep continuity or because normal periods of nocturnal waking are somehow less well tolerated. Nocturnal panic attacks can make patients fearful of going off to sleep.
• Bipolar patients in the hypomanic or manic phase will sleep less than usual, and often changes in sleep pattern give early warning that an episode is imminent.
Pharmacological
• Non-prescription drugs such as caffeine or alcohol. Alcohol reduces the time to onset of sleep, but disrupts sleep later in the night. Regular and excessive consumption disrupts sleep continuity; insomnia is a key feature of alcohol withdrawal. Excessive intake of caffeine and theophylline, in tea, coffee or cola drinks, also contributes to sleeplessness, probably because caffeine acts as an antagonist to adenosine, the endogenous sleep-promoting neurotransmitter.
• Starting treatment with certain antidepressants, especially serotonin reuptake inhibitors (e.g. fluoxetine, fluvoxamine), or monoamine uptake inhibitors; sleep disruption is likely to resolve after 3–4weeks.
• Other drugs that increase central noradrenergic and serotonergic activity include stimulants, such as amfetamine, cocaine and methylphenidate, and sympathomimetics, such as the β-adrenergic agonist salbutamol and associated substances.
• Withdrawal from hypnotic drugs; this is usually short lived.
• Treatment with β-adrenoceptor blockers may disrupt sleep, perhaps because of their serotonergic action; a β-blocking drug that crosses blood–brain barrier less readily is preferred, e.g. atenolol.
Physical
• Pain, in which case adequate analgesia will improve sleep.
• Pregnancy.
• Coughing or wheezing: adequate control of asthma with stimulating drugs as above, may paradoxically improve sleep by reducing waking due to breathlessness.
• Respiratory and cardiovascular disorders.
• Need to urinate; this may be affected by timing of diuretic medication.
• Neurological disorders, e.g. stroke, movement disorders.
• Periodic leg movements of sleep (frequent jerks or twitches during the descent into deeper sleep); rarely reduce subjective sleep quality but are more likely to cause them in the subject's sleeping partner.
• Restless legs syndrome (irresistible desire to move the legs), which is usually worse in the evening and early night, and can prevent sleep.
Timely treatment of short-term sleep disturbance is valuable, as it may prevent progression to a chronic condition, which is much harder to alleviate. Approach is:
• Treat any precipitating cause (see above).
• Educate and reassure.
• Establish good sleep habits.
Keep regular bedtimes and rising times.
Avoid daytime napping.
Daytime (but not evening) exercise and exposure to daylight.
Avoid stimulants, alcohol and cigarettes in the evening.
Establish bedtime routine: ‘wind-down’ – a milk drink may be helpful.
Avoid dwelling on problems in bed – set aside a time early in the evening for planning.
Bed should be comfortable.
• Consider hypnotic medication.
In the treatment of chronic insomnia the most important factor is anxiety about sleep, arising from conditioning behaviours that predispose to heightened arousal and tension at bedtime. Thus the bedroom is associated with not sleeping, and automatic negative thoughts about the sleeping process occur in the evening. Cognitive behavioural therapy for insomnia (CBTi), if available, is an effective treatment for insomnia delivered either individually or in small group format and has been found to be as effective as prescription medications for short-term treatment of chronic insomnia. Moreover, there are indications that the beneficial effects of CBT may last well beyond the termination of active treatment. Cognitive behavioural therapists help the patient to change behaviour and thoughts about sleep, particularly concentrating on learned, sleep-incompatible behaviours and automatic negative thoughts at bedtime.
Drugs for insomnia
Sleep–wake function involves a complex balance between arousing and sleep-inducing physiological systems. Current research suggests that arousal and wakefulness are promoted by parallel neurotransmitter systems whose cell bodies are located in brainstem or midbrain centres, with projections to the thalamus and forebrain. These activating neurotransmitters are noradrenaline/norepinephrine, serotonin, acetylcholine, dopamine and histamine. In addition the newly discovered orexin system with cell bodies in the hypothalamus promotes wakefulness through regulating arousal ‘pathways’ (and inhibiting sedative ones). For all these arousal neurotransmitters, sleep can be promoted by blocking their post-synaptic actions, leading to reduced arousal. For example many over-the-counter sleep-promoting agents contain antihistamines, which block the histamine H1-receptor and so decrease arousal. The relatively low efficacy of these compounds may be explained by the fact that they target only one of the parallel arousal systems. The same is true for any drug which blocks one of the other arousal systems; they produce a degree of sedation but are not generally effective hypnotics.
The promotion of sleep is regulated by a number of other neurotransmitters; primary among these is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. The majority of brain cells are inhibited by GABA so increasing its function reduces arousal and produces sleep, and eventually anaesthesia. There are many subsets of GABA neurones distributed throughout the brain but a particular cluster in the hypothalamus (ventrolateral preoptic nucleus) can be considered to be the sleep ‘switch’.5 These neurones switch off brain arousal systems at the level of the cell bodies and therefore promote sleep. GABA receptors in the cortex can also promote sedation and sleep by inhibiting the target neurones of the arousal system. Most drugs used in insomnia act by increasing the effects of GABA at the GABAA receptor.
The GABAA–benzodiazepine receptor complex
γ-Aminobutyric acid (GABA) is the most important inhibitory transmitter in the central nervous system, comprising up to 40% of all synapses. GABAergic neurones are distributed widely in the CNS and GABA controls the state of neuronal excitability in all brain areas. The balance between excitatory inputs (mostly glutamatergic) and inhibitory GABAergic activity determines neuronal activity. If the balance swings in favour of GABA, then sedation, amnesia, muscle relaxation and ataxia appear and nervousness and anxiety are reduced. The mildest reduction of GABAergic activity (or increase in glutamate) elicits arousal, anxiety, restlessness, insomnia and exaggerated reactivity.
When GABA binds with the GABAAreceptor, the permeability of the central pore of the receptor complex opens, so allowing more chloride ions into the neurone and decreasing excitability. Classical benzodiazepines (BZDs) in clinical use bind to another receptor on the complex (the benzodiazepine receptor) and enhance the effectiveness of GABA, producing a larger inhibitory effect (Fig. 20.5). These drugs are agonists at the receptor and an antagonist, flumazenil, prevents agonists from binding at the receptor site; it is used clinically to reverse benzodiazepine actions.
Fig. 20.5 Schematic representation of the binding sites on the GABAA–benzodiazepine receptor complex. Note that drugs binding to the benzodiazepine (BZD) receptor site do not open the chloride channel directly, but rather augment the capacity of GABA to do so. Conversely agents such as the barbiturates both potentiate GABA and at higher concentrations have a direct effect on the chloride channel. This explains why barbiturates and alcohols are more toxic in overdose than the benzodiazepines.
Benzodiazepines
A general account of the benzodiazepines is appropriate here, although their indications extend beyond use as hypnotics. All benzodiazepines, and newer benzodiazepine-like drugs such as zopiclone and zolpidem, are safe and effective for insomnia if the substance with the right timing of onset of action and elimination is chosen. They should not be used for patients with sleep-related breathing disorders such as obstructive sleep apnoea (see below) which is exacerbated by benzodiazepines. Objective measures of sleep show that they decrease time to sleep onset and waking during the night. They also improve subjective sleep. Other changes in sleep architecture are to some extent dependent on duration of action, with the very short-acting compounds having the least effect. Most commonly very light (stage 1) sleep is decreased, and stage 2 sleep is increased. Higher doses of longer-acting benzodiazepines partially suppress slow wave sleep.
Pharmacokinetics
Benzodiazepines are effective after administration by mouth but enter the circulation at very different rates that are reflected in the speed of onset of action, e.g. alprazolam is rapid, oxazepam is slow (Table 20.8). Hepatic breakdown produces metabolites, some with long t½ which greatly extend drug action, e.g. chlordiazepoxide, clorazepate and diazepam all form demethyldiazepam (t½ 80 h).
Table 20.8 Properties of drugs used for insomnia
Uses
Oral benzodiazepines are used for: insomnia, anxiety, alcohol withdrawal states, muscle spasm due to a variety of causes, including tetanus and cerebral spasticity. Injectable preparations are used for rapid tranquillisation in psychosis (see previous section), anaesthesia and sedation for minor surgery and invasive investigations (see Index). The choice of drug as hypnotic and anxiolytic is determined by pharmacokinetic properties (see before, and Table 20.7).
Doses
Oral doses appear in Table 20.8.
Tolerance
to the anxiolytic effects does not seem to be a problem. In sleep disorders the situation is not so clear; studies of subjective sleep quality show enduring efficacy, and the necessity for dose escalation in sleep disorders is rare, but the objective sleep effects have not been studied systematically over weeks and months.
Dependence
Both animal and human research has shown that brain GABAA receptors do change in function during chronic treatment with benzodiazepines, and therefore will take time to return to pre-medication status after cessation. Features of withdrawal and dependence vary. Commonly there is a kind of psychological dependence based on the fact that the treatment works to reduce patients’ anxiety or sleep disturbance, and therefore they are unwilling to stop. If they do stop, there can be relapse, where original symptoms return. There can also be a rebound of symptoms, particularly after stopping hypnotics, with a worsening of sleep disturbance for one or two nights, longer sleep onset latency and increased waking during sleep – this is common. In anxiety disorders there may be a few days of increased anxiety and edginess which then resolves, probably in 10–20% of patients. More rarely, there is a longer withdrawal syndrome that is characterised by the emergence of symptoms not previously experienced, e.g. agitation, headache, dizziness, dysphoria, irritability, fatigue, depersonalisation, hypersensitivity to noise and visual stimuli. Physical symptoms include nausea, vomiting, muscle cramps, sweating, weakness, muscle pain or twitching and ataxia. After prolonged high doses abrupt withdrawal may cause confusion, delirium, psychosis and convulsions. The syndrome is ameliorated by resuming medication but resolves in weeks; in a very few patients it persists, and these people have been the subject of much research, mainly focusing on their personality and cognitive factors.
Withdrawal
of benzodiazepines should be gradual after as little as 3 weeks’ use, but for long-term users it should be very slow, e.g. about ⅛ of the dose every 2 weeks, aiming to complete it in 6–12 weeks. Withdrawal should be slowed if marked symptoms occur and it may be useful to substitute a long t½ drug (diazepam) to minimise rapid fluctuations in plasma concentrations. Abandonment of the final dose may be particularly distressing. In difficult cases withdrawal may be assisted by concomitant use of an antidepressant.
Adverse effects
In addition to the above, benzodiazepines affect memory and balance. Hazards with car driving or operating machinery can arise from sedation, amnesia and impaired psychomotor function. Amnesia for events subsequent to administration occurs with high doses given i.v., e.g. for endoscopy, dental surgery (with local anaesthetic), cardioversion, and in these situations it can be regarded as a blessing. Paradoxical behaviour effects and perceptual disorders, e.g. hallucinations occur occasionally. Headache, giddiness, alimentary tract upsets, skin rashes and reduced libido can occur.
Benzodiazepines in pregnancy
Benzodiazepines should be avoided in early pregnancy as far as possible as their safety is not established with certainty. Safety in pregnancy is not only a matter of avoiding prescription during an established pregnancy, for individuals may become pregnant on long-term therapy. Benzodiazepines cross the placenta and can cause fetal cardiac arrhythmia, muscular hypotonia, poor suckling, hypothermia and respiratory depression in the newborn.
Interactions
The benzodiazepines offer scope for adverse interaction with numerous agents but the underlying mechanisms can be summarised. The principal pharmacodynamic interaction of concern is exacerbation of sedation with other centrally depressant drugs including, antidepressants, H1-receptor antihistamines, antipsychotics, opioids, alcohol and general anaesthetics. All are likely to exacerbate breathing difficulties where this is already compromised, e.g. in obstructive sleep apnoea. Unexpected hypotension may occur with any co-prescribed antihypertensive drug, and vasodilators, e.g. nitrates.
Pharmacokinetic interactions occur with drugs that slow metabolism by enzyme inhibition, e.g. ritonavir, indinavir, itraconazole, olanzapine, cimetidine, fluvoxamine, erythromycin, increasing benzodiazepine effect. By contrast, acceleration of metabolism, lowering of plasma concentration and reduced effect occur with enzyme inducers, e.g. rifampicin.
Overdose
Benzodiazepines are remarkably safe in acute overdose and even 10 times the therapeutic dose only produces deep sleep from which the subject is easily aroused. It is said that there is no reliably recorded case of death from a benzodiazepine taken alone by a person in good physical (particularly respiratory) health, which is a remarkable tribute to their safety (high therapeutic index); even if the statement is not absolutely true, death must be extremely rare. But deaths have occurred in combination with alcohol (which combination is quite usual in those seeking to end their own lives) and opiates, e.g. buprenorphine and methadone. Flumazenil selectively reverses benzodiazepine effects and is useful in diagnosis, and in treatment (see below).
Benzodiazepine antagonist
Flumazenil is a highly selective competitive antagonist at benzodiazepine receptors so does not oppose sedation due to non-benzodiazepines, e.g. barbiturates, alcohol.
Clinical uses include reversal of benzodiazepine sedation after endoscopy, dentistry and in intensive care. Heavily sedated patients become alert within 5 minutes. The t½ of 1 h is much shorter than that of most benzodiazepines (see Table 20.7), so that repeated i.v. administration may be needed to maintain the effect. Thus the recovery period needs supervision lest sedation recurs; if used in day surgery it is important to tell patients that they may not drive a car home. The dose is 200 micrograms by i.v. injection given over 15 s, followed by 100 micrograms over 60 s if necessary, to a maximum of 300–600 micrograms. Flumazenil is useful for diagnosis of self-poisoning, and also for treatment, when 100–400 micrograms are given by continuous i.v. infusion and adjusted to the degree of wakefulness.
Adverse effects can include brief anxiety, seizures in epileptics treated with a benzodiazepine and precipitation of withdrawal syndrome in dependent subjects.
Non-benzodiazepine hypnotics that act at the GABAA-benzodiazepine receptor
Although structurally unrelated to the benzodiazepines, these drugs act on the same receptor, so their effects can be blocked by flumazenil, the receptor antagonist. Those described below are all effective in insomnia, have low propensity for tolerance, rebound insomnia, withdrawal symptoms and abuse potential. Data from long-term studies suggests these agents are safe and effective over at least 12 months. Withdrawal effects similar to the benzodiazepines hypnotics occur but to a lesser extent.
Zopiclone, a cyclopyrrolone, has an onset of action that is relatively rapid (about 1 h) and that lasts for 6–8 h, making it suitable for both initial and maintenance treatment of insomnia. It may cause fewer problems on withdrawal than benzodiazepines. The duration of action is prolonged in the elderly, and in hepatic insufficiency. About 40% of patients experience a metallic aftertaste (genetically determined). People who take zopiclone have been shown to be at increased risk of road traffic accidents. Care should be taken with concomitant medication that affects its metabolic pathway (see Table 20.2A).
Zolpidem is an imidazopyridine, and has a faster onset (30–60 min) and shorter duration of action. In patients over 80 years clearance is slower and action longer lasting.
Zaleplon, a pyrazolopyrimidine, has a fast onset and short duration of action. In volunteers, it appeared to have no effect on psychomotor (including driving) skills when taken at least 5 h before testing. It may be taken during the night when the patient has awoken and cannot get back to sleep, as long as this is at least 5 h before having to drive.
Other drugs that act on the GABAA-benzodiazepine receptor
Chloral hydrate, clomethiazole and barbiturates also enhance GABA function, but at high doses have the additional capacity directly to open the membrane chloride channel; this may lead to potentially lethal respiratory depression and explains their low therapeutic ratio. These drugs also have a propensity for abuse/misuse and thus are very much second-line treatments.
Chloral hydrate has a fast (30–60 min) onset of action and 6–8 h duration of action. Chloral hydrate, a prodrug, is rapidly metabolised by alcohol dehydrogenase into the active hypnotic trichloroethanol (t½ 8 h). Chloral hydrate is dangerous in serious hepatic or renal impairment, and aggravates peptic ulcer. Interaction with ethanol is to be expected since both are metabolised by alcohol dehydrogenase. Alcohol (ethanol) also appears to induce the formation of trichloroethanol which attains higher concentrations if alcohol is taken, increasing sedation. Triclofos and chloral betaine are related compounds.
Clomethiazole is structurally related to vitamin B1 (thiamine) and is a hypnotic, sedative and anticonvulsant. When taken orally, it is subject to extensive hepatic first-pass metabolism (which is defective in the old and in liver-damaged alcoholics who exhibit higher peak plasma concentrations); the t½ is 4 h. It may also be given i.v. It is comparatively free from hangover but it can cause nasal irritation and sneezing. Dependence occurs and use should always be brief.
Barbiturates are hardly ever used as they have a low therapeutic index, i.e. relatively small overdose may endanger life; they also cause dependence and have been popular drugs of abuse.
Other drugs used in insomnia
Antihistamines. Most proprietary (over-the-counter) sleep remedies contain H1-receptor antihistamines with sedative action (see Ch. 9). Promethazine (Phenergan) has a slow (1–2 h) onset and long duration of action (t½ 12 h). It reduces sleep onset latency and awakenings during the night after a single dose, but there have been no studies showing enduring action. It is sometimes used as a hypnotic in children. There are no controlled studies showing improvements in sleep after other antihistamines. Alimemazine (trimeprazine) is used for short-term sedation in children. Most antihistamine sedatives have a relatively long action and may cause daytime sedation.
Antidepressants. In the depressed patient, improvement in mood is almost always accompanied by improvement in subjective sleep, and therefore choice of antidepressant should not usually involve additional consideration of sleep effects. Nevertheless, some patients are more likely to continue with medication if there is a short-term improvement, in which case mirtazapine or trazodone may provide effective antidepressant together with sleep-promoting effects. Antidepressant drugs, particularly those with 5HT2-blocking effects, may occasionally be effective in long-term insomnia (but see Table 20.7). Antipsychotics have been used to promote sleep in resistant insomnia occurring as part of another psychiatric disorder, probably because of the combination of 5HT2-antagonism, α1-adrenoceptor antagonism and histamine H1-receptor antihistamine effects in addition to their primary dopamine antagonist effects. Their long action leads to daytime sedation, and extrapyramidal movement disorders may result from their blockade of dopamine receptors (see above, Antipsychotics). They therefore should be used with great care in the context of insomnia. Nevertheless, modern antipsychotics, e.g. quetiapine, are being used for intractable insomnia, usually at a dose well below the one required to treat psychosis, e.g. 25–50 mg/day.
Melatonin, the hormone produced by the pineal gland during darkness, has been investigated for insomnia. A prolonged release formulation is licensed for insomnia characterised by poor quality of sleep in people over 55 years, whose melatonin rhythm may be supposed to be reduced. Melatonin may also be used therapeutically to reset circadian rhythm to prevent jet-lag on long-haul flights, and for blind or partially sighted people who cannot use daylight to synchronise their natural rhythm.
Melatonin is metabolised mainly by CYP 1A enzymes and may interact with other active substances that affect these enzymes. For this reason it should not be taken with fluvoxamine, 5- or 8-methoxypsoralen, or cimetidine, and caution should be exercised in patients on oestrogens (e.g. contraceptive or hormone replacement therapy).
Herbal preparations. Randomised trials have shown some effect of valerian in mild to moderate insomnia.
Summary of pharmacotherapy for insomnia
• Drug treatment is usually effective for a short period (2–4 weeks).
• Some patients may need long-term medication.
• Intermittent medication which is taken only on nights that symptoms occur is desirable and may often be possible with modern, short-acting, compounds.
• Discontinuing hypnotic drugs is usually not a problem if the patient knows what to expect. There will be a short period (usually 1–2 nights) of rebound insomnia on stopping hypnotic drugs, which can be ameliorated by phased withdrawal.
Hypersomnia
Sleep-related breathing disorders
causing excessive daytime sleepiness are rarely treated with drugs. Sleepiness caused by the night-time disruption of sleep apnoea syndrome is sometimes not completely abolished by the standard treatment of continuous positive airway pressure overnight, and wake-promoting drugs, e.g. modafinil, may have a role in these patients.
Narcolepsy
is a chronic neurological disorder, characterised by excessive daytime sleepiness (EDS) and sleep attacks, usually accompanied by cataplexy (attacks of muscle weakness on emotional arousal). These symptoms are often associated with the intrusion into wakefulness of other elements of rapid eye movement (REM) sleep, such as sleep paralysis and hypnagogic hallucinations, i.e. in a transient state preceding sleep.
Stimulants are effective in the treatment of EDS due to narcolepsy. Modafinil is usually preferred as it is not a controlled drug, failing which methylphenidate or dexamfetamine are added or substituted. In narcolepsy, patients usually need a stimulant for their hypersomnia and an antidepressant for their cataplexy. Combining an SSRI antidepressant with modafinil has been shown to be safe, but dexamfetamine and methylphenidate must not be given with MAOIs. Cataplexy is most effectively treated with 5HT uptake-blocking drugs such as clomipramine or fluoxetine, or other antidepressant drugs, e.g. reboxetine, or the MAOI selegiline.
Modafinil is a wake-promoting agent whose specific mechanism of action is not properly known; it does not appear to be overtly stimulant like the amfetamines. Its onset of action is slow and lasts 8–12 h. Potential for abuse is low. Modafinil is used in narcolepsy and other hypersomnias (e.g. that with sleep apnoea), and also promotes wakefulness in normal people who need to stay awake for long periods, e.g. military personnel. Its use is associated with a wide variety of gastrointestinal, CNS and other unwanted effects; contraindications to its use include moderate to severe hypertension, a history of left ventricular hypertrophy or cor pulmonale. Modafinil accelerates the metabolism of oral contraceptives, reducing their efficacy.
Amfetamines release dopamine and noradrenaline/norepinephrine in the brain. This causes a behavioural excitation, with increased alertness, elevation of mood, increase in physical activity and suppression of appetite. Dexamfetamine, the dextrorotatory isomer of amfetamine, is about twice as active in humans as the laevo- isomer and is the main prescribed amfetamine. It is rapidly absorbed orally and acts for 3–24 h; most people with narcolepsy find twice a day dosing optimal to maintain alertness during the day. About 40% of narcoleptic patients find it necessary to increase their dose, suggesting some tolerance. Although physical dependence does not occur, mental and physical depression may develop following withdrawal.
Unwanted effects include edginess, restlessness, insomnia and appetite suppression, weight loss, and increase in blood pressure and heart rate. Amfetamines are commonly abused because of their stimulant effect but this is rare in narcolepsy. Contraindications to its use include moderate to severe hypertension, hyperthyroidism, and a history of drug or alcohol abuse.
Methylphenidate also promotes dopamine release but its principal action is to inhibit uptake of central neurotransmitters. Its effects and adverse effects resemble those of the amfetamines. Methylphenidate has a low systemic availability and slow onset of action, making it less liable to abuse. Its short duration of effect (3–4 h) requires that patients with narcolepsy need to plan the timing of tablet-taking to fit with daily activities. It is also used used in attention deficit/hyperactivity disorder (see below). Unwanted effects include anxiety, anorexia and difficulty sleeping; these usually subside. Methylphenidate reduces expected weight gain and has been associated with slight growth retardation. Monitoring of therapy should include height and weight, also blood pressure and blood counts (thrombocytopenia and leucopenia occur). It should not be used in patients with hyperthyroidism, severe angina, or cardiac arrhythmias.
Parasomnias
Nightmares
arise out of REM sleep and are reported by the patient as structured, often stereotyped dreams that are very distressing. Usually the patient wakes up fully and remembers the dream. Psychological methods of treatment may be appropriate, e.g. a programme of rehearsing the dream and inventing a different pleasant ending. Nightmares of a particularly distressing kind are a feature of post-traumatic stress disorder. Case reports indicate benefit from various pharmacological agents, but no particular drug emerges as superior.
Night terrors and sleep-walking
arise from slow wave sleep, and they are often coexistent. There is usually a history dating from childhood, and often a family history. Exacerbations commonly coincide with periods of stress, and alcohol increases their likelihood. In a night terror, patients usually sit or jump up from deep sleep (mostly in the first few hours of sleep ) with a loud cry, look terrified and move violently, sometimes injuring themselves or others. They appear asleep and uncommunicative, often returning to sleep without being aware of the event. These terrors are thought to be a welling up of anxiety from deep centres in the brain which is normally inhibited by cortical mechanisms. If the disorder is sufficiently frequent or disabling, night terrors respond to the SSRI paroxetine (also effective in sleepwalkers) or the benzodiazepine clonazepam.
REM behaviour disorder
first described in 1986, consists of lack of paralysis during REM sleep which results in brief acting out of dreams, often vigorously with injury to self or others. Rarely, it can occur acutely as a result of drug or alcohol withdrawal, or in patients taking high doses of antidepressants such as clomipramine, venlafaxine or mirtazapine. More commonly it is chronic and either idiopathic or associated with neurological disorder. It is much commoner among older patients and approximately 90% are male. It may be a very early prodrome to the onset of Parkinson's disease, Lewy body dementia or multiple system atrophy many years after its onset. Successful symptomatic relief has been described with clonazepam or clonidine.
Other sleep disorders
Restless legs syndrome (RLS) is a disorder characterised by disagreeable leg sensations usually prior to sleep onset, and an almost irresistible urge to move the legs. The sensation is described as ‘crawling’, ‘aching’, ‘tingling’ and is partially or completely relieved with leg motion returning after movement ceases. Most, if not all, patients with this complaint also have periodic limb movements of sleep (PLMS), which may occur independently of RLS. These periodic limb movements consist of highly stereotyped movements, usually of the legs, that occur repeatedly (typically every 20–40 s) during the night. They may wake the patient, in which case there may be a complaint of daytime sleepiness or occasionally insomnia, but often only awaken the sleeping partner, who is usually kicked. RLS may respond to formulations of levodopa or dopamine agonists.
Sleep scheduling disorders. Circadian rhythm disorders are often confused with insomnia and both can be present in the same patient. With such sleep scheduling disorders, sleep occurs at the ‘wrong’ time, i.e. at a time that does not fit with work, social or family commitments. A typical pattern may be a difficulty in initiating sleep for a few nights due to stress, whereupon once asleep the subject continues sleeping well into the morning to ‘catch up’ the lost sleep. Thereafter the ‘time since last sleep’ cue for sleep initiation is delayed, and the sleep period gradually becomes more delayed until the subject is sleeping in the day instead of at night. A behavioural programme with strategic light exposure is appropriate, with pharmacological treatment as an adjunct, e.g. melatonin, to help reset the sleep–wake schedule.
Drugs for Alzheimer's6 disease (dementia)
Dementia is described as a syndrome ‘due to disease of the brain, usually of chronic or progressive nature, in which there is disturbance of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement, without clouding of consciousness’.7 Deterioration in emotional control, social behaviour or motivation may accompany or precede cognitive impairment. Alzheimer's and vascular (multi-infarct) disease are the two most common forms of dementia, accounting for about 80% of presentations. Alzheimer's disease is associated with deposition of β-amyloid in brain tissue and abnormal phosphorylation of the intracellular tau (τ) proteins causing abnormalities of microtubule assembly and collapse of the cytoskeleton. Pyramidal cells of the cortex and subcortex are particularly affected.
In Western countries, the prevalence of dementia is less than 1% in those aged 60–64 years, but doubles with each 5-year cohort to a figure of around 16% in those aged 80–84 years. The emotional impact of dementia on relatives and carers and the cost to society in social support and care facilities are great. Hence the impetus for an effective form of treatment is compelling.
Evidence indicates that cholinergic transmission is diminished in Alzheimer's disease. The first three drugs available for use in Alzheimer's each act to enhance acetylcholine activity by inhibiting the enzyme acetylcholinesterase which metabolises and inactivates synaptically released acetylcholine. Consequently acetylcholine remains usable for longer. Individual drugs are categorised by the type of enzyme inhibition they cause. Donepezil is classed as a ‘reversible’ agent, as binding to the acetylcholinesterase enzymes lasts only minutes, whereas rivastigmine is considered ‘pseudo-irreversible’ as inhibition lasts for several hours. Galantamine is associated both with reversible inhibition and with enhanced acetylcholine action on nicotinic receptors.8 Clinical trials show that these agents produce an initial increase in patients’ cognitive ability. There also may be associated global benefits, including improvements in non-cognitive aspects such as depressive symptoms. But the drugs do not alter the underlying process, and the relentless progress of the disease is paralleled by a reduction in acetylcholine production with a decline in cognition.
A fourth drug licensed for use in Alzheimer's disease is memantine. Overactive glutamate signalling has been linked to cell death and this drug is known to be a glutamine modulator through antagonism of NMDA receptors. Initially thought to have an entirely novel mode of action related to its effects on dampening excess glutamate neurotransmission, subsequent work suggests that memantine does have additional activity as an acetylcholine stimulant.
The beneficial effects of drugs are therefore to:
• stabilise the condition initially and sometimes improve cognitive function
• delay the overall pace of decline (and therefore the escalating levels of support required)
• postpone the onset of severe dementia.
The severity of cognitive deficits in patients suffering from, or suspected of having, dementia can be quantified by a simple 30-point schedule, the mini mental state examination (MMSE) of Folstein. A score of 21–26 denotes mild, 10–20 moderate and less than 10 severe Alzheimer's disease. The MMSE can also be used to monitor progress.
In 2001 the view of the UK National Institute for Health and Clinical Excellence (NICE) was that, subject to certain conditions, the drugs available at that time should be available as adjuvant therapy for those with a MMSE score above 12 points. Subsequent guidelines first suggested that the cost:benefit ratio for the three anticholinesterase inhibitor drugs was favourable only in those with moderate dementia (MMSE score between 10 and 20 points), only for this limitation to be subsequently removed. Guidelines for prescribing anticholinesterase inhibitors also advise the following:
• Alzheimer's disease must be diagnosed and assessed in a specialist clinic; the clinic should also assess cognitive, global and behavioural functioning, activities of daily living, and the likelihood of compliance with treatment.
• Treatment should be initiated by specialists but may be continued by family practitioners under a shared-care protocol.
• The carers’ views of the condition should be sought before and during drug treatment.
• The patient should be assessed every 6 months and drug treatment should continue only if the MMSE score remains at or above 10 points and if treatment has had a worthwhile effect on global, behavioural and functional parameters.
Use of memantine in dementia is now supported by good quality evidence and it has been widely prescribed in the UK and many other countries. It enabled a reduction in the co-prescription of antipsychotic medication previously used for behavioural symptoms such as agitation and aggression. A small evidence base also suggests that the combination of memantine with an acetylcholinesterase inhibitor may be more effective than the acetylcholinesterase inhibitor alone.
Doses
are:
• Donepezil 5–10 mg nocte increasing to 10 mg nocte after 1 month.
• Galantamine 4 mg twice daily increasing to 8–12 mg twice daily at 4-week intervals.
• Rivastigmine 1.5 mg twice daily increasing to 3–6 mg twice daily at 2-week intervals.
• Memantine 5 mg daily increasing weekly by 5 mg to a maximum of 20 mg daily.
Adverse effects
of the three anticholinesterse inhibitors inevitably include cholinergic symptoms, with nausea, diarrhoea and abdominal cramps appearing commonly. There may also be bradycardia, sinoatrial or atrioventricular block. Additionally, urinary incontinence, syncope, convulsions and psychiatric disturbances occur. Rapid dose increase appears to make symptoms more pronounced. Hepatotoxicity is a rare association with donepezil.
Memantine has a different side-effect profile with constipation, hypertension, headache, dizziness and drowsiness being highlighted as the most common adverse effects. Memantine has been reported as having an association with seizures, which may be a consideration in patients who have had previous fits.
The deterioration of function in dementia of Alzheimer's disease is often accompanied by acute behavioural disturbance. Memantine and the acetylcholinesterase inhibitors may be helpful in controlling this but in severe cases or where psychotic symptoms are present treatment with antipsychotics may be required. Be aware that if a person with dementia has Lewy body disease rather than Alzheimer's, antipsychotics may worsen the presentation.
Drugs in attention deficit/hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) affects 5% of children and between 2% and 3% of adults in the UK (NICE 2008). ADHD is characterised by inattention, impulsivity and motor overactivity. For diagnostic purposes, symptoms should be present before the age of 7 years and cause pervasive impairment across situations, mostly (but not exclusively) school and home in children, and work and relationships in adults. Treatment of ADHD should be initiated only by a specialist and form part of a comprehensive treatment programme of psychological, educational and social measures.
Stimulant drugs are the first-choice treatment for ADHD in both children and adults (Table 20.9). Methylphenidate and dexamfetamine increase synaptic dopamine and noradrenaline/norepinephrine; dexamfetamine also blocks the reuptake of both neurotransmitters. Methylphenidate is the first-line treatment in the UK for ADHD; it is available both in conventional and extended release formulations which can be combined to obtain maximum therapeutic effect. Treatment in children is frequently restricted to school terms, giving the child a ‘drug holiday’ when out of school. Drug holidays are necessary to determine efficacy of treatment, adjust or change dosage and avoid tolerance effects. Treatment in adults is more complex as attentional requirements are often continuous, so drug holidays may not be possible. Dosage tends to be slightly higher and combinations of different psychotropic drugs are more common. Dexamfetamine is an alternative that has similar efficacy to methylphenidate in ADHD and is the preferred drug in children with epilepsy. It has a greater potential for abuse than methylphenidate.
Table 20.9 Summary of the main pharmacological treatments of ADHD in children and adults
Unwanted effects of stimulants include some slowing of growth, loss of appetite and sleep, irritability, increased blood pressure and occasionally other cardiovascular problems. Weight, blood pressure and pulse should be monitored in both adults and children. In children height should also be monitored to assess growth. Stimulants in instant release formulations can be abused and some have been diverted to intravenous injection; prodrug and retarded release formulations have recently been introduced to combat this problem. Both methylphenidate and dexamfetamine are controlled drugs in the UK (class B schedule 2 of the Misuse of Drugs Act), so prescribing restrictions apply.
Atomoxetine, a noradrenaline/norepinephrine reuptake inhibitor (like reboxetine), is now licenced for ADHD. It is thought to act by increasing noradrenaline/norepinephrine and dopamine availability in the frontal cortex (where dopamine is taken up into noradrenergic nerve terminals). It has no known abuse liability and is not a controlled drug. The α-adrenoceptor blocker clonidine, tricyclic antidepressants (TCAs), bupropion and the stimulant modafinil may have a role in ADHD where methylphenidate, dexamfetamine and atomoxetine are contraindicated or have failed to produce benefit.
Drugs for psychiatric illness in childhood
Children do suffer psychiatric illnesses. Many drugs used in childhood psychiatric illness are not properly tested in young people. Now there are regulatory pressures for drugs (in general) to have safety tests in children subsequent to their licensing in adults. Some drugs are deemed not to have adequate risk:benefit ratios in children, e.g. in depression most SSRI drugs are not recommended (an exception is fluoxetine for which evidence of efficacy and safety in children does exist). Similar caveats apply to the use of TCAs in childhood. By contrast, there are good efficacy data for several SSRIs in obsessive–compulsive disorder and social anxiety disorder, and for benefit of risperidone for aggression in children with autism.
Summary
Table 20.10 summarises indications of the major groups of psychotropic drugs. Remember that psychiatric illnesses are often associated with co-morbid conditions, which may themselves require treatment; for example, schizophrenia may be associated with depression, so both antipsychotics and antidepressants may be required.
Table 20.10 Summary of indications for psychotropic drugs
Guide to further reading
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Ballenger J.C., Davidson J.R.T., Lecrubier Y., et al. Consensus statement on social anxiety disorder from the International Consensus Group on Depression and Anxiety. J. Clin. Psychiatry. 1998;59:54–60.
Ballenger J.C., Davidson J.R.T., Lecrubier Y., et al. Consensus statement on posttraumatic stress disorder from the International Consensus Group on Depression and Anxiety. J. Clin. Psychiatry. 2000;61:60–66.
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Heyman I., Mataix-Cols D., Fineberg N.A. Obsessive–compulsive disorder. Br. Med. J.. 2006;333:424–429.
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Lieberman J.A., Mataix-Cols D., Fineberg N.A., for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 2005;353(12):1209–1223.
Mann J.J. The medical management of depression. N. Engl. J. Med.. 2005;353(17):1819–1834.
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8 Irreversible antagonists exist but, not surprisingly, are not used in therapeutics (sarin nerve gas is an example).