Antidepressants are logically classified based on their chemical structures and their acute neuropharmacologic effects (Table 43-2). The precise mechanism by which antidepressants work is unknown, but they appear to act by altering noradrenergic neurotransmission and/or serotoninergic neurotransmission (see Table 43-2). This suggests that antidepressants work by increasing the amount of norepinephrine and serotonin in synapses. Nevertheless, the most important observation not explained by this hypothesis is the time course of clinical improvement. Neurobiologically, reuptake blockade or monoamine oxidase (MAO) inhibition (necessary for breakdown of free norepinephrine and serotonin) occurs promptly after initiation of antidepressant therapy, but clinical improvement typically does not occur for 2 to 4 weeks. Perhaps adaptive changes including downregulation of neurotransmitter receptors are necessary before evidence of clinical improvement appears.
Selective Serotonin Reuptake Inhibitors
The selective serotonin reuptake inhibitors (SSRIs) are the most broadly prescribed class of antidepressants and are the drugs of choice for the treatment of mild to moderate depression.4 SSRIs are the first-line pharmacotherapy for panic disorder and obsessive-compulsive syndrome. These drugs are also effective in treatment of social phobia and posttraumatic stress disorder. SSRIs that share the ability to block the reuptake of serotonin (and thus enhance serotonergic activity) include fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram. Other newer SSRIs are believed to act on serotonin and norepinephrine pathways in the brain by a variety of mechanisms, including dual serotonin and norepinephrine reuptake blockade (venlafaxine) and α2-receptor blockade (mirtazapine).5 Different SSRIs have different side effect profiles, and patients who do not respond to one drug or who fail to tolerate the drug may do well on a different SSRI. Standard practice dictates trying several SSRIs before moving to another class of medication.
There is abundant evidence that serotonin receptors are involved in the etiology of anxiety. Potent inhibition of serotonin reuptake appears to be necessary for effectiveness in the treatment of obsessive-compulsive disorders. Compared with tricyclic antidepressants, SSRIs lack anticholinergic properties, do not cause postural hypotension or delayed conduction of cardiac impulses, and do not appear to have a major effect on the seizure threshold. Perhaps the most important advantage of SSRIs compared with tricyclic antidepressants is the relative safety of SSRIs when taken in overdose.6 The exception may be venlafaxine that may be similar to tricyclic antidepressants with respect to elevated overdose-associated risk associated with proconvulsant and cardiac side effects.7 Common side effects of SSRIs include insomnia, agitation, headache, nausea, and diarrhea. A prominent cause of noncompliance with SSRI therapy is drug-induced sexual dysfunction in both men and women (delayed ejaculation, anorgasmia, decreased libido).8
Abrupt discontinuation of SSRIs with short elimination half-times (paroxetine, venlafaxine) may be associated with dizziness, paresthesias, myalgias, irritability, insomnia, and visual disturbances. Tapering all SSRIs before discontinuance is recommended especially for drugs with short elimination half-times.9
In September 2004, the U.S. Food and Drug Administration recommended a “black box” warning for newer antidepressant drugs, primarily SSRIs.10 This warning is based on evidence that suicidal tendencies in children and adolescents may be increased in those age groups when they are treated with SSRIs. Nevertheless, the risk is small and many patients benefit from treatment with SSRIs emphasizing the need to individualize therapy.
Fluoxetine
Fluoxetine was the first SSRI introduced in the United States in 1988.11 The drug is commonly administered once daily in the morning to decrease the risk of insomnia. Because fluoxetine has a prolonged elimination half-time (1 to 3 days for acute administration and 4 to 6 days for chronic administration), the drug can be taken every other day. An active metabolite, norfluoxetine, has an elimination half-time of 4 to 16 days. A therapeutic effect produced by fluoxetine is usually evident in 2 to 4 weeks. Because of this drug’s prolonged elimination half-time, increases in dosage are often limited to no more often than once every 4 weeks.
Side Effects
The most common side effects of fluoxetine are nausea, anorexia, insomnia, sexual dysfunction, agitation, and neuromuscular restlessness, which may mimic akathisia. Appetite suppression associated with fluoxetine therapy may help patients achieve weight loss.12 Like tricyclic antidepressants, fluoxetine may be an effective analgesic for treatment of chronic pain as may be associated with rheumatoid arthritis.13 Fluoxetine does not cause hypotension, and changes in conduction of cardiac impulses seem infrequent. Bradycardia causing syncope has been reported in occasional elderly patients.14 Because of its long elimination half-time, fluoxetine should be discontinued for about 5 weeks before initiating treatment with an MAO inhibitor. The long elimination half-time of fluoxetine appears to prevent withdrawal symptoms induced by abrupt discontinuance of the drug. An overdose with fluoxetine alone is not associated with the risk of cardiovascular and central nervous system (CNS) toxicity.
Drug Interactions
Among the SSRIs, fluoxetine is the most potent inhibitor of certain hepatic cytochrome P-450 enzymes. As a result, this drug may increase the plasma concentrations of drugs that depend on hepatic metabolism for clearance. For example, the addition of fluoxetine to treatment with a tricyclic antidepressant drug may result in a two- to fivefold increase in the plasma concentration of the tricyclic drug. Neuroleptic drugs may inhibit the metabolism of fluoxetine or vice versa. Several cardiac antidysrhythmic drugs as well as some β-adrenergic antagonists may be metabolized by the same enzyme system that is inhibited by fluoxetine, resulting in potentiation of these drug effects. MAO inhibitors combined with fluoxetine may cause the development of a serotonin syndrome characterized by anxiety, restlessness, chills, ataxia, and insomnia.14 The combination of fluoxetine and lithium or carbamazepine may also provoke this potentially fatal syndrome.
Sertraline
Sertraline was the second SSRI introduced in the United States and has a spectrum of efficacy similar to fluoxetine. This drug has a shorter elimination half-time (25 hours) than fluoxetine and is a less potent inhibitor of hepatic microsomal enzymes. A potentially active metabolite has an elimination half-time of 60 to 70 hours.
Compared with fluoxetine, sertraline may cause more gastrointestinal symptoms (nausea, diarrhea) but may be less likely to cause insomnia and agitation. The recommended washout period before starting an MAO inhibitor is 14 days.
Paroxetine
Paroxetine was the third SSRI introduced in the United States and has an efficacy similar to that of fluoxetine. This drug has a relatively short elimination half-time (24 hours), and there are no active metabolites. Side effects resemble those of other SSRIs with the exception of a possibly increased incidence of sedation. The levels of paroxetine in breast milk are greater than levels in patients receiving fluoxetine or sertraline. Paroxetine produces less inhibition of hepatic cytoplasmic P-450 enzymes than is fluoxetine. Enhancement of the anticoagulant effect of warfarin reflects competition for common protein-binding sites. The recommended washout period before starting an MAO inhibitor is 14 days.
Citalopram/Escitalopram
Citalopram was the fourth SSRI introduced in the United States. Escitalopram is simply the S isomer of citalopram, which is the more pharmacologically active stereoisomer. Citalopram causes dose-dependent QT interval prolongation, which can place patients at risk for torsades de pointes.15,16 Escitalopram may also prolong the QT interval but possibly to a lesser degree. Citalopram should be used with caution in patients at risk for prolonged QT intervals.
Fluvoxamine
Fluvoxamine is effective in the management of obsessive-compulsive disorders. In addition, this drug probably has a spectrum of therapeutic efficacy similar to that of other SSRIs. The most common side effects associated with this drug are nausea, vomiting (possibly a greater frequency than with other SSRIs), headache, sedation, insomnia, and sexual dysfunction. Although it produces less inhibition of hepatic cytoplasmic P-450 enzymes than the other SSRIs, fluvoxamine may still cause clinically significant drug interactions.
Bupropion
Bupropion, which is structurally related to amphetamine, is effective in the treatment of major depression, producing improvement in 2 to 4 weeks. In addition, bupropion is effective for smoking cessation. The mechanism of action of bupropion is obscure but may include inhibition of dopamine and norepinephrine reuptake. This drug does not inhibit MAO. Bupropion is associated with a greater incidence of seizures (about 0.4%) than other antidepressants.17 Some patients experience stimulant-like effects early in therapy. Like the SSRIs, bupropion has no anticholinergic effects, does not cause postural hypotension, and lacks significant effects on conduction of cardiac impulses. Unlike the SSRIs, bupropion is not associated with significant drug interactions and is not commonly associated with sexual dysfunction. Ataxia and myoclonus have occurred rarely. Bupropion should not be administered in combination with an MAO inhibitor; elevated blood pressure and serotonin syndrome have been reported.18
Venlafaxine
Venlafaxine is perceived to have a profile of efficacy similar to that of the tricyclic antidepressants but has a more favorable side effect profile. Like the tricyclic antidepressants, this drug inhibits the reuptake of norepinephrine and serotonin and may potentiate the action of dopamine in the CNS. Unlike tricyclic antidepressants, venlafaxine does not produce anticholinergic effects or postural hypotension. Side effects include insomnia, sedation, and nausea. At high doses, a modest but persistent increase in diastolic blood pressure occurs in 5% to 7% of patients. Some studies have suggested that venlafaxine may be beneficial in patients with neuropathic pain. Venlafaxine is metabolized by cytochrome P-450 enzymes and also acts as a weak inhibitor of these enzymes. The elimination half-time is 5 hours and that of its active metabolite is 11 hours. Venlafaxine should not be used in combination with an MAO inhibitor, and the recommended washout period is 14 days.
Duloxetine
Duloxetine is a serotonin and noradrenaline reuptake inhibitor, similar to venlafaxine. Indications for its use include major depression, fibromyalgia, and diabetic neuropathy.19,20 Its side effect profile includes nausea, dry mouth, insomnia, and sexual dysfunction. It does not cause significant changes in blood pressure and is a moderate inhibitor of CYP2D6.21 Duloxetine should be avoided in patients with severe renal dysfunction and chronic liver disease. Like venlafaxine, duloxetine should not be used in combination with an MAO inhibitor. The potential for the development of serotonin syndrome is present when this drug is used in conjunction with another serotonergic drug.
Trazodone
Trazodone inhibits serotonin reuptake and may also act as a serotonin agonist via an active metabolite. Although effective in the management of depression, its greatest efficacy may be treatment of insomnia induced by SSRIs or bupropion. Common side effects of trazodone include sedation, orthostatic hypotension, nausea, and vomiting. Priapism may occur in males. This drug lacks effects on conduction of cardiac impulses but on rare occasions has been associated with cardiac dysrhythmias. The elimination half-time of this drug is brief (3 to 9 hours), and toxicity associated with an overdose is less than what accompanies an overdose of tricyclic antidepressants and MAO inhibitors. Combination therapy with an MAO inhibitor is not recommended.
Nefazodone
Nefazodone is chemically related to trazodone but with fewer α1-adrenergic blocking properties. Like trazodone, this drug inhibits reuptake of serotonin and norepinephrine. The risk of sedation and priapism may be less than in patients treated with trazodone. The principal side effects are nausea, dry mouth, and sedation. Orthostatic hypotension may occur. Nefazodone-induced inhibition of cytochrome P-450 results in elevated plasma concentrations of benzodiazepines, antihistamines, and of protease inhibitors used in the treatment of HIV infection. Combination therapy with an MAO inhibitor is not recommended.
Management of Anesthesia
Several studies have suggested that SSRIs may have antiplatelet activity and increase the risk of bleeding particularly in the setting of antiplatelet medication use.22–24 The risks of discontinuing an SSRI may take 2 to 3 weeks for full washout and reinitiation may require 2 to 4 weeks for reestablishment of clinical antidepressant effect. Furthermore, discontinuation of a patient’s SSRI may expose them to the risks of a major depressive episode. Anesthesia providers may consider holding antiplatelet medication in the perioperative setting if their patients are taking SSRIs, as there may be increased risk of bleeding in the setting of SSRI and antiplatelet medication use.
Tricyclic and Related Antidepressants
Before the availability of SSRIs, tricyclic antidepressants and related cyclic antidepressants were the most commonly used drugs to treat depression (see Table 43-2). Although tricyclic antidepressants are highly effective, they have been supplanted as first-line drugs in many clinical situations because of their unfavorable side effect profile (largely resulting from their anticholinergic, antiadrenergic, and antihistaminic properties). Tricyclic antidepressants also have a narrow therapeutic index and are potentially lethal in overdose (resulting in part from inhibition of sodium ion channels) reflecting a slowing of conduction of cardiac impulses and appearance of life-threatening cardiac dysrhythmias.
Measurement of plasma drug levels for the tricyclics imipramine, desipramine, and nortriptyline can be useful in guiding therapeutic decisions. Generally, plasma levels should not exceed 225 ng/mL when imipramine is administered. Plasma levels should not exceed 125 ng/mL when desipramine is administered, and the therapeutic range for nortriptyline is 50 to 150 ng/mL. It is preferable to taper tricyclic and tetracyclic antidepressants during a 4-week period to avoid the risk of withdrawal symptoms (chills, coryza, muscle aches). These symptoms have been attributed to supersensitivity of the cholinergic nervous system.
Chronic Pain Syndromes
The tricyclic antidepressants (especially amitriptyline and imipramine), in doses lower than those used to treat depression, may be useful in the treatment of chronic neuropathic pain and other chronic pain syndromes including fibromyalgia. Although there is no consensus on the mechanism of pain relief, current hypotheses include serotonin activity and reuptake inhibition, potentiation of CNS endogenous opioids, and antiinflammatory effects.25 Because of their structural similarities to local anesthetics and known sodium channel blockade, it is possible that tricyclic antidepressants produce antiinflammatory effects similar to local anesthetics. Because many chronic pain syndromes include an inflammatory component, it is possible that the clinical efficacy of tricyclic antidepressants in chronic pain patients is due to inhibition of an overactive inflammatory system.26 The efficacy of tricyclic antidepressants on chronic pain syndromes may be limited by a narrow therapeutic index and intolerability of side effects.
Structure–Activity Relationships
The structure of tricyclic antidepressants resembles that of local anesthetics and phenothiazines. Similar to local anesthetics, tricyclic antidepressants include a hydrophobic portion linked to an amide via a linear intermediate moiety. Tricyclic denotes the three-ring chemical structure of the central portion of the molecule. Imipramine, which is the prototype of the tricyclic antidepressants, differs from phenothiazine only in the replacement of the sulfur atom with an ethylene linkage to produce a seven-membered central ring. Desipramine is the principal metabolite of imipramine, and nortriptyline is the demethylated metabolite of amitriptyline. Maprotiline is a tetracyclic antidepressant with a clinical profile that resembles imipramine. Mirtazapine is a tetracyclic antidepressant that may enhance central norepinephrine and serotonin activity in the CNS. Maprotiline and mirtazapine should not be administered to patients being treated with MAO inhibitors.
Mechanism of Action
Tricyclic antidepressants act at several transporters and receptors, but their antidepressant effect is likely produced by blocking the reuptake (uptake) of serotonin and/or norepinephrine at presynaptic terminals, thereby increasing the availability of these neurotransmitters. These drugs can be categorized into tertiary amines, which inhibit reuptake of both serotonin and norepinephrine (amitriptyline, imipramine, clomipramine) and secondary amines, which are primarily norepinephrine reuptake inhibitors (desipramine, nortriptyline). Despite the prompt onset of this effect, the development of a therapeutic antidepressant effect is inexplicably delayed for 2 to 3 weeks. For this reason, there is doubt that antidepressant effects are totally due to an accumulation of biogenic amines in the brain. Furthermore, some drugs without effects on uptake of biogenic amines are effective antidepressants. It seems likely that potentiation of monoaminergic neurotransmission in the brain is only an early event in a complex cascade of events that eventually results in an antidepressant effect. Indeed, chronic administration of these drugs is associated with (a) decreased sensitivity of postsynaptic β1 and serotonin2 receptors and of presynaptic α2 receptors, and (b) increased sensitivity of postsynaptic α1 receptors.
Pharmacokinetics
Tricyclic antidepressants are efficiently absorbed from the gastrointestinal tract after oral administration, reflecting high lipid solubility. Peak plasma concentrations occur within 2 to 8 hours after oral administration. Therapeutic plasma concentrations (parent drug plus the pharmacologically active demethylated metabolites) are 100 to 300 ng/ mL, whereas toxicity is likely at levels greater than 500 ng/mL. Tricyclic antidepressants are strongly bound to plasma and tissue proteins, which, in combination with high lipid solubility, results in a large volume of distribution (up to 50 L/kg) for these drugs. The long elimination half-time (17 to 30 hours) and wide range of therapeutic plasma concentrations make once-daily dosing intervals effective.
Metabolism
Tricyclic antidepressants are oxidized by microsomal enzymes in the liver with subsequent conjugation with glucuronic acid. The individual variation in rate of metabolism between patients is 10- to 30-fold. Metabolism is likely to be slowed in elderly patients. The elimination of tricyclic antidepressants occurs over several days, with 1 week or longer required for excretion.
Imipramine is metabolized to the active compound desipramine. Both these active compounds are inactivated by oxidation of hydroxy metabolites and by conjugation with glucuronic acid. Nortriptyline, which is the pharmacologically active demethylated metabolite of imipramine and amitriptyline, can accumulate to levels that exceed the precursors. Doxepin also appears to be converted to an active metabolite, nordoxepin, by demethylation.
Side Effects
The side effects of tricyclic antidepressants occur frequently, most commonly manifesting as (a) anticholinergic effects, (b) cardiovascular effects, and (c) CNS effects (see Table 43-2). Individual variation in the incidence and type of side effects may be related to the plasma concentrations of the tricyclic antidepressant and its active metabolites.
Anticholinergic Effects
The anticholinergic effects of tricyclic antidepressants are prominent, especially at high doses. Amitriptyline causes the highest incidence of anticholinergic effects (dry mouth, blurred vision, tachycardia, urinary retention, slowed gastric emptying, ileus), whereas desipramine produces the fewest such effects (see Table 43-2). Anticholinergic delirium may occur in elderly patients even at therapeutic doses of these drugs. Serious anticholinergic toxicity may reflect the results of polypharmacy with more than one anticholinergic drug (over-the-counter preparations to treat diarrhea or insomnia). Elderly patients have greater sensitivity to anticholinergic and other receptor effects compared with younger patients being treated with tricyclic antidepressants.
Cardiovascular Effects
Orthostatic hypotension and modest increases in heart rate are the most common cardiovascular side effects of tricyclic antidepressants, presumably reflecting drug-induced inhibition of norepinephrine reuptake into presynaptic nerve terminals. Orthostatic hypotension may be particularly hazardous in elderly patients, who are at increased risk of fractures when they fall. The risk of hypotension during general anesthesia in patients treated with tricyclic antidepressants is low but has been reported.27 Previous suggestions that tricyclic antidepressants increase the risks of cardiac dysrhythmias and sudden death have not been substantiated in the absence of drug overdose.28 Furthermore, in the absence of severe preexisting cardiac dysfunction, tricyclic antidepressants lack adverse effects on left ventricular function and may even possess cardiac antidysrhythmic properties.29
Tricyclic antidepressants produce depression of conduction of cardiac impulses through the atria and ventricles, manifesting on the electrocardiogram (ECG) as prolongation of the P-R interval, widening of the QRS complex, and flattening or inversion of the T wave. Nevertheless, these changes on the ECG are probably benign and gradually disappear with continued therapy.28 Atropine is a useful treatment when tricyclic antidepressants dangerously slow atrioventricular or intraventricular conduction of cardiac impulses.
Direct cardiac depressant effects may reflect quinidine-like actions of tricyclic antidepressants on the heart. Conceivably, there could also be enhancement of depressant cardiac effects of anesthetics by tricyclic antidepressants. Quinidine-like properties of tricyclic antidepressants are thought to reflect slowing of sodium ion flux into cells, resulting in altered repolarization and conduction of cardiac impulses.
Central Nervous System Effects
Sedation associated with tricyclic antidepressant therapy may be desirable for management of depressed patients with insomnia. Amitriptyline and doxepin produce the greatest degree of sedation (see Table 43-2). Tricyclic antidepressants, especially maprotiline and clomipramine, lower the seizure threshold, raising the question of the advisability of administering these drugs to patients with seizure disorders or to those receiving drugs that may produce seizures. Children seem to be especially vulnerable to the seizure-inducing effects of tricyclic antidepressants. Treatment with tricyclic antidepressants may enhance the CNS-stimulating effects of enflurane. Weakness and fatigue are attributable to CNS effects and may resemble those seen in patients treated with phenothiazines. Extrapyramidal reactions are rare, although a fine tremor develops in about 10% of patients, especially the elderly. Because of their cardiac toxicity, tendency to cause seizures, and depressant properties on the CNS, the tricyclic antidepressants may be fatal if taken in an overdose. The combination of a tricyclic antidepressant and an MAO inhibitor may result in CNS toxicity manifesting as hyperthermia, seizures, and coma.
Drug Interactions
The anticholinergic effects and catecholamine uptake blocking properties of tricyclic antidepressants are most likely to be responsible for drug interactions. Drug interactions may be prominent with (a) sympathomimetics, (b) inhaled anesthetics, (c) anticholinergics, (d) antihypertensives, and (e) opioids. Binding of tricyclic antidepressants to plasma albumin can be decreased by competition from other drugs, including phenytoin, aspirin, and scopolamine.
Sympathomimetics
The systemic blood pressure response to the administration of sympathomimetics to patients treated with tricyclic antidepressants is complex and unpredictable. It has been suggested that indirect-acting sympathomimetics may produce exaggerated pressor responses due to an increased amount of norepinephrine available to stimulate postsynaptic adrenergic receptors. Although acute administration of tricyclic antidepressants increases sympathetic nervous system synaptic activity due to norepinephrine reuptake blockade, chronic administration of these drugs may result in decreased sympathetic nervous system transmission due to downregulation of β-adrenergic receptors.30,31 It would appear that for patients recently started on tricyclic antidepressants, exaggerated pressor responses should be anticipated whether or not direct-acting or indirect-acting sympathomimetics are administered, although pressor responses may be more pronounced with an indirect-acting drug such as ephedrine. Smaller than usual doses of direct-acting sympathomimetics that are titrated to a specific hemodynamic response are recommended. For individuals chronically treated with tricyclic antidepressants (>6 weeks), administration of either a direct-acting or indirect-acting sympathomimetic is acceptable, although a prudent approach may be to decrease the initial dose of drug to about one-third the usual dose. Conversely, conventional sympathomimetics may not be effective in restoring systemic blood pressure in patients chronically treated with tricyclic antidepressants because adrenergic receptors are either desensitized or catecholamine stores are depleted. In these patients, a potent direct-acting sympathomimetic such as norepinephrine may be the only effective management for hypotension.32
Induction of anesthesia may be associated with an increased incidence of cardiac dysrhythmias in patients treated with tricyclic antidepressants. Likewise, the dose of exogenous epinephrine necessary to produce cardiac dysrhythmias during anesthesia with a volatile anesthetic is decreased by tricyclic antidepressants.33 Theoretically, increased availability of norepinephrine in the CNS could result in increased anesthetic requirements for inhaled anesthetics.
Anticholinergics
Because the anticholinergic side effects of drugs may be additive, the use of centrally active anticholinergic drugs for preoperative medication of patients treated with tricyclic antidepressants could increase the likelihood of postoperative delirium and confusion (central anticholinergic syndrome). Glycopyrrolate would theoretically be less likely to evoke this type of drug interaction in patients being treated with tricyclic antidepressants.
Antihypertensives
Rebound hypertension after abrupt discontinuation of clonidine may be accentuated and prolonged by concomitant tricyclic antidepressant therapy.34 Conceivably, increased plasma concentrations of catecholamines can persist for longer periods in the presence of tricyclic antidepressants that prevent uptake of norepinephrine back into sympathetic nerve endings.
Opioids
In animals, tricyclic antidepressants augment the analgesic and ventilatory depressant effects of opioids. If these responses also occur in patients, doses of these drugs should be carefully titrated to avoid exaggerated or prolonged depressant effects.
Tolerance
Tolerance to anticholinergic effects (dry mouth, blurred vision, tachycardia) and orthostatic hypotension develops during chronic therapy with tricyclic antidepressants. Conversely, tolerance to desirable effects often fails to develop. Abrupt discontinuation of high doses of tricyclic antidepressants may be associated with a mild withdrawal syndrome characterized by malaise, chills, coryza, and skeletal muscle aching.
Overdose
Tricyclic antidepressant overdose is life-threatening, as the progression from an alert state to unresponsiveness may be rapid.35 Intractable myocardial depression or ventricular cardiac dysrhythmias are the most frequent terminal events.
Presenting features of tricyclic antidepressant overdose include agitation and seizures followed by coma, depression of ventilation, hypotension, hypothermia, and striking evidence of anticholinergic effects including mydriasis, flushed dry skin, urinary retention, and tachycardia. The QRS complex on the ECG may be prolonged to greater than 100 milliseconds. Indeed, the likelihood of seizures and ventricular dysrhythmias is increased when the duration of the QRS complex is greater than 100 milliseconds.36 Conversely, plasma concentrations of tricyclic antidepressants do not allow prediction of the likely occurrence of seizures or cardiac dysrhythmias.36
The comatose phase of tricyclic antidepressant overdose lasts 24 to 72 hours. Even after this phase passes, the risk of life-threatening cardiac dysrhythmias persists for up to 10 days, necessitating continued monitoring of the ECG in these patients.
Treatment of a life-threatening overdose of a tricyclic antidepressant is directed toward management of CNS and cardiac toxicity (Table 43-3).35 Coma usually resolves in 24 hours but is frequently severe enough to require invasive airway support. Extrapyramidal effects and organic brain syndrome usually require supportive care only, although judicious use of physostigmine, 0.5 to 2 mg given intravenously (IV), for treatment of anticholinergic psychosis may be indicated.
Seizures may precede cardiac arrest and should be treated aggressively with a benzodiazepine. After initial suppression of seizure activity with diazepam, it may be necessary to provide sustained effects with a longer acting drug such as phenytoin. Acidosis associated with seizure activity may abruptly increase the unbound fraction of tricyclic antidepressants in the circulation and predispose to cardiac dysrhythmias. In this regard, alkalization of the plasma (pH >7.45) either by IV administration of sodium bicarbonate or deliberate hyperventilation of the patient’s lungs can temporarily reverse drug-induced cardiotoxicity. Lidocaine and phenytoin may be used subsequently to provide sustained suppression of cardiac ventricular dysrhythmias.
Hypotension may be the result of direct tricyclic antidepressant–induced vasodilation, α-adrenergic blockade, or myocardial depression. Patients remaining hypotensive despite intravascular fluid replacement and alkalinization of the plasma may require systemic blood pressure support with sympathomimetics, inotropes, or both.
Gastric lavage may be useful in the early treatment, but this is most safely performed with a cuffed tracheal tube already in place. Activated charcoal significantly absorbs drugs throughout the gastrointestinal tract (“intestinal dialysis”). Conversely, avid protein binding of tricyclic antidepressants negates any therapeutic value of hemodialysis or drug-induced diuresis.
Monoamine Oxidase Inhibitors
MAO inhibitors constitute a heterogenous group of drugs, which block the enzyme that metabolizes biogenic amines, increasing the availability of these neurotransmitters in the CNS and peripheral autonomic nervous system. MAO inhibitors are used less commonly because their administration is complicated by side effects (hypotension), lethality in overdose, and lack of simplicity in dosing. Patients treated with MAO inhibitors must follow a specific tyramine-free diet because of the potential for pharmacodynamic interactions with tyramine that can result in systemic hypertension (Table 43-4). However, many patients with major depression who do not respond to cyclic antidepressants improve with MAO inhibitors. MAO inhibitors are also effective in the treatment of panic disorder. The dosage of MAO inhibitors is the same in the elderly as in younger adults because elderly persons often have higher levels of MAO and because the metabolism of these drugs does not seem to be affected by age.
The only MAO inhibitors approved in the United States for the treatment of depression or panic disorder are phenelzine, tranylcypromine, and isocarboxazid. Selegiline, which is a MAO-B selective inhibitor (formerly termed deprenyl), has been shown to be effective in the treatment of early Parkinson’s disease. These drugs are administered orally, being readily absorbed from the gastrointestinal tract.
Monoamine Oxidase Enzyme System
MAO is a flavin-containing enzyme found principally on outer mitochondrial membranes. The enzyme functions via oxidative deamination to inactivate several monoamines including dopamine, serotonin (5-hydroxytryptamine), norepinephrine, and epinephrine. MAO is divided into two subtypes (MAO-A and MAO-B) based on different substrate specificities (Fig. 43-1).2,3 MAO-A preferentially deaminates serotonin, norepinephrine, and epinephrine, whereas MAO-B preferentially deaminates phenylethylamine. Platelets contain exclusively MAO-A and the placenta exclusively MAO-B. About 60% of human brain MAO activity is of the A subtype.
Mechanism of Action
MAO inhibitors act by forming a stable, irreversible complex with MAO enzyme, especially with cerebral neuronal MAO.37 As a result, the amount of neurotransmitter (norepinephrine) available for release from CNS neurons increases. These effects, however, are not limited to the brain, and the concentration of norepinephrine also increases in the sympathetic nervous system. Because MAO inhibitors cause irreversible enzyme inhibition, their effects are prolonged, as the synthesis of new enzyme is a slow process.
Due to its location in the outer mitochondrial membrane, MAO in neurons is only capable of deaminating substrates that are free within the cytoplasm and are unable to gain access to substrates once they are bound in the storage vesicles. As a result, cytoplasmic concentrations of monoamines are maintained at a low level.
Side Effects
The most common serious side effect of MAO inhibitors is orthostatic hypotension, which may be especially prominent in elderly patients. Orthostatic hypotension may reflect accumulation of the false neurotransmitter octopamine in the cytoplasm of postganglionic sympathetic nerve endings. Release of this less potent vasoconstrictor in response to neural impulses is the most likely explanation for orthostatic hypotension as well as the antihypertensive effect that has been associated with chronic MAO inhibitor therapy.
Phenelzine has anticholinergic-like side effects and may produce sedation in some patients. Tranylcypromine has no anticholinergic side effects but has mild stimulant effects, which may cause insomnia. Impotence and anorgasmy are side effects of MAO inhibitors. Some patients complain of paresthesias, which may respond to pyridoxine therapy. Weight gain is a common side effect of treatment with MAO inhibitors. Hepatitis is a rare complication of MAO inhibitor therapy. Effects of MAO inhibitors on the electroencephalogram (EEG) are minimal and not seizure-like, which contrasts with tricyclic antidepressants. Also in contrast with tricyclic antidepressants is the failure of MAO inhibitors to produce cardiac dysrhythmias.33
Dietary Restrictions
MAO enzyme present in the liver, gastrointestinal tract, kidneys, and lungs seems to perform a protective function in deactivating circulating monoamines. In particular, this enzyme appears to form the initial defense against monoamines absorbed from foods, such as tyramine and β-phenylethanolamine, which would otherwise produce an indirect sympathomimetic response and precipitous hypertension. MAO-A is found in the gastrointestinal tract and liver, where it acts to metabolize bioactive amines such as tyramine. The MAO inhibitors used in the United States as antidepressants inhibit MAO-A and MAO-B nonselectively. Selegiline, when used to treat Parkinson’s disease, selectively inhibits MAO-B and patients do not need to follow a tyramine-free diet. At high doses (30 mg per day), however, even selegiline becomes a nonselective MAO inhibitor, making dietary precautions necessary (see Table 43-4).
Because patients treated with MAO inhibitors cannot metabolize dietary tyramine and other monoamines, these compounds can enter the systemic circulation and be taken up by sympathetic nervous system nerve endings. This uptake can elicit massive release of endogenous catecholamines and result in a hyperadrenergic crisis characterized by hypertension, hyperpyrexia, and cerebral vascular accident. Therefore, patients taking MAO inhibitors should be instructed to report promptly the onset of serious headache, nausea, vomiting, or chest pain. The precipitous hypertension resembles that which occurs with the release of catecholamines from a pheochromocytoma. Treatment of hypertension is with a peripheral vasodilator such as nitroprusside. Cardiac dysrhythmias that persist after control of systemic blood pressure are treated with lidocaine or a β-adrenergic antagonist.
Drug Interactions
In addition to interacting with foods, MAO inhibitors can interact adversely with opioids, sympathomimetic drugs, tricyclic antidepressants, and SSRIs. These interactions can result in hypertension, CNS excitation, delirium, seizures, and death. In animals, anesthetic requirements for volatile anesthetics are increased, presumably reflecting accumulation of norepinephrine in the CNS.
Opioids and Monoamine Oxidase Inhibitors
Administration of meperidine to a patient treated with MAO inhibitors may result in an excitatory (type I) response (agitation, headache, skeletal muscle rigidity, hyperpyrexia) or a depressive (type II) response characterized by hypotension, depression of ventilation, and coma.38 Enhanced serotonin activity in the brain is presumed to be responsible for excitatory reactions evoked by meperidine. Meperidine is capable of inhibiting neuronal serotonin uptake. Slowed breakdown of meperidine due to N-demethylase inhibition by MAO inhibitors is the presumed explanation for hypotension and depression of ventilation. About 20% of MAO inhibitor–treated patients have experienced excitatory reactions in response to meperidine. There is evidence that meperidine toxicity is increased only when both MAO-A and MAO-B are inhibited.3 Derivatives of meperidine (fentanyl, sufentanil, alfentanil) have been associated with adverse reactions in patients treated with MAO inhibitors, although the incidence seems to be less than with meperidine.39 Morphine does not inhibit uptake of serotonin, but its opioid effects may be potentiated in the presence of MAO inhibitors.
Sympathomimetics and Monoamine Oxidase Inhibitors
There is no experimental evidence to support the recommendation that all sympathomimetic drugs be avoided in patients treated with MAO inhibitors. The most consistent observation has been an occasional patient who experienced an exaggerated systemic blood pressure response after the administration of an indirect-acting vasopressor such as ephedrine. The hypertensive response is presumed to reflect an exaggerated release of norepinephrine from neuronal nerve endings. If needed, the use of a direct-acting sympathomimetic (phenylephrine) is preferable to an indirect-acting drug, keeping in mind that receptor hypersensitivity may enhance the systemic blood pressure response to these drugs as well. Regardless of the drug selected, the recommendation is to decrease the dose to about one-third of normal, with additional titration of doses based on cardiovascular responses.3
Overdose
Overdose with an MAO inhibitor is reflected by signs of excessive sympathetic nervous system activity (tachycardia, hyperthermia, mydriasis), seizures, and coma. Treatment is supportive in addition to gastric lavage. Dantrolene has been suggested as a treatment for skeletal muscle rigidity and associated symptoms of hypermetabolism after an overdose with MAO inhibitors.40
Management of Anesthesia
In the past, it was a common recommendation to discontinue MAO inhibitors 2 to 3 weeks before elective surgery based on the concern that life-threatening cardiovascular and CNS instability could occur during anesthesia and surgery when these drugs were present. This policy of drug withdrawal seems to be based more on anecdotes and isolated responses than on controlled scientific studies. Furthermore, discontinuation of effective therapy potentially places patients at risk from their psychiatric disturbances. There is growing appreciation that anesthesia can be safely administered in most patients being chronically treated with MAO inhibitors.3 When anesthesia is administered to patients treated with MAO inhibitors, it remains prudent to consider certain drug interactions and to avoid certain drugs, if possible.3,37
Selection of Drugs Used during Anesthesia
The anesthetic technique selected should minimize the possibility of sympathetic nervous system stimulation or drug-induced hypotension. Regional anesthesia as in parturients is acceptable, recognizing the disadvantage of these techniques should hypotension require administration of a sympathomimetic.38 If regional anesthesia is performed, a cautious approach is not to add epinephrine to the local anesthetic solution, although problems have not been reported with a 1:200,000 dilution. An advantage of regional anesthesia is postoperative analgesia such that the need for opioids is negated or minimized. Etomidate and thiopental have been administered to MAO inhibitor–treated patients undergoing electroconvulsive therapy without adverse effects. Responses to nondepolarizing neuromuscular blocking drugs are not altered by MAO inhibitors.
Serotonin Syndrome
Serotonin syndrome occurs when there is an excess of serotonin agonism in the central and peripheral nervous systems. The clinical findings can vary widely from mild tremor to altered mental status, clonus, and hyperthermia.41 SSRIs, tricyclic antidepressants, and MAO inhibitors, particularly in combination, have all been associated with serotonin syndrome. The differential diagnosis includes malignant hyperthermia, neuroleptic malignant syndrome, and anticholinergic poisoning (Table 43-5). Management of serotonin syndrome includes hemodynamic and respiratory supportive care, discontinuation of offending serotonergic agents, control of agitation with sedatives, control of hyperthermia, and administration of 5-HT2A antagonists.
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