Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 30 Treatment of Affective Disorders

MAJOR DRUG CLASSES

Antidepressants

Tricyclic antidepressants

Serotonin selective reuptake inhibitors

Serotonin/norepinephrine reuptake inhibitors

Atypical antidepressants

Monoamine oxidase inhibitors

Drugs for bipolar disorder

Lithium

Anticonvulsants

Atypical antipsychotics

Therapeutic Overview

Depression is a heterogeneous disorder that involves bodily functions, moods, and thoughts and is characterized by feelings of sadness, anxiety, guilt, and worthlessness; disturbances in sleep and appetite; fatigue and loss of interest in daily activities; and difficulties in concentration. In addition, individuals with depression are often obsessed with suicidal ideations. Symptoms of depression can last for weeks, months, or years, and depression is a major cause of morbidity and mortality. In any given year, 9.5% of the population (approximately 18.8 million adults in the United States) suffers from a depressive illness, and depression is a factor in more than 30,000 suicides per year in the United States, making it one of the most widespread of all life-threatening disorders. Although depression can affect any age, the current mean age of onset is 25 to 35 years. Of particular concern is that the rate of depression and suicide among children, adolescents, and the elderly is increasing at an alarming pace and often goes unrecognized.

Depression is a symptom of many different illnesses. It may arise as a result of substance abuse (alcohol, steroids, cocaine, etc.), a medical illness (pancreatic carcinoma, hypothyroidism, etc.), or a major life stress event. However, it may also arise from unknown causes.

Three of the most important psychiatric illnesses that present with depressive symptoms are major depression, dysthymia, and bipolar depression. Major depression (also referred to as unipolar depression) may be totally disabling (interfering with work, sleeping, and eating); episodes may occur several times during a lifetime and may progress to psychosis. Dysthymia is less severe and involves long-term chronic symptoms that do not disable but keep a person from functioning at his or her highest level. Finally, bipolar disorder (manic-depressive disease) is a syndrome in which there are cycling mood

Abbreviations

DA

Dopamine

5-HT

Serotonin

MAO

Monoamine oxidase

MAOI

Monoamine oxidase inhibitor

NE

Norepinephrine

SNRI

Serotonin/norepinephrine reuptake inhibitor

SSRI

Serotonin selective reuptake inhibitor

TCA

Tricyclic antidepressant

changes characterized by severe highs and gut-wrenching lows, which may worsen to a psychotic state. In addition, depression is often associated with comorbid anxiety disorders.

Major depression, dysthymia, and the depression associated with anxiety disorders are treated with compounds classified as antidepressants. These compounds fall into three broad categories:

• The amine reuptake inhibitors, which include the tricyclic antidepressants (TCAs), the serotonin selective reuptake inhibitors (SSRIs), and the serotonin/norepinephrine reuptake inhibitors (SNRIs).

• The atypical antidepressant drugs, which represent a heterogeneous group of compounds.

• The monoamine oxidase inhibitors (MAOIs).

Although their specific mechanisms of action differ, these drugs all share the ability to increase monoaminergic neurotransmission in the brain, primarily increasing the activities of pathways usingserotonin (5-HT) and norepinephrine (NE) and possibly dopamine (DA) as neurotransmitters.

Although the molecular and cellular etiology of depression remains unknown, it is generally accepted that depression involves impaired monoaminergic neurotransmission, leading to alterations in the expression of specific genes. This is supported by studies demonstrating that antidepressants increase the expression of the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) and brain-derived neurotrophic factor (BNDF), both of which are critical for maintaining normal cell structure in limbic regions of the brain that are targets for monoaminergic projections. In addition, postmortem and imaging studies have demonstrated neuronal loss and shrinkage in the prefrontal cortex and hippocampus in depressed patients, some of which could be reversed by antidepressants.

Within the past several years, as evidence of adult neurogenesis has become increasingly clear, the idea has emerged that depression may be caused by impaired neurogenesis in adult hippocampus. Studies have demonstrated that new neurons can proliferate from progenitor cells in the hippocampus, a process impaired by stress and stress hormones such as the glucocorticoids and enhanced by antidepressants. Furthermore it has been shown that neurogenesis is required for antidepressants to exert their behavioral effects in laboratory animals. Thus impaired monoaminergic transmission in specific brain regions may lead to a decreased expression of transcription or growth factors required for maintaining neurogenesis and perhaps increasing dendritic branching, resulting in depression.

In contrast to unipolar depression, bipolar disorder is characterized by depressive cycles with manic episodes, interspersed with periods of normal mood. The characteristics of the depressive phase resemble those of unipolar depression, whereas the manic phase manifests as increased psychomotor activity and grandiosity, feelings of euphoria, poor judgment and recklessness, extreme irritability, and symptoms sometimes resembling psychotic behavior. Bipolar disorder affects 2 million people in the United States, often begins in adolescence or early adulthood, and may persist for life. Evidence suggests a role for genetic factors, because the concordance rate in identical twins is 61% to 75%. However, the disorder cannot be attributed to a single major gene, suggesting multifactorial inheritance.

The treatment of bipolar disorder has changed over the past decade. Lithium has been the mainstay of treatment for many years, particularly for control of the manic phase. However, the anticonvulsants lamotrigine, valproic acid, and carbamazepine have been frequently used as well (see Chapter 34), especially in cases in which the bipolar disorder was characterized by rapid cycling. Recently, the atypical antipsychotic drugs aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone were approved as monotherapy for bipolar disorder (see Chapter 29). Antidepressants may also be warranted to treat the depressive phase of the illness.

The pharmacology of the antipsychotics is discussed in Chapter 29 and that of the anticonvulsants in Chapter 34. Therapeutic actions related to the antidepressants and lithium are summarized in the Therapeutic Overview Box.

Mechanisms of Action

The antidepressants may be generally classified according to their mechanisms of action as amine reuptake inhibitors, MAOIs, and mixed-action atypical drugs—the latter representing a heterogeneous group that includes compounds often referred to as second- or third-generation antidepressants.

Amine Reuptake Inhibitors and Atypical Antidepressants

The TCAs were the first group of antidepressants developed in the 1950s, and the prototypical compound imipramine

Therapeutic Overview

Antidepressants

Prolong the action of biogenic amines at the synapse by inhibiting amine reuptake, increasing amine release or decreasing amine catabolism

Enhance neurogenesis and dendritic branching in the adult hippocampus

Lithium

Interferes with receptor-activated phosphatidylinositol turnover; blocks the conversion of inositol phosphate to free inositol

Antagonizes 5-HT1A and 5-HT1B autoreceptors, alleviating feedback inhibition of 5-HT release

Enhances glutamate reuptake system, clearing glutamate from the synapse

was the first agent demonstrated to have antidepressant efficacy. The TCAs have a three-ring structure with a side chain containing a tertiary or secondary amine attached to the central ring, resembling the phenothiazine antipsychotics (Fig. 30-1). The tertiary amines include imipramine, amitriptyline, clomipramine, and doxepin; the secondary amines include desipramine and nortriptyline.

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FIGURE 30–1 Structures of prototypical antidepressants.

The TCAs block the reuptake of NE, 5-HT, or both into noradrenergic and/or serotonergic nerve terminals, respectively, by specific interactions with plasma membrane transporters (Fig. 30-2). As a consequence of this inhibition, the actions of NE and 5-HT released from these neurons are not rapidly terminated, resulting in a prolonged stimulation of NE receptors, 5-HT receptors, or both. The TCAs do not affect the reuptake of DA by dopaminergic nerve terminals, and their selectivity for NE versus 5-HT transporters differs among the different compounds (Table 30-1).

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FIGURE 30–2 A noradrenergic and serotonergic synapse and sites at which antidepressants may exert their actions. TCAs, SSRIs, and some atypical antidepressants inhibit the reuptake transporter for NE, 5-HT, or both. Monoamine oxidase, which is targeted by MAO inhibitors, is localized at the outer mitochondrial membrane.

TABLE 30–1 Relative Selectivity of Antidepressants for Amine Reuptake

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In addition to inhibiting NE and 5-HT reuptake, the TCAs also block muscarinic cholinergic receptors, α1 adrenergic receptors, and histamine H1 receptors. These actions underlie many of the side effects of these compounds.

The SSRIs and SNRIs also inhibit the reuptake of biogenic amines, and as their name implies, the SSRIs have the highest affinity for 5-HT transporters, whereas the SNRIs have high affinity for 5-HT transporters and moderate affinity for NE transporters. It is important to note, however, that specificity and selectivity are always dose-related such that the SSRIs sertraline and paroxetine inhibit both NE and DA reuptake at the upper end of their dose ranges (see Table 30-1). Similarly, it is also important to keep in mind that the classification of newly developed compounds is based on their affinity for specific transporters, whereas that of the TCAs is based on chemical structure. Thus, although clomipramine is classified chemically as a TCA, its ability and selectivity to inhibit 5-HT and NE reuptake matches that of the SSRI paroxetine. Likewise, the selectivity of the TCAs imipramine and amitriptyline resemble that of the SNRI duloxetine. Thus, at times, classification schemes may be misleading.

As mentioned, the atypical compounds are a very heterogeneous group of drugs. Among these, maprotiline and nefazodone are relatively selective inhibitors of NE reuptake (see Table 30-1). Trazodone is a weak inhibitor of 5-HT reuptake, bupropion weakly inhibits DA reuptake, and mirtazapine appears devoid of activity at any reuptake transporter.

Trazodone, nefazodone, mirtazapine, and several TCAs have also been shown to block 5-HT2A receptors with a high potency, and these drugs are at least fivefold more potent in vitro as antagonists of this receptor than as inhibitors of 5-HT reuptake. These receptors are widely distributed throughout the brain at regions containing 5-HT nerve terminals, and their stimulation produces depolarization. Interestingly, chronic antagonism of these receptors leads to their paradoxical down regulation, although the role of this mechanism in mediating the antidepressant actions of these compounds remains to be elucidated.

Mirtazapine also blocks α2 adrenergic receptors on noradrenergic and serotonergic nerve terminals and on noradrenergic dendrites (Fig. 30-3). Stimulation of α2 autoreceptors on noradrenergic neurons decreases NE release, whereas stimulation of α2 heteroreceptors on serotonergic neurons inhibits 5-HT release. In addition, stimulation of α1 adrenergic receptors on serotonergic cell bodies and dendrites increases their firing rate. Thus mirtazapine, by inhibiting α2 autoreceptors, enhances noradrenergic cell firing and the release of NE, which activates α1 adrenergic receptors to increase 5-HT release while concurrently blocking α2 heteroreceptors, further facilitating the release of 5-HT.

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FIGURE 30–3 Receptor mechanisms controlling NE and 5-HT release. 1, Stimulation of α2 adrenergic autoreceptors on NE nerve terminals decreases NE release by a negative feedback process. 2, Stimulation of α2 adrenergic heteroreceptors on 5-HT nerve terminals decreases 5-HT release. 3, Stimulation of α1 adrenergic receptors on 5-HT dendrites and perikarya increases the firing of 5-HT neurons. Thus a drug that blocks α2 but not α1 adrenergic receptors increases NE and 5-HT release.

Monoamine Oxidase Inhibitors

The MAOIs used for the treatment of depression are phenelzine and tranylcypromine (see Fig. 30-1) and the recently approved selegiline transdermal patch. Phenelzine and selegiline are irreversible MAO inhibitors, and tranylcypromine is a long-lasting MAO inhibitor. At the doses used for depression, all these compounds are nonselective and inhibit both MAO-A and MAO-B. These enzymes are distinct gene products with MAO-A present in human placenta, intestinal mucosa, liver, and brain—responsible for the catabolism of 5-HT, NE, and tyramine; and MAO-B present in human platelets, liver, and brain—responsible predominantly for the catabolism of DA and tyramine. These enzymes are located in the outer membrane of mitochondria and function to maintain low cytoplasmic concentrations of the monoamines, facilitating inward-directed transporter activity (i.e., monoamine reuptake). MAO inhibition causes an increase in monoamine concentrations in the cytosol of the nerve terminal. All the effects of the MAOIs have been attributed to enhanced aminergic activity resulting from enzyme inhibition.

Research with selective MAOIs has shown that inhibition of MAO-A is necessary for antidepressant activity. Thus, although selegiline is a selective inhibitor of MAO-B at low doses and is used at these doses for the treatment of Parkinson’s disease (see Chapter 28), at higher doses selectivity is lost, and selegiline inhibits both MAO-A and MAO-B and has antidepressant activity.

Lithium

Although lithium has been the standard prophylactic agent for the treatment of bipolar disorder for decades, its cellular mechanisms of action remain unclear. Currently, three actions of lithium have been postulated to mediate its clinical efficacy. The first is interference with receptor-activated phosphoinositide turnover (see Chapter 1). Lithium blocks the hydrolysis of inositol phosphate to free inositol, thereby reducing free inositol concentrations and depleting further formation of phosphatidylinositol in the cell membrane. Hence, the effects of agonists working through this signaling system will be blunted. Lithium has also been shown to inhibit 5-HT1A and 5-HT1B autoreceptors on serotonergic dendrites and nerve terminals, thereby preventing feedback inhibition of 5-HT release. Last, sustained lithium exposure enhances glutamate reuptake by glutamatergic neurons, thereby decreasing the time glutamate is present at glutamatergic synapses and dampening the ability of glutamate to stimulate its receptors. Clearly, additional studies are needed to elucidate the actions of lithium that underlie its unique efficacy in bipolar disorder.

Pharmacokinetics

Pharmacokinetic parameters of representative antidepressants are presented in Table 30-2. In general, antidepressants are readily absorbed, primarily in the small intestine, and undergo significant first-pass hepatic metabolism. Peak plasma concentrations are achieved within hours after ingestion, with steady-state concentrations achieved after 4 to 7 days at a fixed dose.

TABLE 30–2 Pharmacokinetic Parameters of Representative Antidepressant Drugs

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Most amine reuptake inhibitors and atypical antidepressants are extensively bound to plasma proteins, are oxidized by hepatic microsomal enzymes to inactive metabolites, and are excreted in the urine as glucuronides or sulfates. A small amount may be excreted in the feces via the bile. Some antidepressants, especially fluoxetine and the tertiary amine TCAs, are metabolized to active compounds, which themselves have antidepressant efficacy. For example, desipramine and nortriptyline are major metabolites of imipramine and amitriptyline, respectively. Nefazodone and trazodone are metabolized relatively rapidly into active compounds with varying half-lives. Some metabolites have properties similar to those of the parent compounds, which may contribute to their antidepressant activity.

The MAOIs phenelzine and tranylcypromine are absorbed readily after oral administration, and maximal inhibition of MAO occurs in 5 to 10 days. The binding of these compounds to MAO leads to their cleavage to active products (hydrazines), which are inactivated primarily by acetylation. Because acetylation depends on genotype, slow acetylators may exhibit an exaggerated effect when given these compounds.

The transdermal administration of selegiline increases systemic delivery of drug because is does not undergo first-pass metabolism. After transdermal absorption, selegiline is metabolized by several hepatic CYP enzymes, and metabolites are excreted in the urine.

Because phenelzine and selegiline inhibit MAO irreversibly and tranylcypromine inhibits it persistently but noncovalently, the biological effects of these compounds outlast their physical presence in the body; that is, a loss of enzyme activity persists after the drugs are metabolized and eliminated. New enzyme must be synthesized for MAO activity to return to normal, a process that takes several weeks.

Lithium is most often administered as a carbonate salt but is also administered as a citrate salt. Orally administered lithium is rapidly absorbed and is present as a soluble ion unbound to plasma proteins. Peak plasma concentrations are reached 2 to 4 hours after an oral dose. Approximately 95% of a single dose is eliminated in the urine with a t1/2 of 20 to 24 hours, and steady-state plasma concentrations are reached 5 to 6 days after initiation of treatment. Approximately 80% of filtered lithium is reabsorbed by the renal proximal tubules.

Lithium has a low therapeutic index; therapeutic levels are 0.6 to 1.4 mEq/L, and toxicity is manifest at 1.6 to 2.0 mEq/L. Thus the concentration of lithium in plasma must be monitored routinely to ensure adequate therapeutic levels without toxicity.

Relationship of Mechanisms of Action to Clinical Response

Antidepressants

Currently available antidepressants significantly improve symptoms in 50% to 65% of patients. The mood-elevating properties of antidepressants are associated with a blunting or amelioration of the depressive state, such that there is an improvement in all signs and symptoms, although rates of improvement of individual symptoms may differ. A major problem, however, is that it takes several weeks for the maximal therapeutic benefit of these compounds to become apparent. This limitation is particularly disturbing given the propensity for depressed patients to commit suicide.

The temporal discrepancy between the therapeutic efficacy of the antidepressants and their ability to immediately facilitate monoaminergic transmission remains unresolved. However, repeated administration of many antidepressants has been shown to produce numerous adaptive changes in the brain, particularly at serotonergic and noradrenergic receptors. For example, studies have shown that acute administration of SSRIs stimulates both somatodendritic and terminal autoreceptors on serotonergic neurons to decrease firing and inhibit 5-HT release. However, chronic administration of SSRIs down regulates or desensitizes these autoreceptors, producing a disinhibition, thereby promoting neuronal firing and 5-HT release. Similarly, several TCAs have been shown to reduce responses elicited by activation of central β adrenergic receptors and to cause a decrease in their density after chronic administration.

Recently many studies have focused on the ability of the antidepressants to increase neurogenesis and dendritic sprouting in the hippocampus. Studies have suggested that depression may involve an induced impairment of neurogenesis and dendritic sprouting, processes that can be reversed by all classes of antidepressants. Interestingly, because these and other adaptive changes induced by antidepressants take weeks to develop, it has been suggested that such alterations are crucial to the clinical efficacy of these drugs.

Because of the frequency of recurrences of depression, attention has focused on whether antidepressants can prevent recurrences and if so, how long they should be given. Eighty percent of recurrently depressed patients maintained for 3 years on the same dose of imipramine used earlier to treat their acute episode had no recurrence of a serious depressive episode. Prophylactic effects of other antidepressants have been described as well. Studies have found that 50% of patients who have a depressive episode will have a recurrence. Of patients who have two depressive episodes, 70% will have a third episode. If a patient has three depressive episodes, there is a 90% chance there will be another. Therefore, if a patient has three depressive episodes, he or she should remain on long-term antidepressant therapy. If the patient has two episodes that are severe (they reach psychotic proportions or the patient becomes suicidal), the clinician should consider maintaining the patient on long-term antidepressant therapy at that time. However, it is not yet clear when, if ever, patients can be taken off long-term maintenance treatment without the risk of recurrence of a depressive episode.

Drugs for Bipolar Disorder

Lithium continues to be the standard treatment for bipolar disorder. However, 20% to 40% of patients do not respond to lithium or cannot tolerate its adverse effects. In those instances the anticonvulsants valproate, carbamazepine, and lamotrigine are widely used. The atypical antipsychotics are approved for the treatment of acute mania or mixed episodes, and olanzapine and aripiprazole are approved for maintenance therapy. Antidepressant monotherapy may precipitate mania, and thus the combination of olanzapine with fluoxetine can be used for the treatment of depression associated with bipolar disorder.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Amine Reuptake Inhibitors and Atypical Compounds

Antihistaminergic, Anticholinergic, and Antiadrenergic Effects

Many of the most common side effects of the TCA and atypical drugs result from their antagonist actions at H1 histaminergic, muscarinic cholinergic, and α1 adrenergic receptors, leading to marked sedative effects, atropine-like effects including dry mouth, constipation, and cycloplegia, and prazosin-like effects such as orthostatic hypotension, respectively (Table 30-3). As a group, these drugs are more potent at blocking H1 than muscarinic and α1 adrenergic receptors.

TABLE 30–3 Side Effect Profile of Representative Antidepressant Drugs

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The TCAs have fairly marked anticholinergic activity at clinical doses. Although the atypical compounds are somewhat less potent than TCAs in blocking muscarinic cholinergic receptors, amoxapine, maprotiline, and mirtazapine do have anticholinergic effects. The SSRI paroxetine also inhibits muscarinic receptors and produces anticholinergic activity, albeit less than that of the TCAs, reflecting a dose-related difference. Other SSRIs, the SNRIs, and other atypical antidepressants are very weak antagonists at muscarinic cholinergic receptors and do not cause anticholinergic side effects.

The TCAs and atypical antidepressants, with the exception of bupropion, are sedating, and trazodone was used as a soporific agent for many years. Among the SSRIs, paroxetine is most likely to induce sedation.

The antiadrenergic, antihistaminergic, and antimuscarinic side effects of the antidepressants are especially bothersome in elderly patients, with postural hypotension a particularly severe problem because it can lead to falls and broken bones. Clinically, amitriptyline has the most pronounced orthostatic hypotensive effect of the TCAs. Interestingly, although trazodone and nefazodone are equally potent at blocking α1 adrenergic receptors, nefazodone causes less orthostatic hypotension than trazodone. In general, this is not a clinically significant problem for the SSRIs, which have low affinities for α1adrenergic receptors.

Cardiovascular Effects

The TCAs affect the heart through a combination of anticholinergic activity, inhibition of amine reuptake, and direct depressant effects. Although these effects may be manifested by a mild tachycardia, conduction disturbances and electrocardiographic changes can occur. The quinidine-like depressant effects on the myocardium can precipitate slowing of atrioventricular conduction or bundle-branch block or premature ventricular contractions. These effects are much more common in patients with preexisting cardiac problems. Abnormalities of cardiac conduction occur in less than 5% of patients receiving therapeutic doses of TCAs, with most being clinically insignificant. Most of the SSRIs have virtually no effect on the heart. There have been a number of cases (some fatal) of citalopram-induced cardiac conduction delay in patients who have taken an overdose of this compound. One of citalopram’s metabolites is cardiotoxic, and when patients take an overdose, this metabolite increases enough to cause changes in the electrocardiogram and clinical symptoms. Therefore citalopram should probably not be a first-line agent in patients with preexisting cardiac disease.

Central Nervous System Effects

TCAs can lower seizure thresholds and are potentially epileptogenic, but this occurs in less than 0.5% of patients; the incidence is even lower in patients receiving SSRIs. Many of the other antidepressants can induce seizures, and this is a particularly pronounced problem with maprotiline and bupropion, especially in patients receiving high doses. In fact, bupropion is contraindicated for use in any patient with a history of seizures. By contrast, the incidence of seizures is very low in patients receiving trazodone, nefazodone, or mirtazapine.

TCA-induced toxicity of the central nervous system can produce delirium, especially in the elderly, which is easily recognizable. Such delirium is usually preceded by what appears to be a worsening of depression. This may lead to administration of increased doses of the TCA, with further worsening of the delirium. In most cases the antimuscarinic activity of the TCAs is the driving force behind the delirium. If the patient is hospitalized, physostigmine can be used to reverse the delirium. The incidence of insomnia, nervousness, restlessness, and anxiety appears to be relatively high in patients taking fluoxetine. It has an activating effect that can be anxiogenic in some patients and should be started at a lower dose in those with an anxiety component to their illness. Venlafaxine has side effects similar to those of SSRIs. Bupropion can cause nervousness and insomnia, as well as tremors and palpitations, and has more of a stimulant than a sedative effect; therefore it should not be administered in the evening. Headaches commonly occur in patients on SSRIs and venlafaxine.

An important central side effect of the antidepressants, including the MAOIs, is induction of mania or hypomania in depressed patients with a bipolar disorder. This manic overshoot requires urgent care, because a patient can switch from deep depression to an agitated manic state overnight. Anecdotally, fluoxetine is believed to be the drug most likely to induce such an overshoot and bupropion the least likely to do so.

The SSRIs and SNRIs have the potential to lead to serious consequences if combined with other compounds that increase brain levels of 5-HT or stimulate 5-HT receptors. Among these are the MAOIs and other antidepressants, as well as meperidine and dextromethorphan, which are potent inhibitors of 5-HT reuptake, and tryptophan, which can enhance 5-HT synthesis. This interaction can lead to a condition known as serotonin syndrome. This syndrome is characterized by alterations in autonomic function (fever, chills, and diarrhea), cognition and behavior (agitation, excitement, hypomania), and motor systems (myoclonus, tremor, motor weakness, ataxia, hyper-reflexia), and may often resemble neuroleptic malignant syndrome (see Chapter 29). Currently it is believed that activation of 5-HT receptors in the brainstem and spinal cord may mediate these effects. The incidence of the disorder is not known, but as the use of SSRIs increases, it may become more prevalent. Thus a heightened awareness is required for prevention, recognition, and prompt treatment. This involves discontinuation of the suspected drugs, administration of 5-HT antagonists such as cyproheptadine or methysergide, administration of the skeletal muscle relaxant dantrolene, and other supportive measures. The syndrome usually resolves within 24 hours but can be fatal.

Metabolic and Sexual Effects

Another important side effect of many of the antidepressants including the MAOIs is weight gain, which reduces patient compliance. Most SSRIs and SNRIs have an anorectic effect and do not cause any clinically significant weight gain. Venlafaxine can cause weight loss, although paroxetine has been reported to cause weight gain over time. Among the atypical antidepressants, bupropion does not cause weight gain, but mirtazapine can cause significant weight gain, perhaps because of its potent antihistamine activity.

Sexual dysfunction—including abnormal ejaculation, anorgasmy, impotence, and decreased libido—are receiving increasing attention in patients receiving antidepressants. These effects occur at least as frequently in patients treated with TCAs or MAOIs as in patients receiving SSRIs. There appears to be little impairment of sexual function in patients treated with bupropion or mirtazapine and perhaps nefazodone. However, care must be taken, because nefazodone has been recently associated with the development of priapism, whereas it has long been known as a potential occurrence with the structurally similar trazodone.

Other Effects

Several extensive retrospective analyses have indicated no association between TCA exposure during pregnancy and the occurrence of fetal malformations or defects. Although most TCAs show little evidence of teratogenicity in humans, there have been a few isolated reports of possible birth defects in the offspring of mothers taking imipramine, nortriptyline, and amitriptyline. In newborns of mothers who take a TCA late in pregnancy, signs and symptoms of withdrawal or TCA intoxication can occur. The SSRIs and SNRIs and atypical antidepressants are not known to have teratogenic or embryocidal effects, but further research is warranted, given the relatively short time these agents have been in use and their increasing use as maintenance therapies.

Nefazodone is associated with hepatic failure and received a black box warning from the United States Food and Drug Administration. Amoxapine produces many of the same side effects as antipsychotic agents, including dystonic reactions, tardive dyskinesia, and neuroleptic malignant syndrome (see Chapter 29).

Patient tolerability is better for all the newer antidepressants than for the TCAs. As with all drugs, though, there are side effects. The SSRIs and SNRIs cause nausea (15% to 35%), vomiting, and diarrhea to a much greater extent than do the TCAs. The incidence of nausea and vomiting in patients treated with the atypical antidepressants is generally less than that seen in patients treated with SSRIs or SNRIs.

Many SSRIs are potent inhibitors of several cytochrome P450 enzymes and thus can lead to potentially dangerous drug interactions. Fluoxetine, paroxetine, and duloxetine inhibit CYP2D6, whereas fluvoxamine inhibits both CYP1A2 and CYP3A4. Sertraline, escitalopram, citalopram, and venlafaxine have little, if any, effect on cytochrome P450s. Most of the TCAs are substrates of the cytochrome P450 system, so using them concurrently with SSRIs may lead to increased serum TCA concentrations and potential toxicity.

Poisoning accounts for approximately 20% of all suicides, and TCAs are the most commonly used drugs in such cases. TCA overdose can produce coma, seizures, hypertension, and cardiac abnormalities, with death resulting primarily from cardiac arrest. A lethal dose of a TCA may be as low as 1 g, which is roughly 4 or 5 days of medication. In general, the SSRIs, SNRIs, and the atypical compounds (except amoxapine and maprotiline) are much safer in overdoses than the TCAs. However, as noted earlier, there have been reports of cardiac conduction problems associated with citalopram overdose.

Monoamine Oxidase Inhibitors

The side effects of the MAOIs are an extension of their pharmacological effects, reflecting enhanced catecholaminergic activity. Primary side effects are central nervous system excitation (hallucinations, agitation, hyper-reflexia, and convulsions), a large suppression of REM sleep that may lead to psychotic behavior, and drug interactions, the latter of which are potentially life-threatening. The MAOIs have not been associated with extensive human teratogenicity.

The interaction between the MAOIs and the other antidepressants may produce serotonin syndrome, as discussed. In addition, because MAOIs lead to increased intracellular stores of NE within adrenergic nerve terminals, these compounds can enhance the action of indirect-acting sympathomimetics that stimulate the release of NE from these sites. Of major importance is the potential for the MAOIs to induce a hypertensive reaction after the ingestion of tyramine-containing compounds, an action known as the tyramine or cheese effect. Tyramine, which is an indirect-acting sympathomimetic, is normally metabolized by MAO within the gastrointestinal tract after ingestion. When MAO activity in the gastrointestinal tract is inhibited, such as occurs after the oral administration of MAOIs, tyramine is not metabolized and enters the circulation, where it can release stored NE from sympathetic nerve endings. Because the amount of NE in the adrenergic nerve ending is increased as a consequence of MAO inhibition, the result is a massive increase in NE released into the synapse, with a resultant hypertensive crisis (see Chapter 11). Therefore patients taking MAOIs are maintained on a tyramine-restricted diet. This may not be a problem with the use of the selegiline transdermal system, because sufficient MAO activity in the gastrointestinal tract remains intact after transdermal drug administration. Although hypertensive crises are associated with tyramine ingestion during MAOI treatment, in all actuality, hypotension is a much more common side effect of MAOI treatment.

Lithium

Numerous side effects occur in patients treated with lithium, involving the central nervous system, thyroid, kidneys, and heart.

Subclinical hypothyroidism can develop in patients taking lithium. Although obvious hypothyroidism is rare, a benign, diffuse, nontender thyroid enlargement (goiter), indicative of compromised thyroid function, occurs in some patients. This results from the ability of lithium to interfere with the iodination of tyrosine and, consequently, the synthesis of thyroxine (see Chapter 42).

Lithium blocks the responsiveness of the renal collecting tubule epithelium to vasopressin, leading to a nephrogenic diabetes insipidus. In addition, polydipsia and polyuria are frequent problems, the latter resulting from uncoupling of vasopressin receptors from their G proteins. It is important to monitor renal function in patients during treatment with lithium.

Lithium can cause substantial weight gain, which may be detrimental to health but also leads to patient noncompliance. Lithium may also cause nausea and diarrhea and daytime drowsiness. All these effects are quite common, even in patients with therapeutic plasma concentrations. Other side effects include allergic reactions, particularly an exacerbation of acne vulgaris or psoriasis. It may also cause a fine hand tremor in some patients.

Lithium is an important human teratogen, and there is evidence of human fetal risk. It has been noted to cause Ebstein’s anomaly, which is an endocardial cushion defect. It is also secreted in breast milk, so breast-feeding should be discouraged in mothers receiving lithium.

Potential changes in the plasma concentration of lithium resulting from changes in renal clearance can be dangerous, because lithium exhibits a very narrow therapeutic index. The major drug class that poses a problem when administered with lithium is the class of thiazide diuretics, which block Na+ reabsorption in renal distal tubules. The resulting Na+ depletion promotes reabsorption of both Na+ and lithium from proximal tubules, reducing lithium excretion and elevating its plasma concentrations. Similarly, nonsteroidal antiinflammatory agents can decrease lithium clearance and elevate plasma lithium concentrations, leading to lithium toxicity. Difficulties can arise if a patient on lithium becomes dehydrated, as that may also increase serum lithium levels to the toxic range.

Lithium toxicity is related both to its absolute plasma concentration and its rate of rise. Symptoms of mild toxicity occur at the peak of lithium absorption and include nausea, vomiting, abdominal pain, diarrhea, sedation, and fine hand tremor. Because lithium is often administered concomitantly with antipsychotics, which may exhibit antinausea effects, it is critical to be aware of the potential of these compounds to mask the initial signs of lithium toxicity. More serious toxicity, which occurs at higher plasma concentrations, produces central effects, including confusion, hyper-reflexia, gross tremor, cranial nerve and focal neurological signs, and even convulsions and coma. Cardiac dysrhythmias may also occur, and death can result

CLINICAL PROBLEMS

Amine Reuptake Inhibitors and Atypical Antidepressants

Anticholinergic, antihistaminergic and antiadrenergic effects

Sexual dysfunction

Seizures

Myocardial depression leading to ventricular arrhythmias

SSRIs and SNRIs

Nervousness, agitation, sweating and fatigue, sexual dysfunction

Serotonin syndrome

Monoamine Oxidase Inhibitors

CNS excitation, suppression of REM sleep, hepatotoxicity

Serotonin syndrome

Tyramine (cheese) effect

Lithium

CNS—tremors, mental confusion, decreased seizure threshold

Thyroid—decreased function

Renal—polydipsia, polyuria, induced diabetes insipidus

Cardiac—dysrhythmias

from severe lithium toxicity. The problems associated with the use of the antidepressants are summarized in the Clinical Problems Box.

New Horizons

Although the introduction of the SSRIs, SNRIs, and atypical antidepressants represent major advances in the treatment of depression, these compounds still have limitations related to efficacy, tolerability, and rapidity of action. Unfortunately, only approximately 50% of patients treated with standard doses of currently available antidepressants exhibit favorable responses after 6 to 8 weeks of treatment, whereas others exhibit suboptimal improvement, and some individuals do not respond at all. Some lack of response may be attributed to patient compliance, because many individuals cannot tolerate the side effects of these compounds. Although the side effects of the newer compounds are clearly less severe than those seen with the TCAs, they are not without their own problems, especially causing sexual dysfunction and weight gain. Last, slow response time is a major issue because many depressed individuals are prone to suicidal ideations.

Clearly, new approaches to the pharmacological treatment of depression are needed, including developing compounds aimed at new targets such as drugs that promote neurogenesis and agents that normalize the hypothalamic-pituitary-adrenal axis, which is hyperactive in many depressed patients. The challenge remains to develop therapeutic agents that are effective in the population of depressive patients that are resistant to currently available antidepressant medications and to decrease side effects to enhance patient compliance.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

TCAs

Amitriptyline (Elavil)

Clomipramine (Anafranil)

Desipramine (Norpramin)

Doxepin (Adapin, Sinequan)

Imipramine (Tofranil)

Nortriptyline (Pamelor)

SSRIs

Citalopram (Celexa)

Escitalopram (Lexapro)

Fluoxetine (Prozac, Sarafem)

Fluvoxamine (Luvox)

Paroxetine (Paxil, Pexeva)

Sertraline (Zoloft)

SNRIs

Duloxetine (Cymbalta)

Venlafaxine (Effexor)

Atypical Antidepressants

Amoxapine (Asendin)

Bupropion (Wellbutrin, Zyban)

Maprotiline (Ludiomil)

Mirtazapine (Remeron)

Nefazodone (Serzone)

Trazodone (Desyrel)

MAOIs

Phenelzine (Nardil)

Selegiline (Emsam)

Tranylcypromine (Parnate)

Drugs for Bipolar Disorder

Carbamazepine (Tegretol)

Lithium (Eskalith, Lithobid)

Lamotrigine (Lamictal)

Olanzepine/fluoxetine (Symbyax)

Valproate (Depakene)

FURTHER READING

Anonymous. Drugs for psychiatric disorders. Treat Guidel Med Lett. 2006;4:35-46.

Berton O, Nestler EJ. New approaches to antidepressant drug discovery: Beyond monoamines. Nature Rev Neurosci. 2006;7:137-151.

SELF-ASSESSMENT QUESTIONS

1. The neurotransmitter most likely to be involved in the beneficial antidepressant effects of fluoxetine is:

A. NE.

B. Serotonin.

C. Dopamine.

D. GABA.

E. Acetylcholine.

2. Fluoxetine is comparable to a tricyclic antidepressant, such as imipramine, in:

A. Producing orthostatic hypotension.

B. Causing dry mouth and blurred vision.

C. Producing nausea and vomiting.

D. Causing urinary retention.

E. Alleviating the symptoms of depression.

3. A 47-year-old man with bipolar depressive illness also has a history of glomerulonephritis. He is actively manic and needs treatment. Which one of the following drugs would be most appropriate for the treatment of his mania?

A. Imipramine

B. Carbamazepine

C. Lithium carbonate

D. Diazepam

E. Buspirone

4. Which drug can enhance both noradrenergic and serotonergic neurotransmission in the brain by blocking α2 adrenergic receptors?

A. Imipramine

B. Mirtazapine

C. Phenelzine

D. Fluoxetine

E. Bupropion