Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II
Neuropharmacology

chapter 15
Drug Therapy of Depression and Anxiety Disorders

Depression and anxiety disorders are the most common mental illnesses, each affecting in excess of 10-15% of the population at some time in their lives. With the advent of more selective and safer drugs, the use of antidepressants and anxiolytics has moved from the domain of psychiatry to other medical specialties, including primary care. The relative safety of the majority of commonly used antidepressants and anxiolytics notwithstanding, their optimal use requires a clear understanding of their mechanisms of action, pharmacokinetics, potential drug interactions, and the differential diagnosis of psychiatric illnesses.

A confluence of symptoms of depression and anxiety may affect an individual patient; some of the drugs discussed here are effective in treating both disorders, suggesting common underlying mechanisms of pathophysiology and response to pharmacotherapy. In large measure, our current understanding of pathophysiological mechanisms underlying depression and anxiety has been inferred from the mechanisms of action of psychopharmacological compounds (see Chapter 14). While depression and anxiety disorders comprise a wide range of symptoms, including changes in mood, behavior, somatic function, and cognition, some progress has been made in developing animal models that respond with some sensitivity and selectivity to antidepressant or anxiolytic drugs. The last half century has seen notable advances in the discovery and development of drugs for treating depression and anxiety.

CHARACTERIZATION OF DEPRESSIVE AND ANXIETY DISORDER

SYMPTOMS OF DEPRESSION

Depression is classified as major depression (i.e., unipolar depression) or bipolar depression (i.e., manic depressive illness); bipolar depression and its treatment are discussed inChapter 16. Lifetime risk of unipolar depression is ~15%. Females are affected twice as frequently as males. Depressive episodes are characterized by sad mood, pessimistic worry, diminished interest in normal activities, mental slowing and poor concentration, insomnia or increased sleep, significant weight loss or gain due to altered eating and activity patterns, psychomotor agitation or retardation, feelings of guilt and worthlessness, decreased energy and libido, and suicidal ideation, occurring most days for a period of at least 2 weeks. In some cases, the primary complaint of patients involves somatic pain or other physical symptoms and can present a diagnostic challenge for primary care physicians. Depressive symptoms also can occur secondary to other illnesses such as hypothyroidism, Parkinson disease, and inflammatory conditions. Further, depression often complicates the management of other medical conditions (e.g., severe trauma, cancer, diabetes, and cardiovascular disease, especially myocardial infarction).

Depression is underdiagnosed and undertreated. Approximately 10-15% of those with severe depression attempt suicide at some time. Thus, it is important that symptoms of depression be recognized and treated in a timely manner. Furthermore, the response to treatment must be assessed and decisions made regarding continued treatment with the initial drug, dose adjustment, adjunctive therapy, or alternative medication.

SYMPTOMS OF ANXIETY. Anxiety disorder symptoms include generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder (PTSD), separation anxiety disorder, social phobia, specific phobias, and acute stress. In general, symptoms of anxiety that lead to pharmacological treatment are those that interfere significantly with normal function. Symptoms of anxiety also are often associated with depression and other medical conditions.

Anxiety is a normal human emotion that serves an adaptive function from a psychobiological perspective. However, in the psychiatric setting, feelings of fear or dread that are unfocused (e.g., generalized anxiety disorder) or out of scale with the perceived threat (e.g., specific phobias) often require treatment. Drug treatment includes acute drug administration to manage episodes of anxiety, and chronic or repeated treatment to manage unrelieved and continuing anxiety disorders.

ANTIDEPRESSANT DRUGS

In general, antidepressants enhance serotonergic or noradrenergic transmission. Sites of interaction of antidepressant drugs with noradrenergic and serotonergic neurons are depicted in Figure 15–1Table 15–1 summarizes the actions of the most widely used antidepressants. The most commonly used medications, often referred to as second-generation antidepressants, are the selective serotonin reuptake inhibitors (SSRIs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs), which have greater efficacy and safety compared to the first-generation drugs, which include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs).

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Figure 15–1 Sites of action of antidepressants at noradrenergic (top) and serotonergic (bottom) nerve terminals. SSRIs, SNRIs, and TCAs increase noradrenergic or serotonergic neurotransmission by blocking the NE or 5HT transporter at presynaptic terminals (NET, SERT). MAOIs inhibit the catabolism of NE and 5HT. Trazodone and related drugs have direct effects on 5HT receptors that contribute to their clinical effects. Chronic treatment with a number of antidepressants desensitizes presynaptic autoreceptors and heteroreceptors, producing long-lasting changes in monoaminergic neurotransmission. Post-receptor effects of antidepressant treatment, including modulation of GPCR signaling and activation of protein kinases and ion channels, are involved in the mediation of the long-term effects of antidepressant drugs. Note that NE and 5HT also affect each other’s neurons.

Table 15–1

Antidepressants: Dose and Dosage Forms, and Side Effects

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In monoamine systems, inhibition of reuptake can enhance neurotransmission, presumably by slowing clearance of the transmitter from the synapse and prolonging the dwell-time of the transmitter in the synapse. Reuptake inhibitors inhibit either SERT, the neuronal serotonin (5-hydroxytryptamine [5HT]) transporter; NET, the neuronal norepinephrine (NE) transporter; or both. Similarly, MAOIs and TCAs enhance monoaminergic neurotransmission: the MAOIs by inhibiting monoamine metabolism and thereby enhancing neurotransmitter storage in secretory granules, the TCAs by inhibiting 5HT and NE reuptake

Long-term effects of antidepressant drugs evoke regulatory mechanisms that enhance the effectiveness of therapy. These responses include increased adrenergic or serotonergic receptor density or sensitivity, increased receptor-G protein coupling and cyclic nucleotide signaling, induction of neurotrophic factors, and increased neurogenesis in the hippocampus. Persistent antidepressant effects depend on the continued inhibition of 5HT or NE transporters, or enhanced serotonergic or noradrenergic neurotransmission achieved by an alternative pharmacological mechanism. Compelling evidence suggests that sustained signaling via NE or 5HT increases the expression of specific downstream gene products, particularly brain-derived neurotrophic factor (BDNF), which appears to be related to the ultimate mechanism of action of these drugs.

CLINICAL CONSIDERATIONS WITH ANTIDEPRESSANT DRUGS

Antidepressant drug treatment has generally a “therapeutic lag” lasting 3-4 weeks before a measurable therapeutic response becomes evident. After the successful initial treatment phase, a 6-12–month maintenance treatment phase is typical, after which the drug is gradually withdrawn. If a patient is chronically depressed (i.e., >2 years), lifelong treatment with an antidepressant is advisable.

A controversial issue regarding the use of all antidepressants is their relationship to suicide. Data establishing a clear link between antidepressant treatment and suicide are lacking. However, the FDA has issued a “black box” warning regarding the use of SSRIs and a number of other antidepressants in children and adolescents due to the possibility of an association between antidepressant treatment and suicide. For seriously depressed patients, the risk of not being on an effective antidepressant drug outweighs the risk of being treated with one.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

The SSRIs are effective in treating major depression. SSRIs also are anxiolytics with demonstrated efficacy in the treatment of generalized anxiety, panic, social anxiety, and obsessive-compulsive disorders. Sertraline and paroxetine are approved for the treatment of PTSD. SSRIs also are used for treatment of premenstrual dysphoric syndrome and for preventing vasovagal symptoms in postmenopausal women.

SERT mediates the reuptake of serotonin into the presynaptic terminal; neuronal uptake is the primary process by which neurotransmission via 5HT is terminated (see Figure 15–1). SSRIs block reuptake and prolong serotonergic neurotransmission. SSRIs used clinically are relatively selective for inhibition of SERT relative to NET (Table 15–2; not shown is vilazodone [VIIBRYD], an SSRI and partial 5HT1A agonist, recently approved by the FDA for treatment of major depression).

Table 15–2

Selectivity of Antidepressants at the Human Biogenic Amine Transporters

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SSRI treatment causes stimulation of 5HT1A and 5HT7 autoreceptors on cell bodies in the raphe nucleus and of 5HT1D autoreceptors on serotonergic terminals, and this reduces serotonin synthesis and release toward predrug levels. With repeated treatment with SSRIs, there is a gradual downregulation and desensitization of these autoreceptor mechanisms. In addition, downregulation of postsynaptic 5HT2A receptors may contribute to antidepressant efficacy directly or by influencing the function of noradrenergic and other neurons via serotonergic heteroreceptors. Other postsynaptic 5HT receptors likely remain responsive to increased synaptic concentrations of 5HT and contribute to the therapeutic effects of the SSRIs.

Later-developing effects of SSRI treatment also may be important in mediating ultimate therapeutic responses. These include sustained increases in cyclic AMP signaling and phosphorylation of the nuclear transcription factor CREB, as well as increases in the expression of trophic factors such as BDNF, and increases of neurogenesis from progenitor cells in the hippocampus and subventricular zone. Repeated treatment with SSRIs reduces the expression of SERT, resulting in reduced clearance of released 5HT and increased serotonergic neurotransmission.

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS

Four medications with a nontricyclic structure that inhibit the reuptake of both 5HT and NE have been approved for use in the U.S. for treatment of depression, anxiety disorders, and pain: venlafaxine and its demethylated metabolite, desvenlafaxine; duloxetine; and milnacipran.

SNRIs inhibit both SERT and NET (see Table 15–2) and cause enhanced serotonergic and/or noradrenergic neurotransmission. Similar to the action of SSRIs, the initial inhibition of SERT induces activation of 5HT1A and 5HT1D autoreceptors. This action decreases serotonergic neurotransmission by a negative feedback mechanism until these serotonergic autoreceptors are desensitized. Then, the enhanced serotonin concentration in the synapse can interact with postsynaptic 5HT receptors. SNRIs were developed with the rationale that they might improve overall treatment response compared to SSRIs. Specifically, the remission rate for venlafaxine appears slightly better than for SSRIs in head-to-head trials. Duloxetine, in addition to being approved for use in the treatment of depression and anxiety, also is used for treatment of fibromyalgia and neuropathic pain associated with peripheral neuropathy. Off-label uses include stress urinary incontinence (duloxetine), autism, binge eating disorders, hot flashes, pain syndromes, premenstrual dysphoric disorders, and PTSDs (venlafaxine).

SEROTONIN RECEPTOR ANTAGONISTS

Several antagonists of the 5HT2 family of receptors are effective antidepressants. These includes 2 close structural analogues, trazodone and nefazodone, as well as mirtazapine (REMERON, others) and mianserin (not marketed in the U.S.).

The efficacy of trazodone may be somewhat more limited than the SSRIs; however, low doses of trazodone (50-100 mg) have been used widely both alone and concurrently with SSRIs or SNRIs to treat insomnia. Both mianserin and mirtazapine are quite sedating and are treatments of choice for some depressed patients with insomnia. Trazodone blocks the 5HT2 and α1-adrenergic receptors. Trazodone also inhibits the serotonin transporter, but is markedly less potent for this action relative to its blockade of 5HT2A receptors. Similarly, the most potent pharmacological action of nefazodone also is the blockade of the 5HT2 receptors. Both mirtazapine and mianserin potently block histamine H1 receptors. They also have some affinity for α2-adrenergic receptors. Their affinities for 5HT2A, 5HT2C, and 5HT3 receptors are high, though less so than for histamine H1 receptors. Both of these drugs have been shown to increase the antidepressant response when combined with SSRIs compared to the action of the SSRIs alone.

BUPROPION

Bupropion (WELLBUTRIN, others) is discussed separately because it appears to act via multiple mechanisms. It enhances both noradrenergic and dopaminergic neurotransmission via inhibition of reuptake (by NET and also by DAT, although effects on this transporter are not potent in animal studies) (see Table 15–2). Its mechanism of action may also involve the presynaptic release of NE and DA and effects on VMAT2, the vesicular monoamine transporter (see Figure 8–6). The hydroxybupropion metabolite may contribute to the therapeutic effects of bupropion: This metabolite appears to have a similar pharmacology and is present in substantial levels. Bupropion is indicated for the treatment of depression, prevention of seasonal depressive disorder, and as a smoking cessation treatment (under the ZYBAN brand). Bupropion has effects on sleep EEG that are opposite those of most antidepressant drugs. Bupropion may improve symptoms of attention deficit hyperactivity disorder (ADHD) and has been used off-label for neuropathic pain and weight loss. Clinically, bupropion is widely used in combination with SSRIs to obtain a greater antidepressant response; however, there are very limited clinical data providing strong support for this practice.

ATYPICAL ANTIPSYCHOTICS

In addition to their use in schizophrenia, bipolar depression, and major depression with psychotic disorders, atypical antipsychotics have gained further, off-label use for major depression without psychotic features. The combination of aripiprazole (ABILIFY) with SSRIs and SNRIs and a combination of olanzapine and the SSRI fluoxetine (SYMBYAX) have been approved by the FDA for treatment-resistant major depression (i.e., following an inadequate response to at least 2 different antidepressants).

The initial recommended dose of aripiprazole is 2-5 mg/day with a recommended maximal dose of 15 mg/day following increments of no more than 5 mg/day every week. The olanzapine-fluoxetine combination is available in fixed-dose combinations of either 6 or 12 mg of olanzapine and 25 or 50 mg of fluoxetine. Quetiapine (SEROQUEL) may have either primary antidepressant actions on its own or adjunctive benefit for treatment-resistant depression; it is used off-label for insomnia. The mechanism of action and adverse effects of the atypical antipsychotics are described in detail in Chapter 16. The major risks of these agents are weight gain and metabolic syndrome, a greater problem for quetiapine and olanzapine than for aripiprazole.

TRICYCLIC ANTIDEPRESSANTS

TCAs may cause serious side effects and generally are not used as first-line drugs for the treatment of depression. TCAs and first-generation antipsychotics are synergistic for the treatment of psychotic depression. Tertiary amine TCAs (e.g., doxepin, amitriptyline) have been used for many years in relatively low doses for treating insomnia. In addition, because of the role of norepinephrine and serotonin in pain transmission, these drugs are commonly used to treat a variety of pain conditions.

The pharmacological action of TCAs is antagonism of serotonin and norepinephrine transporters (see Table 15–2). In addition to inhibiting NET somewhat selectively (desipramine, nortriptyline, protriptyline, amoxapine) or both SERT and NET (imipramine, amitriptyline), these drugs also block other receptors (H1, 5HT2, α1, and muscarinic). Given the superior activity of clomipramine over SSRIs, some combination of these additional pharmacological actions may contribute to the therapeutic effects of TCAs. One TCA, amoxapine, also is a dopamine-receptor antagonist; its use, unlike that of other TCAs, poses some risk for the development of extrapyramidal side effects such as tardive dyskinesia.

MONOAMINE OXIDASE INHIBITORS

MAOIs have efficacy equivalent to that of the TCAs but are rarely used because of their toxicity and major drug and food interactions. The MAOIs approved for treatment of depression include tranylcypromine (PARNATE, others), phenelzine (NARDIL), and isocarboxazid (MARPLAN). Selegiline (EMSAM) is available as a transdermal patch; transdermal delivery may reduce the risk for diet-associated hypertensive reactions.

The MAOIs nonselectively and irreversibly inhibit both MAO-A and MAO-B, which are located in the mitochondria and metabolize monoamines, including 5HT and NE (see Chapter 8). Selegiline inhibits MAO-B at lower doses, with effects on MAO-A at higher doses. Selegiline also is a reversible inhibitor of MAO, which may reduce the potential for serious adverse drug and food interactions. While both MAO-A and MAO-B are involved in metabolizing 5HT, only MAO-B is found in serotonergic neurons (see Chapter 13).

PHARMACOKINETICS

The metabolism of most antidepressants is mediated by hepatic CYPs (Table 15–3). Some antidepressants inhibit the clearance of other drugs by the CYP system, and this possibility of drug interactions should be a significant factor in considering the choice of agents.

Table 15–3

Disposition of Antidepressants

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SELECTIVE SEROTONIN REUPTAKE INHIBITORS. All of the SSRIs are orally active and possess elimination half-lives consistent with once-daily dosing. In the case of fluoxetine, the combined action of the parent and the desmethyl metabolite norfluoxetine allows for a once-weekly formulation (PROZAC WEEKLY). CYP2D6 is involved in the metabolism of most SSRIs and the SSRIs are at least moderately potent inhibitors of this isoenzyme. This creates a significant potential for drug interaction for postmenopausal women taking the breast cancer drug and estrogen antagonist, tamoxifen (seeChapter 63). Because venlafaxine and desvenlafaxine are weak inhibitors of CYP2D6, these antidepressants are not contraindicated in this clinical situation. However, care should be used in combining SSRIs with drugs that are metabolized by CYPs.

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS. Both immediate-release and extended-release (tablet or capsule) preparations of venlafaxine (EFFEXOR XR, others) produces steady state-levels of drug in plasma within 3 days. The elimination half-lives for the parent venlafaxine and its active and major metabolite desmethyl venlafaxine are 5 and 11 h, respectively. Desmethyl venlafaxine is eliminated by hepatic metabolism and by renal excretion. Venlafaxine dose reductions are suggested for patients with renal or hepatic impairment. Duloxetine has a t1/2 of 12 h. Duloxetine is not recommended for those with end-stage renal disease or hepatic insufficiency.

SEROTONIN RECEPTOR ANTAGONISTS. Mirtazapine has an elimination t1/2 of 16-30 h. Thus, dose changes are suggested no more often than 1-2 weeks. The recommended initial dosing of mirtazapine is 15 mg/day with a maximal recommended dose of 45 mg/day. Clearance of mirtazapine is decreased in the elderly and in patients with moderate to severe renal or hepatic impairment. Pharmacokinetics and adverse effects of mirtazapine may have an enantiomer-selective component. Steady-state trazodone is observed within 3 days following dosing regimen. Trazodone typically is started at 150 mg/day in divided doses with 50 mg increments every 3-4 days. The maximally recommended dose is 400 mg/day for outpatients and 600 mg/day for inpatients. Nefazodone has a t1/2 of only 2-4 h; its major metabolite hydroxynefazodone has a t1/2 of 1.5-4 h.

BUPROPION. Bupropion elimination has a t1/2 of 21 h and involves both hepatic and renal routes. Patients with severe hepatic cirrhosis should receive a maximum dose of 150 mg every other day while consideration for a decreased dose should also be made in cases of renal impairment.

TRICYCLIC ANTIDEPRESSANTS. The TCAs, or their active metabolites, have plasma half-lives of 8-80 h; this makes once-daily dosing possible for most of the compounds. Steady-state concentrations occur within several days to several weeks of beginning treatment. TCAs are largely eliminated by hepatic CYPs (see Table 15–3). Dosage adjustments of TCAs are typically made according to patient’s clinical response, not based on plasma levels. Nonetheless, monitoring the plasma exposure has an important relationship to treatment response: there is a relatively narrow therapeutic window. About 7% of patients metabolize TCAs slowly due to a variant CYP2D6 isoenzyme, causing a 30-fold difference in plasma concentrations among different patients given the same TCA dose. To avoid toxicity in “slow metabolizers,” plasma levels should be monitored and doses adjusted downward.

MONOAMINE OXIDASE INHIBITORS. MAOIs are metabolized by acetylation. A significant portion of the population (50% of the Caucasian population and an even higher percentage among Asians) are “slow acetylators” and will exhibit elevated plasma levels. The nonselective MAOIs used in the treatment of depression are irreversible inhibitors; thus, it takes up to 2 weeks for MAO activity to recover, even though the parent drug is excreted within 24 h. Recovery of normal enzyme function is dependent on synthesis and transport of new MAO to monoaminergic nerve terminals. Despite this irreversible enzyme inhibition, MAOIs require daily dosing.

ADVERSE EFFECTS

SELECTIVE SEROTONIN REUPTAKE INHIBITORS. The SSRIs have no major cardiovascular side effects. The SSRIs are generally free of antimuscarinic side effects (dry mouth, urinary retention, confusion), do not block histamine or α-adrenergic receptors, and are not sedating (Table 15–4).

Table 15–4

Potencies of Selected Antidepressants at Muscarinic, Histamine H1, and Alpha1 Adrenergic Receptors

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Adverse side effects of SSRIs from excessive stimulation of brain 5HT2 receptors may result in insomnia, increased anxiety, irritability, and decreased libido, effectively worsening prominent depressive symptoms. Excess activity at spinal 5HT2 receptors causes sexual side effects including erectile dysfunction, anorgasmia, and ejaculatory delay; these effects may be more prominent with paroxetine. Stimulation of 5HT3 receptors in the CNS and periphery contributes to GI effects, which are usually limited to nausea but may include diarrhea and emesis. Some patients experience an increase in anxiety, especially with the initial dosing of SSRIs. With continued treatment, some patients also report a dullness of intellectual abilities and concentration. In general, there is not a strong relationship between SSRI serum concentrations and therapeutic efficacy. Thus, dosage adjustments are based more on evaluation of clinical response and management of side effects.

Sudden withdrawal of antidepressants can precipitate a withdrawal syndrome. For SSRIs or SNRIs, the symptoms of withdrawal may include dizziness, headache, nervousness, nausea, and insomnia. This withdrawal syndrome appears most intense for paroxetine and venlafaxine compared to other antidepressants due to their relatively short half-lives and, in the case of paroxetine, lack of active metabolites. Conversely, the active metabolite of fluoxetine, norfluoxetine, has such a long t1/2 (1-2 weeks) that few patients experience any withdrawal symptoms when discontinuing fluoxetine.

Unlike the other SSRIs, paroxetine is associated with an increased risk of congenital cardiac malformations when administered in the first trimester of pregnancy. Venlafaxine also is associated with an increased risk of perinatal complications.

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS. SNRIs have a side effect profile similar to that of the SSRIs, including nausea, constipation, insomnia, headaches, and sexual dysfunction. The immediate release formulation of venlafaxine can induce sustained diastolic hypertension (diastolic blood pressure >90 mm Hg at consecutive weekly visits) in 10-15% of patients at higher doses; this risk is reduced with the extended-release form. This effect of venlafaxine may not be associated simply with inhibition of NET, since duloxetine does not share this side effect.

SEROTONIN RECEPTOR ANTAGONISTS. The main side effects of mirtazapine, seen in >10% of the patients, are somnolence, increased appetite, and weight gain. A rare side effect of mirtazapine is agranulocytosis. Trazodone use is associated with priapism in rare instances. Nefazodone was voluntarily withdrawn from the market after rare cases of liver failure were associated with its use. Generic nefazodone is still available in the U.S.

BUPROPION. At doses higher than that recommended for depression (450 mg/day), the risk of seizures increases significantly. The use of extended-release formulations often blunts the maximum concentration observed after dosing and minimizes the chance of reaching drug levels associated with an increased risk of seizures.

TRICYCLIC ANTIDEPRESSANTS. TCAs are potent antagonists at histamine H1 receptors; H1-receptor antagonism contributes to the sedative effects of TCAs (see Table 15–4). Antagonism of muscarinic acetylcholine receptors contributes to cognitive dulling as well as a range of adverse effects mediated by the parasympathetic nervous system (blurred vision, dry mouth, tachycardia, constipation, difficulty urinating). Some tolerance does occur for these anticholinergic effects. Antagonism of α1 adrenergic receptors contributes to orthostatic hypotension and sedation. Weight gain is another side effect of this class of antidepressants.

TCAs also have quinidine-like effects on cardiac conduction that can be life threatening with overdose and limit the use of TCAs in patients with coronary heart disease. This is the primary reason that only a very limited supply should be available to the patient at any given time. Like other antidepressant drugs, TCAs also lower the seizure threshold.

MONOAMINE OXIDASE INHIBITORS. Hypertensive crisis resulting from food or drug interactions is one of the life-threatening toxicities associated with use of the MAOIs. Foods containing tyramine are a contributing factor. MAO-A within the intestinal wall and MAO-A and MAO-B in the liver normally degrade dietary tyramine. When MAO-A is inhibited, the ingestion of tyramine-containing foods leads to accumulation of tyramine in adrenergic nerve endings and neurotransmitter vesicles and induces norepinephrine and epinephrine release. The released catecholamines stimulate postsynaptic receptors in the periphery, increasing blood pressure to dangerous levels. The use of prescription or over-the-counter medications that contain sympathomimetic compounds also result in a potentially life-threatening elevation of blood pressure. In comparison to tranylcypromine and isocarboxazid, the selegiline transdermal patch is better tolerated and safer. Another serious, life-threatening issue with chronic administration of MAOIs is hepatotoxicity.

MAO-A inhibitors are efficacious in treating depression. However, MAO-B inhibitors such as selegiline (with oral formulations) are effective in treating depression only when given at doses that block both MAO-A and MAO-B. While not available in the U.S., reversible inhibitors of MAO-A (RIMAs, such as moclobemide) have been developed. Because these drugs are selective for MAO-A, significant MAO-B activity remains. Further, since the inhibition of MAO-A by RIMAs is reversible and competitive, as concentrations of tyramine rise, enzyme inhibition is surmounted. Thus, RIMAs produce antidepressant effects with reduced risk of tyramine-induced hypertensive crisis.

DRUG INTERACTIONS

Many of these drugs are metabolized by hepatic CYPs, especially CYP2D6. Thus, other agents that are substrates or inhibitors of CYP2D6 can increase plasma concentrations of the primary drug. The combination of other classes of antidepressant agents with MAOIs is inadvisable and can lead to serotonin syndrome.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS. Paroxetine and, to a lesser degree, fluoxetine are potent inhibitors of CYP2D6. The other SSRIs, outside of fluvoxamine, are at least moderate inhibitors of CYP2D6. This inhibition can result in disproportionate increases in plasma concentrations of drugs metabolized by CYP2D6 when doses of these drugs are increased. Fluvoxamine directly inhibits CYP1A2 and CYP2C19; fluoxetine and fluvoxamine also inhibit CYP3A4. A prominent interaction is the increase in TCA exposure that may be observed during coadministration of TCAs and SSRIs.

MAOIs enhance the effects of SSRIs due to inhibition of serotonin metabolism. Administration of these drugs together can produce synergistic increases in extracellular brain serotonin, leading to the serotonin syndrome. Symptoms of the serotonin syndrome include hyperthermia, muscle rigidity, myoclonus, tremors, autonomic instability, confusion, irritability, and agitation; this can progress toward coma and death. Other drugs that may induce the serotonin syndrome include substituted amphetamines such as methylenedioxymethamphetamine (Ecstasy), which directly releases serotonin from nerve terminals.

SSRIs should not be started until at least 14 days following discontinuation of treatment with an MAOI; this allows for synthesis of new MAO. For all SSRIs but fluoxetine, at least 14 days should pass prior to beginning treatment with an MAOI following the end of treatment with an SSRI. Because the active metabolite norfluoxetine has a t1/2 of 1-2 weeks, at least 5 weeks should pass between stopping fluoxetine and beginning an MAOI.

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS. While 14 days are suggested to elapse from ending MAOI therapy and starting venlafaxine treatment, an interval of only 7 days is considered safe. Duloxetine has a similar interval to initiation following MAOI therapy, but requires only a 5-day waiting period to begin MAOI treatment after ending duloxetine. Failure to observe these required waiting periods can result in the serotonin syndrome.

SEROTONIN RECEPTOR ANTAGONISTS. Trazodone dosing may need to be lowered when given together with drugs that inhibit CYP3A4. Mirtazapine is metabolized by CYPs 2D6, 1A2, and 3A4. Trazodone and nefazodone are weak inhibitors of serotonin uptake and should not be administered with MAOIs due to concerns about the serotonin syndrome.

BUPROPION. The major route of metabolism for bupropion is CYP2B6. While there does not appear to be any evidence for metabolism by CYP2D6 and this drug is frequently administered with SSRIs, the potential for interactions with drugs metabolized by CYP2D6 should be kept in mind until the safety of the combination is firmly established.

TRICYCLIC ANTIDEPRESSANTS. Drugs that inhibit CYP2D6, such as SSRIs, may increase plasma exposures of TCAs. Other drugs that may act similarly are phenothiazine antipsychotic agents, type 1C anti-arrhythmic drugs, and other drugs with antimuscarinic, antihistaminic, and α-adrenergic antagonistic effects. TCAs can potentiate the actions of sympathomimetic amines and should not be used concurrently with MAOIs or within 14 days of stopping MAOIs.

MONOAMINE OXIDASE INHIBITORS. CNS depressants including meperidine and other narcotics, alcohol, and anesthetic agents should not be used with MAOIs. Meperidine and other opioid agonists in combination with MAOIs also induce the serotonin syndrome. SSRIs and SNRIs are contraindicated in patients on MAOIs to avoid the serotonin syndrome. In general, other antidepressants such as TCAs and bupropion also should be avoided in patients taking an MAOI.

ANXIOLYTIC DRUGS

Primary treatments for anxiety-related disorders include the SSRIs, SNRIs, benzodiazepines, buspirone, and β adrenergic antagonists. The SSRIs and the SNRI venlafaxine have anxiolytic activity with chronic treatment. The benzodiazepines are effective anxiolytics as both acute and chronic treatment. Buspirone, like the SSRIs, is effective following chronic treatment. It acts, at least in part, via the serotonergic system, where it is a partial agonist at 5HT1A receptors. Buspirone also has antagonistic effects at dopamine D2 receptors, but the relationship between this effect and its clinical actions is uncertain. β adrenergic antagonists (e.g., propranolol and nadolol) are occasionally used for performance anxiety such as fear of public speaking; their use is limited due to significant side effects such as hypotension.

The antihistamine hydroxyzine and various sedative-hypnotic agents have been used as anxiolytics, but are generally not recommended because of their side effect profiles. Hydroxyzine, which produces short-term sedation, is used in patients who cannot use other types of anxiolytics (e.g., those with a history of drug or alcohol abuse where benzodiazepines would be avoided). Chloral hydrate has been used for situational anxiety, but there is a narrow dose range where anxiolytic effects are observed in the absence of significant sedation, and, therefore, the use of chloral hydrate is not recommended.

CLINICAL CONSIDERATIONS WITH ANXIOLYTIC DRUGS. The choice of pharmacological treatment for anxiety is dictated by the specific anxiety-related disorders and the clinical need for acute anxiolytic effects. The benzodiazepines and β adrenergic antagonists are effective acutely. Chronic treatment with SSRIs, SNRIs, and buspirone is required to produce and sustain anxiolytic effects.

Benzodiazepines, such as alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam, and oxazepam, are effective in the treatment of generalized anxiety disorder, panic disorder, and situational anxiety. In addition to their anxiolytic effects, benzodiazepines produce sedative, hypnotic, anesthetic, anticonvulsant, and muscle relaxant effects. The benzodiazepines also impair cognitive performance and memory, adversely affect motor control, and potentiate the effects of other sedatives including alcohol. The anxiolytic effects of this class of drugs are mediated by allosteric interactions with the pentameric benzodiazepine-GABAA receptor complex, in particular those GABAA receptors comprised of α2, α3, and α5 subunits (see Chapters 14 and 17). The primary effect of the anxiolytic benzodiazepines is to enhance the inhibitory effects of the neurotransmitter GABA. The use of benzodiazepines in the treatment of anxiety has the potential for habituation, dependence, and abuse. Withdrawal of benzodiazepines after chronic treatment, particularly those with short durations of action, can include increased anxiety and seizures. For this reason, it is important that discontinuation be carried out in a gradual manner.

Benzodiazepines cause many adverse effects, including sedation, mild memory impairments, decreased alertness, and slowed reaction time. Occasionally, paradoxical reactions can occur with benzodiazepines such as increases in anxiety, sometimes reaching panic attack proportions. Other pathological reactions can include irritability, aggression, or behavioral disinhibition. Amnesic reactions (i.e., loss of memory for particular periods) can also occur. Benzodiazepines should not be used in pregnant women; there have been rare reports of craniofacial defects. In addition, benzodiazepines taken prior to delivery may result in sedated, under-responsive newborns and prolonged withdrawal reactions. In the elderly, benzodiazepines increase the risk for falls and must be used cautiously. These drugs are safer than classical sedative-hypnotics in overdosage and typically are fatal only if combined with other CNS depressants.

Benzodiazepines have some abuse potential. When these agents are abused, it is generally in a multidrug abuse pattern. In fact, the primary reason for misuse of these agents often is failed attempts to control anxiety. Tolerance to the anxiolytic effects develops with chronic administration, with the result that some patients escalate the dose of benzodiazepines over time. Ideally, benzodiazepines should be used for short periods of time and in conjunction with other medications (e.g., SSRIs) or evidence-based psychotherapies (e.g., cognitive behavioral therapy for anxiety disorders).

SSRIs and the SNRI venlafaxine are first-line treatments for most types of anxiety disorders, except when an acute drug effect is desired; fluvoxamine is approved only for obsessive-compulsive disorder. As for their antidepressant actions, the anxiolytic effects of these drugs become manifest following chronic treatment. Other drugs with actions on serotonergic neurotransmission, including trazodone, nefazodone, and mirtazapine, also are used in the treatment of anxiety disorders. Details regarding the pharmacology of these classes of were presented earlier. Both SSRIs and SNRIs are beneficial in specific anxiety conditions such as generalized anxiety disorder, social phobias, obsessive-compulsive disorder, and panic disorder. These effects appear to be related to the capacity of serotonin to regulate the activity of brain structures such as amygdala and locus coeruleus that are thought to be involved in the genesis of anxiety. Anxious patients appear to be particularly prone to severe discontinuation reactions with certain medications such as venlafaxine and paroxetine; therefore, slow off-tapering is required.

Buspirone requires chronic treatment for effectiveness. Buspirone is primarily effective in the treatment of generalized anxiety disorder, but not for other anxiety disorders.