Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 30. Antidepressants

Antidepressants: Introduction

Major depressive disorder, or endogenous depression, is a depression of mood without any obvious medical or situational causes, manifested by an inability to cope with ordinary events or experience pleasure. The drugs used in major depressive disorder are of varied chemical structures; many have effects that enhance the CNS actions of norepinephrine, serotonin, or both.

High Yield Terms to Learn

Amine hypothesis of mood The hypothesis that major depressive disorders result from a functional deficiency of norepinephrine or serotonin at synapses in the CNS MAO inhibitors (MAOIs) Drugs inhibiting monoamine oxidases that metabolize norepinephrine and serotonin MAO type A) and dopamine (MAO type B) Tricyclic antidepressants (TCAs) Structurally related drugs that block reuptake transporters of both norepinephrine (NE) and serotonin (5-HT) Selective serotonin reuptake inhibitors (SSRIs) Drugs that selectively inhibit serotonin (5-HT) transporters with only modest effects on other neurotransmitters Serotonin-norepinephrine reuptake inhibitors (SNRIs) Heterocyclic drugs that block NE and 5-HT transporters, but lack the alpha blocking, anticholinergic and antihistaminic actions of TCAs 5-HT2 receptor antagonists Structurally related drugs that block this subgroup of serotonin receptors with only minor effects on amine transporters Heterocyclics Term used for antidepressants of varying chemical structures, the characteristics of which do not strictly conform to any of the above designations

The Amine Hypothesis of Mood

The amine hypothesis of mood postulates that brain amines, particularly norepinephrine (NE) and serotonin (5-HT), are neurotransmitters in pathways that function in the expression of mood. According to the hypothesis, a functional decrease in the activity of such amines is thought to result in depression; a functional increase of activity results in mood elevation. The amine hypothesis is largely based on studies showing that many drugs capable of alleviating symptoms of major depressive disorders enhance the actions of the central nervous system (CNS) neurotransmitters 5-HT and NE. Difficulties with this hypothesis include the facts that (1) postmortem studies do not reveal any decreases in the brain levels of NE or 5-HT in patients suffering from depression; (2) although antidepressant drugs may cause changes in brain amine activity within hours, weeks may be required for them to achieve clinical effects; (3) most antidepressants ultimately cause a downregulation of amine receptors; and (4) at least 1 effective antidepressant, bupropion, has minimal effects on brain NE or 5-HT.

Drug Classification & Pharmacokinetics

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs; eg, imipramine, amitriptyline ) are structurally related to the phenothiazine antipsychotics and share certain of their pharmacologic effects. The TCAs are well absorbed orally but may undergo first-pass metabolism. They have high volumes of distribution and are not readily dialyzable. Extensive hepatic metabolism is required before their elimination; plasma half-lives of 8-36 h usually permit once-daily dosing. Both amitriptyline and imipramine form active metabolites, nortriptyline and desipramine, respectively.

Selective Serotonin Reuptake Inhibitors

Fluoxetine is the prototype of a group of drugs that are selective serotonin reuptake inhibitors (SSRIs). All of them require hepatic metabolism and have half-lives of 18-24 h. However, fluoxetine forms an active metabolite with a half-life of several days (the basis for a once-weekly formulation). Other members of this group (eg, citalopram, escitalopram, fluvoxamine, paroxetine, and sertraline) do not form long-acting metabolites.

Heterocyclics

These drugs have varied structures and include drugs that are serotonin-norepinephrine reuptake inhibitors (SNRIs, duloxetine, venlafaxine ), 5-HT 2 receptor antagonists ( nefazodone, trazodone ) and miscellaneous other heterocyclic agents including amoxapine, bupropion, maprotiline, and mirtazapine. The pharmacokinetics of most of these agents are similar to those of the TCAs. Nefazodone and trazodone are exceptions; their half-lives are short and usually require administration 2 or 3 times daily.

Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs; eg, phenelzine, tranylcypromine ) are structurally related to amphetamines and are orally active. The older, standard drugs inhibit both MAO-A (monoamine oxidase type A), which metabolizes NE, 5-HT, and tyramine, and MAO-B (monoamine oxidase type A), which metabolizes dopamine. Tranylcypromine is the fastest in onset of effect but has a shorter duration of action (about 1 week) than other MAOIs (2-3 weeks). In spite of these prolonged actions, the MAOIs are given daily. They are inhibitors of hepatic drug-metabolizing enzymes and cause drug interactions. Selegiline, a selective inhibitor of MAO type B, was recently approved for treatment of depression.

Mechanisms of Antidepressant Action

Potential sites of action of antidepressants at CNS synapses are shown in Figure 30-1. By means of several mechanisms, most antidepressants cause potentiation of the neurotransmitter actions of NE, 5-HT, or both. However, nefazodone and trazodone are weak inhibitors of NE and 5-HT transporters, and their main action appears to be antagonism of the 5-HT2A receptor. Long-term use of tricyclics and MAOIs, but not SSRIs, leads to downregulation of  receptors.

FIGURE 30-1

Possible sites of action of antidepressant drugs. Inhibition of neuronal uptake of norepinephrine (NE) and serotonin (5-HT) increases the synaptic activities of these neurotransmitters. Inhibition of monoamine oxidase increases the presynaptic stores of both NE and 5-HT, which leads to increased neurotransmitter effects. Blockade of the presynaptic 2 autoreceptor prevents feedback inhibition of the release of NE. Note: These are acute actions of antidepressants.

TCAs

The acute effect of tricyclic drugs is to inhibit the reuptake mechanisms (transporters) responsible for the termination of the synaptic actions of both NE and 5-HT in the brain. This presumably results in potentiation of their neurotransmitter actions at postsynaptic receptors.

SSRIs

The acute effect of SSRIs is a highly selective action on the serotonin transporter (SERT). SSRIs allosterically inhibit the transporter, binding at a site other than that of serotonin. They have minimal inhibitory effects on the NE transporter, or blocking actions on adrenergic and cholinergic receptors.

SNRIs

SNRIs bind to transporters for both serotonin and NE, presumably enhancing the actions of both neurotransmitters. Venlafaxine has less affinity for the NE transporter than desvenlafaxine or duloxetine. The SNRIs differ from the TCAs in lacking significant blocking effects on peripheral receptors including histamine H1, muscarinic, or -adrenergic receptors.

Serotonin 5-HT2 Receptor Antagonists

The major antidepressant actions of nefazodone and trazodone appear to result from block of the 5-HT 2A receptor, a G-protein-coupled receptor located in several CNS regions including the neocortex. Antagonism of this receptor is equated with both the antianxiety and antidepressant actions of these drugs.

Other Heterocyclic Antidepressants

Mirtazapine has a unique action to increase amine release from nerve endings by antagonism of presynaptic 2 adrenoceptors involved in feedback inhibition. The drug is also an antagonist at serotonin 5-HT 2 receptors. The mechanism of antidepressant action of bupropion is unknown—the drug has no effect on either 5-HT or NE receptors nor on amine transporters.

MAOIs

The MAOIs increase brain amine levels by interfering with their metabolism in the nerve endings, resulting in an increase in the vesicular stores of NE and 5-HT. When neuronal activity discharges the vesicles, increased amounts of the amines are released, presumably enhancing the actions of these neurotransmitters.

Pharmacologic Effects

Amine Uptake Blockade

The drugs that block NE transporters in the CNS (eg, tricyclics, maprotiline, venlafaxine) also inhibit the reuptake of NE at nerve endings in the autonomic nervous system. Likewise, MAOIs increase NE in sympathetic nerve terminals. In both cases, this can lead to peripheral autonomic sympathomimetic effects. However, long-term use of MAOIs can decrease blood pressure.

Sedation

Sedation is a common CNS effect of tricyclic drugs and some heterocyclic agents, especially mirtazapine and the 5-HT2 receptor antagonists nefazodone and trazodone (Table 30-1), the latter commonly prescribed for this purpose and as a sleeping aid. MAOIs, SSRIs, and bupropion are more likely to cause CNS-stimulating effects.

TABLE 30-1 Pharmacodynamic characteristics of selected antidepressants.

Drug Sedation Muscarinic Receptor Block NE Reuptake Block 5-HT Reuptake Block Tricyclics Amitriptylinea

+++ +++ + ++ Desipramine + + +++ + Doxepina

+ ++ +++ + Imipramine ++ ++ + ++ Nortriptyline ++ + ++ + SSRIs Citalopram, etc 0 0 0 +++ Heterocyclics—SNRIs Duloxetine 0 0 ++ +++ Venlafaxine 0 0 + +++ Heterocyclics—5-HT2 antagonistsNefazodone ++ + 0/+ + Trazodone ++ 0 0 + Heterocyclics—other Amoxapine ++ ++ ++ + Bupropion 0 0 0 0 Maprotiline + + ++ 0 Mirtazapineb

++ ++ + 0

SNRI, serotonin-norepinephrine reuptake inhibitor.

aSignificant 1 antagonism.

bSignificant H1 and 2 antagonism.

0/+, minimal activity; +, mild activity; ++, moderate activity; +++, high activity.

Muscarinic Receptor Blockade

Antagonism of muscarinic receptors occurs with all tricyclics and is particularly marked with amitriptyline and doxepin (Table 30-1). Atropine-like adverse effects may also occur with nefazodone, amoxapine and maprotiline. Atropine-like effects are minimal with the other heterocyclics, the SSRIs, and bupropion.

Cardiovascular Effects

Cardiovascular effects occur most commonly with tricyclics and include hypotension from -adrenoceptor blockade and depression of cardiac conduction. The latter effect may lead to arrhythmias. There have been reports of cardiotoxicity with overdose of venlafaxine.

Seizures

Because the convulsive threshold is lowered by TCAs and MAOIs, seizures may occur with overdoses of these agents. Overdoses of maprotiline and the SSRIs have also caused seizures.

Clinical Uses

Major Depressive Disorders

Major depression is the primary clinical indication for antidepressant drugs. Patients typically vary in their responsiveness to individual agents. Because of more tolerable side effects and safety in overdose (see later discussion), the newer drugs (SSRIs, SNRIs, 5-HT antagonists, and certain heterocyclics) are now the most widely prescribed agents. However, none of the newer antidepressants has been shown to be more effective overall than tricyclic drugs. As alternative agents, tricyclic drugs continue to be most useful in patients with psychomotor retardation, sleep disturbances, poor appetite, and weight loss. MAOIs are thought to be most useful in patients with significant anxiety, phobic features, and hypochondriasis. Selegiline, the MAO type B inhibitor used in parkinsonism (see Chapter 28), is now available in a skin-patch formulation for treatment of depression. SSRIs may decrease appetite; overweight patients often lose weight on these drugs, at least during the first 6-12 months of treatment. Concerns have been expressed that SSRIs, SNRIs, and newer heterocyclics may increase suicide risk in children and adolescents.

Other Clinical Uses

TCAs are also used in the treatment of bipolar affective disorders, acute panic attacks, phobic disorders (compare with alprazolam; Chapter 22), enuresis, attention deficit hyperkinetic disorder, and chronic pain states. The SNRIs (eg, duloxetine, venlafaxine) are effective in patients with neuropathic pain and fibromyalgia; duloxetine is also approved for the pain of diabetic neuropathy. Clomipramine and the SSRIs are effective in obsessive-compulsive disorders. SSRIs are approved for patients who suffer from generalized anxiety disorders, panic attacks, social phobias, post-traumatic stress disorder, bulimia, and premenstrual dysphoric disorder, and they may also be useful in the treatment of alcohol dependence. Bupropion is used for management of patients attempting to withdraw from nicotine dependence.

Toxicity & Drug Interactions

TCAs

The adverse effects of TCAs are largely predictable from their pharmacodynamic actions. These include (1) excessive sedation, lassitude, fatigue, and, occasionally, confusion; (2) sympathomimetic effects, including tachycardia, agitation, sweating, and insomnia; (3) atropine-like effects; (4) orthostatic hypotension, electrocardiogram (ECG) abnormalities, and cardiomyopathies; (5) tremor and paresthesias; and (6) weight gain. Overdosage with tricyclics is extremely hazardous, and the ingestion of as little as a 2-week supply has been lethal. Manifestations include (1) agitation, delirium, neuromuscular irritability, convulsions, and coma; (2) respiratory depression and circulatory collapse; (3) hyperpyrexia; and (4) cardiac conduction defects and severe arrhythmias. The "3 Cs"—coma, convulsions, and cardiotoxicity—are characteristic.

Tricyclic drug interactions (Table 30-2) include additive depression of the CNS with other central depressants, including ethanol, barbiturates, benzodiazepines, and opioids. Tricyclics may also cause reversal of the antihypertensive action of guanethidine by blocking its transport into sympathetic nerve endings. Less commonly, tricyclics may interfere with the antihypertensive actions of methylnorepinephrine (the active metabolite of methyldopa) and clonidine.

TABLE 30-2 Drug interactions involving antidepressants.

Antidepressant Taken With Consequence Fluoxetine Lithium, TCAs, warfarin Increased blood levels of second drug Fluvoxamine Alprazolam, theophylline, TCAs, warfarin Increased blood levels of second drug MAO inhibitors SSRIs, sympathomimetics, tyramine-containing foods Hypertensive crisis, serotonin syndrome Nefazodone Alprazolam, triazolam Increased blood levels of second drug Paroxetine Theophylline, TCAs, warfarin Increased blood levels of second drug Sertraline TCAs, warfarin Increased effects of second drug TCAs Ethanol, sedative hypnotics Increased CNS depression

MAO, monoamine oxidase; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.

SSRI Toxicity

Fluoxetine and the other SSRIs may cause nausea, headache, anxiety, agitation, insomnia, and sexual dysfunction. Jitteriness can be alleviated by starting with low doses or by adjunctive use of benzodiazepines. Extrapyramidal effects early in treatment may include akathisia, dyskinesias, and dystonic reactions. Seizures are a consequence of gross overdosage. Cardiac effects of citalopram overdose include QT prolongation. A withdrawal syndrome has been described for SSRIs, which includes nausea, dizziness, anxiety, tremor, and palpitations.

Certain SSRIs are inhibitors of hepatic cytochrome P450 isozymes, an action that has led to increased activity of other drugs, including TCAs and warfarin (Table 30-2). Fluoxetine inhibits CYP2D6 and to a lesser extent 3A4 isoforms; fluvoxamine inhibits CYP1A2 and paroxetine CYP2D6. Through its inhibition of CYP2D6, fluoxetine can increase plasma levels of several drugs including dextromethorphan, propranolol, tamoxifen, and the TCAs. Citalopram causes fewer drug interactions than other SSRIs.

serotonin syndrome was first described for an interaction between fluoxetine and an MAOI (see later discussion). This life-threatening syndrome includes severe muscle rigidity, myoclonus, hyperthermia, cardiovascular instability, and marked CNS stimulatory effects, including seizures. Drugs implicated include MAOIs, TCAs, dextromethorphan, meperidine, St. John's wort, and possibly illicit recreational drugs such as MDMA ("ecstasy"). Antiseizure drugs, muscle relaxants, and blockers of 5-HT receptors (eg, cyproheptadine) have been used in the management of the syndrome.

Toxicity of SNRIs, 5-HT2 Antagonists, and Heterocyclic Drugs

Mirtazapine causes weight gain and is markedly sedating, as is trazodone. Amoxapine, maprotiline, mirtazapine, and trazodone cause some autonomic effects. Amoxapine is also a dopamine receptor blocker and may cause akathisia, parkinsonism, and the amenorrhea-galactorrhea syndrome. Adverse effects of bupropion include anxiety, agitation, dizziness, dry mouth, aggravation of psychosis, and, at high doses, seizures. Seizures and cardiotoxicity are prominent features of overdosage with amoxapine and maprotiline. Venlafaxine causes a dose-dependent increase in blood pressure and has CNS stimulant effects similar to those of the SSRIs. Severe withdrawal symptoms can occur, even after missing a single dose of venlafaxine. Both nefazodone and venlafaxine are inhibitors of cytochrome P450 isozymes. Through its inhibitory action on CYP3A4, nefazodone enhances the actions of several drugs including carbamazepine, clozapine, HMG-CoA reductase inhibitors ("statins"), and TCAs. Though rare, nefazodone has caused life-threatening hepatotoxicity requiring liver transplantation. Duloxetine is also reported to cause liver dysfunction.

MAOI Toxicity

Adverse effects of the traditional MAOIs include hypertensive reactions in response to indirectly acting sympathomimetics, hyperthermia, and CNS stimulation leading to agitation and convulsions. Hypertensive crisis may occur in patients taking MAOIs who consume food that contains high concentrations of the indirect sympathomimetic tyramine. In the absence of indirect sympathomimetics, MAOIs typically lower blood pressure; overdosage with these drugs may result in shock, hyperthermia, and seizures. MAOIs administered together with SSRIs have resulted in the serotonin syndrome.

Checklist

When you complete this chapter, you should be able to:

Describe the probable mechanisms of action and the major characteristics of TCAs, including receptor interactions, adverse effects (from chronic use and in overdose), drug interactions, and clinical uses.

Identify the drugs classified as SSRIs and SNRIs, and describe their characteristics, including clinical uses, adverse effects and toxicity, and potential drug interactions.

Identify drugs thought to act via block of serotonin receptors, and describe their characteristics including clinical uses, adverse effects and toxicity, and potential drug interactions.

 Be aware of the limited role of MAO inhibitors in affective disorders.

Drug Summary Table: Antidepressants

Subclass Mechanism of Action Clinical Applications Pharmacokinetics & Drug Interactions Toxicities Tricyclic antidepressants Amitriptyline, clomipramine, imipramine, etc Block norepinephrine (NE) and 5-HT transporters Major depression (backup), chronic pain obsessive-compulsive disorder (OCD)—clomipramine CYP substrates: interactions with inducers and inhibitors Long half-lives  block, M block, sedation, weight gain; Overdose: arrhythmias, seizures Selective serotonin reuptake inhibitors (SSRIs) Citalopram, fluoxetine, paroxetine, sertraline, etc Block 5-HT transporters Major depression, anxiety disorders, OCD, PMDD, PTSD, bulimia, etc CYP 2D6 and 3A4 inhibition (fluoxetine, paroxetine); 1A2 (fluvoxamine) Half-lives: 15+ h Sexual dysfunction Serotonin-norepinephrine reuptake inhibitors (SNRIs) Venlafaxin Desvenlafaxine Duloxetine Block NE and 5-HT transporters Major depression, chronic pain, fibromyalgia, menopausal symptoms Half-lives: 10+ h Anticholinergic, sedation, hypertension (venlafaxine) 5-HT2 antagonists Nefazodone Trazodone Block 5-HT2 receptors

Major depression, hypnosis (trazodone) Usually require bid dosing; CYP3A4 inhibition (nefazodone) Short half-lives Sedation; modest  and H1 blockade (trazodone)

Other heterocyclics Amoxapine Bupropion Maprotilin Mirtazepine Mirtazepine blocks presynaptic 2 receptors; mechanism of action of others uncertain

Major depression, smoking cessation (bupropion), sedation (mirtazepine) Extensive hepatic metabolism; CYP2D6 inhibition (bupropion) Lowers seizure threshold (amoxapine, bupropion); sedation and weight gain (mirtazepine) Monoamine oxidase inhibitors (MAOIs) Isocarboxazid Phenelzine Selegiline Inhibit MAO-A and MAO-B; selegiline more active vs MAO-B Major depression unresponsive to other drugs Hypertension with tyramine and sympathomimetics Serotonin syndrome with SSRIs Very long half-lives Hypotension, insomnia

MAO-A, monoamine oxidase type A; MAO-B, monoamine oxidase type B; PMDD, premenstrual dysphoric disorder; OD, overdose; PTSD, post-traumatic stress disorder.



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