VA Class:CN602

AHFS Class:

• Monoamine Oxidase Inhibitors 28:16.04.12

Associated Monographs

• Phenelzine Sulfate

• Rasagiline Mesylate

• Safinamide Mesylate

• Selegiline Hydrochloride

• Tranylcypromine Sulfate

Nonselective monoamine oxidase inhibitors block oxidative deamination of naturally occurring monoamines and are used as antidepressants.

Major Depressive Disorder

Monoamine oxidase (MAO) inhibitors with antidepressant action (phenelzine, tranylcypromine) are used in the treatment of major depressive disorder. A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks).149 According to DSM-IV criteria, a major depressive episode includes at least 5 of the following 9 symptoms (with at least one of the symptoms being depressed mood or loss of interest or pleasure): depressed mood most of the day as indicated by subjective report (e.g., feels sad or empty) or observation made by others; markedly diminished interest or pleasure in all, or almost all, activities most of the day; significant weight loss (when not dieting) or weight gain (e.g., a change of more than 5% of body weight in a month) or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation (observable by others, not merely subjective feelings of restlessness or being slowed down); fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick); diminished ability to think or concentrate or indecisiveness (either by subjective account or as observed by others); and recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide.149

Treatment of major depressive disorder generally consists of an acute phase (to induce remission), a continuation phase (to preserve remission), and a maintenance phase (to prevent recurrence).146,147,148 Various interventions (e.g., psychotherapy, antidepressant drug therapy, electroconvulsive therapy [ECT]) are used alone or in combination to treat major depressive episodes.146,147,148 Treatment should be individualized and the most appropriate strategy for a particular patient is determined by clinical factors such as severity of depression (e.g., mild, moderate, severe), presence or absence of certain psychiatric features (e.g., suicide risk, catatonia, psychotic or atypical features, alcohol or substance abuse or dependence, panic or other anxiety disorder, cognitive dysfunction, dysthymia, personality disorder, seasonal affective disorder), and concurrent illness (e.g., asthma, cardiac disease, dementia, seizure disorder, glaucoma, hypertension).146 Demographic and psychosocial factors as well as patient preference also are used to determine the most effective treatment strategy.146

While use of psychotherapy alone may be considered as an initial treatment strategy for patients with mild to moderate major depressive disorder (based on patient preference and presence of clinical features such as psychosocial stressors), combined use of antidepressant drug therapy and psychotherapy may be useful for initial treatment of patients with moderate to severe major depressive disorder with psychosocial issues, interpersonal problems, or a comorbid axis II disorder.146 In addition, combined use of antidepressant drug therapy and psychotherapy may be beneficial in patients who have a history of poor compliance or only partial response to adequate trials of either antidepressant drug therapy or psychotherapy alone.146

Antidepressant drug therapy can be used alone for initial treatment of patients with mild major depressive disorder (if preferred by the patient) and usually is indicated alone or in combination with psychotherapy for initial treatment of patients with moderate to severe major depressive disorder (unless ECT is planned).146 ECT is not generally used for initial treatment of uncomplicated major depression, but is recommended as first-line treatment for severe major depressive disorder when it is coupled with psychotic features, catatonic stupor, severe suicidality, food refusal leading to nutritional compromise, or other situations when a rapid antidepressant response is required.146 ECT also is recommended for patients who have previously shown a positive response or a preference for this treatment modality and can be considered for patients with moderate or severe depression who have not responded to or cannot receive antidepressant drug therapy.146 In certain situations involving severely depressed patients unresponsive to adequate trials of individual antidepressant agents, adjunctive therapy with another agent (e.g., buspirone, lithium) or concomitant use of a second antidepressant agent (e.g., bupropion) has been used; however, such combination therapy is associated with an increased risk of adverse reactions, may require dosage adjustments, and (if not contraindicated) should be undertaken only after careful consideration of the relative risks and benefits.146 (See Drug Interactions: Drugs Associated with Serotonin Syndrome and see Drug Interactions: Tricyclic Antidepressants.)

A variety of antidepressant drugs are available for the treatment of major depressive disorder, including selective serotonin-reuptake inhibitors (SSRIs) (e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline), tricyclic antidepressants (e.g., amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), MAO inhibitors (e.g., phenelzine, tranylcypromine), and other antidepressants (e.g., bupropion, duloxetine, maprotiline, nefazodone, trazodone, venlafaxine).146,165 Most clinical studies have shown that the antidepressant effect of usual dosages of various antidepressant agents in patients with major depression are similar.146 Therefore, the choice of antidepressant agent for a given patient depends principally on other factors such as potential adverse effects, safety or tolerability of these adverse effects in the individual patient, psychiatric and medical history, patient or family history of response to specific therapies, patient preference, quantity and quality of available clinical data, cost, and relative acute overdose safety.146 No single antidepressant can be recommended as optimal for all patients because of substantial heterogeneity in individual responses and in the nature, likelihood, and severity of adverse effects.146 In addition, patients vary in the degree to which certain adverse effects and other inconveniences of drug therapy (e.g., cost, dietary restrictions) affect their preferences.146

Because of the potential for serious adverse effects, MAO inhibitors generally are not used as initial therapy in the management of depression, but are reserved for patients who do not respond adequately to other antidepressant agents (e.g., SSRIs, tricyclic antidepressants) or in whom other therapies are contraindicated.103,146 It has been suggested that patients most likely to respond to MAO inhibitors are those who have depression with atypical features,146 including those who exhibit reactivity of mood and weight gain or increased appetite, sleep, and libido; those with a history of agoraphobia with secondary depression or agoraphobia with panic attacks; those with primary depression in whom pain or other somatic discomfort is the major complaint; and those with psychogenic pain or hypochondriasis and secondary depression. Phenelzine has been found to be effective in depressed patients clinically characterized as atypical, nonendogenous, or neurotic (these patients often have mixed anxiety and depression and phobic or hypochondriacal features), but there is less conclusive evidence that phenelzine is useful in severely depressed patients with endogenous features.103 Tranylcypromine is indicated for the treatment of major depressive episodes without melancholia, and effectiveness of the drug in patients who have major depressive episodes with melancholia (endogenous features) has not been established.104 MAO inhibitors appear to be particularly effective in reducing psychomotor retardation and morbid preoccupation. Somatic signs and symptoms associated with depression, including sleep and eating disturbances, also are reduced during MAO inhibitor therapy.146

For further information on treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant agent for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidal risks, see Considerations in Choosing Antidepressants under Uses: Major Depressive Disorder, in the Tricyclic Antidepressants General Statement 28:16.04.28.

Parkinsonian Syndrome

Certain MAO inhibitors that have increased selectivity for MAO-B (i.e., rasagiline, safinamide, selegiline) are used for the symptomatic treatment of parkinsonian syndrome (e.g., parkinsonism, Parkinson disease [paralysis agitans]); these drugs generally are not used for the management of major depressive disorder. For additional information on the use of MAO-B inhibitors in the management of parkinsonian syndrome, see the individual monographs for Rasagiline Mesylate, Safinamide Mesylate, and Selegiline Hydrochloride in 28:36.32.

Eating Disorders

MAO inhibitors (e.g., phenelzine) have been used with some success in the management of bulimia nervosa†.153 However, MAO inhibitors potentially are dangerous in patients with chaotic binge eating and purging behaviors and the American Psychiatric Association (APA) states that MAO inhibitors should be used with caution in the management of bulimia nervosa.153 For information on the diagnosis and treatment of bulimia nervosa and other eating disorders, see Uses: Eating Disorders, in Fluoxetine Hydrochloride 28:16.04.20.

Administration

Monoamine oxidase (MAO) inhibitors are administered orally.

Dosage

There is a wide range of individual requirements for MAO inhibitor dosage, and dosage must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage. The initial dosage may be increased gradually according to the patient's tolerance and therapeutic response; however, because therapeutic response to the drugs may be delayed for several days to up to 4 weeks or more, sufficient time should be allowed between increases in dosage. Some manufacturers recommend that at least 1-2 weeks elapse between dosage adjustments. Dosage should be increased more gradually in debilitated, emaciated, or geriatric patients.

Patients receiving MAO inhibitors should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.154,155,160 (See Worsening of Depression and Suicidality Risk under Cautions: Precautions and Contraindications.)

The potential adverse effects of monoamine oxidase (MAO) inhibitors are more varied and potentially more serious than those reported for most other classes of antidepressant agents.150 Because monoamine oxidase is widely distributed throughout the body, MAO inhibitor therapy can be expected to cause diverse pharmacologic effects.103 Many adverse effects of MAO inhibitors are mild to moderate in severity and often subside as therapy is continued.103 However, serious reactions requiring discontinuance of therapy can occur and usually involve the cardiovascular, CNS, and hepatic systems.103,150 Some of the most serious adverse effects reported with MAO inhibitors (e.g., hypertensive crisis, serotonin syndrome) have occurred when MAO inhibitors were administered concomitantly with certain foods or prescription or nonprescription (OTC) drugs.103,150

The adverse effect profiles of phenelzine and tranylcypromine are similar;103,104,151 reports of differences among the individual MAO inhibitors have been poorly substantiated.151

Cardiovascular Effects

Orthostatic Hypotension

Orthostatic hypotension is a common adverse effect of MAO inhibitors. Although it has been reported most frequently in patients with preexisting hypertension, it also has occurred in normotensive and hypotensive patients.103,104 Hypertensive patients may occasionally experience a transient moderate rise in blood pressure while receiving MAO inhibitors, but these patients more commonly exhibit symptoms of orthostatic hypotension. Unlike hypotension reported with tricyclic antidepressants, hypotension related to MAO inhibitors affects both supine and postural blood pressure changes.151

Orthostatic hypotension reported with MAO inhibitors is dose related, and may result in syncope at high doses.104 In patients who show some hypotensive response during initiation of MAO inhibitor therapy, dosage should be increased gradually.104 Postural hypotension may be relieved by having the patient lie down until blood pressure returns to normal.104 If orthostatic hypotension persists or is severe, dosage should be reduced or therapy with the drugs discontinued.103

Hypertensive Crisis

One of the most serious adverse effects associated with MAO inhibitor therapy is hypertensive crisis, which has been fatal in some patients.103,104,151 Several cases of spontaneous hypertension or significant increases in supine blood pressure without similar changes in standing blood pressure have been reported in patients receiving phenelzine or tranylcypromine, and it has been suggested that a family history of hypertension may be a risk factor for MAO inhibitor-induced hypertensive events.151 However, most reported cases of hypertensive crisis in patients receiving MAO inhibitor therapy usually have occurred when the drugs were used concomitantly with certain food or prescription or nonprescription drugs.103,104,150 (See Drug Interactions: Food and Drugs Associated with Hypertensive Crisis.)

Hypertensive crisis is characterized by severe headache (occipital headache which may radiate frontally); palpitation; neck stiffness or soreness; nausea or vomiting; sweating (sometimes with fever and sometimes with cold, clammy skin); and mydriasis and/or visual disturbances such as photophobia.103,104 Tachycardia or bradycardia may be present, and associated constricting chest pain and dilated pupils may occur.103,104 Intracranial hemorrhage, which may be fatal, has also been reported to occur in some patients with hypertensive crisis.103,104

If a hypertensive crisis or prodromal signs of a hypertensive crisis occur, MAO inhibitor therapy should be discontinued and appropriate therapy to lower blood pressure should be instituted immediately.103,104 Phentolamine has been considered the hypotensive drug of choice for the management of MAO inhibitor-induced hypertensive crisis.103,104 Phentolamine should be given by IV injection; the drug should be administered slowly to avoid producing an excessive hypotensive effect.103 The usual adult dose of phentolamine for the treatment of hypertensive crisis is 5 mg.103,104 In general, headache tends to subside as blood pressure is lowered.104 Fever should be managed by external cooling.104 Other symptomatic and supportive measures may be necessary in some patients; however, administration of parenteral reserpine should be avoided.104 (See Sympathomimetic Agents and Catecholamine-releasing Agents under Drug Interactions: Food and Drugs Associated with Hypertensive Crisis.)

Nervous System Effects

The most common adverse CNS effects of MAO inhibitors include dizziness,103,104 headache (without increases in blood pressure),103,104 drowsiness,103 sleep disturbances (e.g., insomnia, hypersomnia),103,104 fatigue,103 weakness,103,104 tremors,103 twitching,103 myoclonic movements,103 and hyperreflexia.103 In addition, confusion, disorientation, memory loss, palilalia,103 euphoria,103 nystagmus,103 akinesia, and paresthesias103 have been reported.

Hyperexcitability, increased anxiety,103 agitation,103,104 restlessness,104 manic symptoms,103 and precipitation of schizophrenia,103 have occurred in some patients receiving high dosages of MAO inhibitors. If these symptoms occur, dosage should be reduced or a phenothiazine agent should be administered concomitantly.104

Worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur with antidepressants.154,155,160,164 (See Worsening of Depression and Suicidality Risk under Cautions: Precautions and Contraindications.)

Rarely, ataxia,103 shock-like coma,103 toxic delirium,103 manic reactions,103 seizures,103 and acute anxiety reaction103 have occurred in patients receiving MAO inhibitors.

Serotonin syndrome has occurred rarely in patients receiving MAO inhibitors when other drugs that increase serotonin availability were used concomitantly.103,104,151 Although serotonin syndrome occurs only rarely, it has the potential to cause fatalities.151 (See Drug Interactions: Drugs Associated with Serotonin Syndrome.)

GI Effects

Adverse GI effects reported with MAO inhibitors include constipation,103 dry mouth,103 and GI disturbances.103 Anorexia, nausea, vomiting, arthralgia, increased appetite, and weight gain also have been reported.

Hepatic Effects

Although the potential for hepatotoxicity with commercially available MAO inhibitors is lower than with prototypical MAO inhibitors (iproniazid), such toxicities, when they do occur, can be serious because the hydrazine derivatives cause cellular damage to the hepatic parenchyma.150 A carefully controlled study has shown that patients with impaired liver function may be especially sensitive to tranylcypromine.151 The manufacturers of commercially available MAO inhibitors report that the most common adverse hepatic effect is elevated plasma transaminase concentrations (without accompanying signs or symptoms of hepatotoxicity).103 Reversible jaundice103 and fatal progressive necrotizing hepatocellular damage103 have been reported rarely.

Genitourinary Effects

Impotence,103 ejaculatory disturbances,103,104 and anorgasmia103 have been reported in patients receiving phenelzine or tranylcypromine. Urinary frequency, urinary retention,103 and urinary incontinence also have been reported in patients receiving MAO inhibitors.103

Dermatologic Effects

Although a causal relationship to MAO inhibitors has not been established, localized scleroderma, flare-up of cystic acne, rash,103 pruritus, urticaria, purpura, increased sweating,103 and photosensitivity151 have been reported in patients receiving MAO inhibitors.

Metabolic Effects

A hypermetabolic syndrome, which may include, but is not limited to, hyperpyrexia, tachycardia, tachypnea, muscular rigidity, elevated creatine kinase (CK, creatine phosphokinase, CPK) concentrations, metabolic acidosis, hypoxia, and coma and may resemble an overdose, has been described in patients receiving MAO inhibitors.

Ocular Effects

Rarely, therapy with MAO inhibitors has been associated with adverse ocular effects (e.g., amblyopia, visual disturbances, blurred vision). Aggravation of glaucoma has also occurred. Retinal degradation, retinal scarring, cataracts, and loss of photoreceptor cells have been observed in animal toxicity studies with safinamide.170

Hematologic Effects

A normocytic, normochromic anemia has reportedly developed in some patients receiving MAO inhibitors. Leukopenia, agranulocytosis, and thrombocytopenia also have been reported.

Other Effects

Other adverse effects of MAO inhibitors include arthralgia, lupus-like syndrome,103 edema of the glottis,103 fissuring in the corner of the mouth, and impaired water excretion resembling syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Precautions and Contraindications

MAO inhibitors can cause potentially serious adverse effects, and should only be used in carefully selected patients who can be closely supervised and only by clinicians who are completely familiar with the proper use, potential adverse effects, and associated precautions and contraindications of the drugs. MAO inhibitors generally are not used as initial therapy in the management of depression, but are reserved for patients who do not respond adequately to other antidepressant agents (e.g., selective serotonin-reuptake inhibitors [SSRIs], tricyclic antidepressants) or in whom other therapies are contraindicated.103,146

Hypertensive Crisis

Potentially fatal hypertensive crisis has been reported in patients receiving MAO inhibitors, and blood pressure should be monitored closely in all patients to detect any evidence of a pressor response; however, full reliance should not be placed on blood pressure determinations alone.103,104 The patient's clinical status should be observed frequently, particularly for signs and symptoms of hypertension. In addition, all patients receiving MAO inhibitors should be warned to contact their clinician promptly if headache or other unusual symptoms occur (e.g., palpitation and/or tachycardia, a sense of constriction of the throat or chest, sweating, dizziness, neck stiffness, nausea or vomiting).104 If palpitation or frequent or severe headaches occur during MAO inhibitor therapy, the drug should be discontinued immediately, since these may be prodromal symptoms of a hypertensive reaction. (See Cautions: Cardiovascular Effects.)

Because hypertensive crisis may occur if MAO inhibitors are used concomitantly with certain foods that contain large amounts of tyramine or tryptophan, patients receiving MAO inhibitors should be warned against eating food that has a high tyramine or tryptophan content and also should be advised not to consume alcohol (since tyramine is present in certain alcoholic beverages) or excessive amounts of caffeine in any form.103,104,151 (See Drug Interactions: Food and Drugs Associated with Hypertensive Crisis.)

Because of the potential for hypertensive crisis, concomitant use of MAO inhibitors and some sympathomimetic agents (e.g., amphetamines, dopamine, epinephrine, norepinephrine, methylphenidate) or related substances (e.g., methyldopa, levodopa, l-tryptophan, l-tyrosine, phenylalanine) is contraindicated.103 In addition, patients receiving MAO inhibitors should be cautioned not to take prescription or nonprescription (OTC) cold, hay fever, or weight-reducing preparations unless under the direction of a clinician, since many of these preparations contain pressor agents. (See Drug Interactions: Food and Drugs Associated with Hypertensive Crisis.) To help avoid possible drug interactions, patients receiving MAO inhibitors should be instructed to inform their other clinicians and their dentist that they are receiving an MAO inhibitor.

MAO inhibitors are contraindicated in patients with pheochromocytoma.103 The drugs also are contraindicated in patients with confirmed or suspected cerebrovascular or cardiovascular disease, including hypertension and congestive heart failure.103,104 Since headache may be the first symptom of a hypertensive reaction during MAO inhibitor therapy, the drugs should not be used in patients with a history of severe or frequent headaches.103,104

Worsening of Depression and Suicidality Risk

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Cautions: Pediatric Precautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.154,155,160,164 This risk may persist until clinically important remission occurs.154,155 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.154,155,160 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.154 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.154,155 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.154,155 It is currently unknown whether the suicidality risk extends to longer-term use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.154,155

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.154,155,160 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior, as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.154,160

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.154,160 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.154 FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.154

Bipolar Disorder

It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder.103,154 Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).154 MAO inhibitors are not approved for use in treating bipolar depression in adults.154

When MAO inhibitors are used in patients with bipolar disorder, there may be a mood swing to mania.103 If such a mood swing occurs, MAO inhibitor therapy should be temporarily withheld and subsequently resumed at a reduced dosage.

Other Precautions and Contraindications

Since MAO inhibitors may suppress anginal pain that would otherwise serve as a warning sign of myocardial ischemia, patients with angina pectoris or coronary artery disease should be warned against overexertion.

MAO inhibitors should be used with caution in patients with impaired renal function, since the drugs may accumulate in plasma in these patients.104

Since MAO inhibitors have a variable effect on the seizure threshold, the drugs should be used with caution in patients with a history of seizures.104

Nonselective MAO inhibitors should be used with caution in patients with parkinsonian syndrome, since the drugs may increase the frequency and severity of signs and symptoms associated with this disorder. Selective MAO-B inhibitors (e.g., rasagiline, safinamide, selegiline), on the other hand, have been used principally for the management of parkinsonian syndrome.

Since hepatic damage (e.g., progressive necrotizing hepatocellular damage) has occurred in some patients receiving MAO inhibitors (e.g., isocarboxazid [no longer commercially available in the US], phenelzine), periodic evaluation of liver function (i.e., bilirubin, serum alkaline phosphatase, serum aminotransferases [transaminases]) is recommended in patients receiving high dosages and in those receiving prolonged therapy with the drugs. MAO inhibitors are contraindicated in patients with a history of liver disease or abnormal liver function tests.103,104

There is conflicting evidence regarding whether MAO inhibitors affect glucose metabolism or potentiate antidiabetic agents. Use of MAO inhibitors in patients receiving insulin or oral antidiabetic agents has been associated with hypoglycemic episodes.104 MAO inhibitors should be used with caution in diabetic patients who are receiving insulin or oral antidiabetic agents.104

MAO inhibitors should be used with caution in patients with hyperthyroidism, since these patients have an increased sensitivity to pressor amines.104

Since inhibition of monoamine oxidase may persist for several days following discontinuance of therapy, it is suggested that MAO inhibitors be discontinued for at least 10 days prior to elective surgery to allow time for recovery of enzymatic activity before general anesthetics are used.103,104 (See Drug Interactions: Anesthetics.)

MAO inhibitors are contraindicated in patients currently receiving, or having recently received, SSRIs or tricyclic antidepressants. (See Drug Interactions: Drugs Associated with Serotonin Syndrome and see Drug Interactions: Tricyclic Antidepressants.)

MAO inhibitors are contraindicated in patients who are hypersensitive to the drugs or any ingredients in the formulations.103

Pediatric Precautions

Safety and efficacy of phenelzine in children younger than 16 years of age have not been established.103 Safety and efficacy of tranylcypromine in pediatric patients have not been established.161

FDA warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.154,155,160 The risk of suicidality for these drugs was identified in a pooled analysis of data from a total of 24 short-term (4-16 weeks), placebo-controlled studies of 9 antidepressants (i.e., bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine)156 in over 4400 children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders.154,155 The analysis revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in pediatric patients receiving antidepressants than in those receiving placebo.154,155 The average risk of such events was 4% among children and adolescents receiving these drugs, twice the risk (2%) that was observed among those receiving placebo.154,155 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.164 No suicides occurred in these pediatric trials.154,155,164

The risk of suicidality in FDA's pooled analysis differed across the various psychiatric indications, with the highest incidence observed in the major depressive disorder studies.154,155 In addition, although there was considerable variation in risk among the antidepressants, a tendency toward an increase in suicidality risk in younger patients was found for almost all drugs studied.154,155 It is currently unknown whether the suicidality risk in pediatric patients extends to longer-term use (i.e., beyond several months).154,155

As a result of this analysis and public discussion of the issue, FDA has directed manufacturers of all antidepressants to add a boxed warning to the labeling of their products to alert clinicians of this suicidality risk in children and adolescents and to recommend appropriate monitoring and close observation of patients receiving these agents.154,155 (See Worsening of Depression and Suicidality Risk under Cautions: Precautions and Contraindications.) The drugs that are the focus of the revised labeling are all drugs included in the general class of antidepressants, including those that have not been studied in controlled clinical trials in pediatric patients, since the available data are not adequate to exclude any single antidepressant from an increased risk.154,155,158 In addition to the boxed warning and other information in professional labeling on antidepressants, FDA currently recommends that a patient medication guide explaining the risks associated with the drugs be provided to the patient each time the drugs are dispensed.154,155,160

Anyone considering the use of antidepressants in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.154,160,164

Geriatric Precautions

Clinical experience to date with MAO inhibitors in geriatric patients has not identified any differences in responses between geriatric and younger adults.103 However, geriatric patients appear to be more susceptible to adverse effects of MAO inhibitors (e.g., episodes of hypertension, malignant hyperthermia) than younger patients, and these adverse effects are associated with increased morbidity in geriatric patients since they have less compensatory reserve to cope with any serious adverse reactions.104 Therefore, MAO inhibitor therapy should be initiated cautiously in geriatric patients103,104 using a low initial dosage and patients observed closely since renal, hepatic, and cardiovascular dysfunction and concomitant disease or other drug therapy are more common in this age group than in younger patients.103

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.154,155 (See Precautions and Contraindications: Worsening of Depression and Suicidality Risk, in Cautions.)

Pregnancy, Fertility, and Lactation

Pregnancy

Safety of MAO inhibitors during pregnancy has not been established.103,104 Administration of phenelzine to pregnant mice resulted in a decrease in the number of viable offspring, and the growth of young dogs and rats has been retarded by phenelzine dosages exceeding the maximum human dosage.103 Tranylcypromine has been shown to cross the placenta in rats.104 It is not known whether MAO inhibitors can cause fetal harm when administered to pregnant women, and the drugs should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.103,104

Fertility

The effect of MAO inhibitors on fertility in humans is not known. Sexual disturbances including impotence and delayed ejaculation have occurred in some individuals during MAO inhibitor therapy.

Lactation

It is not known if MAO inhibitors are distributed into human milk; however, tranylcypromine is distributed into the milk of lactating dogs. MAO inhibitors should be used with caution in nursing women.103,104

Food and Drugs Associated with Hypertensive Crisis

Concomitant use of MAO inhibitors and certain food or prescription or nonprescription (over-the-counter, OTC) drugs can result in interactions that have the potential to cause hypertensive crisis due to the release and potentiation of catecholamines similar to that experienced in pheochromocytoma.151 The severity and consequences of such interactions vary among individuals.151 If only minor increases in blood pressure occur, patients may be unaware of the interactions.151 However, if substantial and rapid increases in blood pressure (an increase of 30 mm Hg or more in systolic blood pressure within 20 minutes) occur, patients may experience symptoms associated with subarachnoid hemorrhage or cardiac failure (sudden severe occipital headache, palpitations) if the cerebral vasculature or cardiac musculature are already weakened. (See Hypertensive Crisis under Cautions: Cardiovascular Effects.)

Food

Hypertensive crises have occurred following ingestion of foods containing large amounts of tyramine or tryptophan in some patients receiving MAO inhibitors. In general, patients should avoid protein foods that have undergone protein breakdown by aging, fermentation, pickling, smoking, or bacterial contamination; protein extracts and liquid or powdered dietary supplements also should be avoided. Patients should be specifically instructed not to eat foods such as cheese, particularly strong or aged varieties (e.g., cheddar, Camembert, Stilton) and processed cheese; sour cream; wine, especially chianti, champagne, and alcohol-free or reduced-alcohol wine products; beer, including alcohol-free and reduced-alcohol beers; pickled herring; anchovies; caviar; shrimp paste; liver, especially chicken liver; dry sausage (e.g., Genoa salami, hard salami, pepperoni, Lebanon bologna); figs, particularly if overripe, or canned figs; raisins; bananas or avocados, particularly if overripe; chocolate; soy sauce; bean curd; yeast extracts (including brewer's yeast in large quantities); yogurt; papaya products, including certain meat tenderizers; and pods of broad beans (e.g., fava beans). Excessive amounts of caffeine may also reportedly precipitate hypertensive crisis. Specialized references on food constituents or a dietician should be consulted for more specific information on the tyramine content of foods and beverages.

Sympathomimetic Agents and Catecholamine-releasing Agents

Because some patients appear to be particularly sensitive to the hypertensive effects of sympathomimetic agents during MAO inhibitor therapy, centrally acting sympathomimetic agents (e.g., amphetamines) or peripherally acting sympathomimetic agents, including prescription or nonprescription cold, hay fever, or weight-reducing preparations that contain pressor agents (e.g., ephedrine) generally should not be administered concomitantly with an MAO inhibitor. The manufacturer of rasagiline states that concomitant use of the drug with sympathomimetic agents should be employed with caution.162 The manufacturer of safinamide states that concomitant use of the drug with methylphenidate or amphetamines is contraindicated and that patients receiving safinamide in conjunction with other prescription or nonprescription sympathomimetics should be monitored for hypertension.170

Parenteral or oral administration of reserpine or guanethidine in patients receiving MAO inhibitors may cause a severe pressor response as a result of a sudden release of accumulated catecholamines.103 Therefore, the manufacturers of MAO inhibitors do not recommend concomitant use of guanethidine in patients receiving an MAO inhibitor and also recommend that reserpine be administered cautiously in patients receiving MAO inhibitors.103

Levodopa and other Catecholamines

Hypertension, headache, hyperexcitability, and related symptoms reportedly have occurred in patients receiving MAO inhibitors concurrently with methyldopa, dopamine, or levodopa. It has been suggested that use of a decarboxylase inhibitor (e.g., carbidopa) with levodopa may prevent hypertensive reactions during concomitant therapy with an MAO inhibitor.

Drugs Associated with Serotonin Syndrome

Serotonin syndrome may occur in patients receiving MAO inhibitors in combination with other serotonergic drugs.113,114,115 Although the syndrome appears to be relatively uncommon and usually mild in severity, serious complications, including seizures, disseminated intravascular coagulation, respiratory failure, severe hyperthermia, and death occasionally have been reported.113,114,115,116,118 The precise mechanism of the syndrome is not fully understood; however, it appears to result from excessive serotonergic activity in the CNS, probably mediated by activation of serotonin 5-HT_1A receptors.113,114,118 The possible involvement of dopamine and 5-HT₂ receptors also has been suggested, although their roles remain unclear.118

The syndrome most commonly occurs when 2 or more serotonergic agents with different mechanisms of action are administered either concurrently or in close succession.113,114,115,116,118 Serotonergic agents include those that increase serotonin synthesis (e.g., the serotonin precursor tryptophan),115,116,118 stimulate synaptic serotonin release (e.g., some amphetamines, dexfenfluramine [no longer commercially available in the US], fenfluramine [no longer commercially available in the US]),115,116,143 inhibit the reuptake of serotonin after release (e.g., selective serotonin-reuptake inhibitors [SSRIs], tricyclic antidepressants, trazodone, dextromethorphan, meperidine, tramadol),115,116,118 decrease the metabolism of serotonin (e.g., MAO inhibitors),115,116 have direct serotonin postsynaptic receptor activity (e.g., buspirone),115,116 or nonspecifically induce increases in serotonergic neuronal activity (e.g., lithium salts).115,116,118

The combination of MAO inhibitors and SSRI antidepressants (e.g., fluoxetine) appears to be responsible for most of the recent case reports of serotonin syndrome.108,110,113,114,115,117,118,120,122,126,133,135,138,139,144,145 The syndrome also has been reported when MAO inhibitors have been combined with tricyclic antidepressants,115,118 tryptophan,113,118 meperidine,115,118 or dextromethorphan.114,115,118 In rare cases, serotonin syndrome reportedly has occurred with the recommended dosage of a single serotonergic agent (e.g., clomipramine)115,118 or during accidental overdosage (e.g., sertraline intoxication in a child).115,118 Some other drugs that have been implicated in certain circumstances include buspirone, bromocriptine, dextropropoxyphene, methylenedioxymethamphetamine (MDMA; “ecstasy”), and selegiline (a selective MAO-B inhibitor).118,127 Other drugs that have been associated with the syndrome but for which less convincing data are available include carbamazepine, fentanyl, and pentazocine.118

Clinicians should be aware of the potential for serious, possibly fatal reactions associated with serotonin syndrome in patients receiving 2 or more drugs that increase the availability of serotonin in the CNS, even if no such interactions with the specific drugs have been reported to date in the medical literature.110,114 Pending further data, all drugs with serotonergic activity should be used cautiously in combination and such combinations avoided whenever clinically possible.110,114 Some clinicians state that patients who have experienced serotonin syndrome may be at higher risk for recurrence of the syndrome upon reinitiation of serotonergic drugs.115 Pending further experience in such cases, some clinicians recommend that therapy with serotonergic agents be limited following recovery.115 In cases in which the potential benefit of the drug is thought to outweigh the risk of serotonin syndrome, lower potency agents and reduced dosages should be used, combination serotonergic therapy should be avoided, and patients should be monitored carefully for symptoms of serotonin syndrome.115 For further information on serotonin syndrome, including manifestations and treatment, see Serotonin Syndrome under Drug Interactions: Drugs Associated with Serotonin Syndrome, in Fluoxetine Hydrochloride 28:16.04.20.

Selective Serotonin-reuptake Inhibitors

Concurrent use of SSRIs and MAO inhibitors potentially is hazardous and may result in serotonin syndrome.113,114,115 Probably because of its extensive clinical use and the prolonged elimination half-life of both fluoxetine and norfluoxetine, fluoxetine has been the SSRI most commonly implicated in serotonin syndrome when combined with MAO inhibitor therapy.115,118,138 In at least 2 cases, serotonin syndrome has developed when MAO inhibitor therapy has been initiated after the discontinuance of fluoxetine therapy.118,138 Shivering, diplopia, nausea, confusion, and anxiety reportedly occurred in one patient 6 days after discontinuance of fluoxetine therapy and 4 days after initiation of tranylcypromine therapy; signs and symptoms resolved without apparent sequelae within 24 hours following discontinuance of the MAO inhibitor in this patient.108 In another case, the initiation of tranylcypromine therapy more than 5 weeks after discontinuance of fluoxetine reportedly resulted in serotonin syndrome.118,138 The manufacturer of fluoxetine, the manufacturers of MAO inhibitors, and some clinicians state that concurrent use of fluoxetine with MAO inhibitors is contraindicated or generally should be avoided.103,104,105,111,127,162,166 Because both fluoxetine and its principal metabolite have relatively long half-lives, the manufacturer of fluoxetine, the manufacturers of MAO inhibitors, and some clinicians recommend that at least 5 weeks elapse between discontinuance of fluoxetine therapy and initiation of MAO inhibitor therapy,103,104,105,108,111 since administration of an MAO inhibitor prior to elapse of this time may increase the risk of serious adverse effects.105 Although the manufacturers of some MAO inhibitors (i.e., phenelzine) recommend that at least 10 days elapse following discontinuance of MAO inhibitor therapy prior to initiation of fluoxetine therapy, based on clinical experience with concurrent administration of tricyclic antidepressants and MAO inhibitors, the manufacturers of fluoxetine and the manufacturers of some MAO inhibitors (e.g., selegiline, tranylcypromine) recommend that at least 2 weeks elapse following discontinuance of an MAO inhibitor prior to initiation of fluoxetine therapy.103,104,105,106,111

Other SSRI antidepressants, including sertraline118,133 and citalopram,118 also have been associated with serotonin syndrome when given in combination with MAO inhibitors.118 Because of the potential risk of serotonin syndrome when SSRIs are combined with MAO inhibitor therapy, the manufacturers of fluvoxamine, paroxetine, and sertraline currently recommend that a drug-free interval of at least 2 weeks elapse when switching from an MAO inhibitor to these agents or when switching from these agents to an MAO inhibitor.140,141,142 The manufacturer of the selective MAO-B inhibitor safinamide states that if safinamide is used concomitantly with an SSRI, the lowest effective dosage of the SSRI should be used.170

Moclobemide, a selective and reversible MAO-A inhibitor (not commercially available in the US), also has been associated with serotonin syndrome and such reactions have been fatal in several cases in which the drug was given in combination with citalopram or with clomipramine.118,120,121 Pending further experience with such combinations, some clinicians recommend that concurrent therapy with moclobemide and SSRIs be used only with extreme caution and that the SSRI should have been discontinued for some time (depending on the elimination half-lives of the drug and its active metabolites) before initiating moclobemide therapy.121

Tryptophan

Although tryptophan sometimes has been used to enhance the antidepressant activity of MAO inhibitors, serotonin syndrome, which was fatal in at least one case, has been reported in a limited number of patients receiving these drugs in combination either with or without concurrent lithium therapy.113,118 While the mechanism for this interaction has not been fully elucidated, it has been suggested that these adverse effects resemble serotonin syndrome and therefore may result from a marked increase in serotonin availability in the CNS when these agents are administered concurrently.113,118 Behavioral and neurologic syndromes, including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations, and Babinski signs, also have been reported in patients receiving MAO inhibitors and tryptophan concomitantly.103 Pending further evaluation of this potential interaction, clinicians should be aware that toxic reactions may occur when MAO inhibitors and tryptophan are administered concomitantly.113

Buspirone

Elevations in blood pressure have been observed in several patients receiving an MAO inhibitor and buspirone concomitantly;100,102,103,104 no adverse sequelae were associated with these elevations. Buspirone may have been partially responsible for a case of serotonin syndrome that resulted in the death of a patient receiving buspirone, an MAO inhibitor (tranylcypromine), and fluoxetine concomitantly.118,139 Pending accumulation of additional data, it is recommended that MAO inhibitors not be used concomitantly with buspirone.100,102,103,104 Some manufacturers recommend that at least 10 days elapse between discontinuance of MAO inhibitor therapy and administration of buspirone.103,104

Tricyclic Antidepressants

Concomitant use of MAO inhibitors with tricyclic antidepressants is contraindicated or generally should be avoided, and it generally is recommended that at least 2 weeks should elapse between discontinuance of tricyclic antidepressant therapy or MAO inhibitor therapy and initiation of therapy with the other class of drugs.101,112,127,128,130,166 Serious, sometimes fatal, reactions including hyperpyrexia, confusion, diaphoresis, myoclonus, rigidity, seizures, cardiovascular disturbances, and coma have occurred in patients who received an MAO inhibitor and a tricyclic antidepressant concomitantly.101,112,128,130 Patients receiving therapeutic dosages of an oral MAO inhibitor and an oral tricyclic antidepressant concomitantly generally have experienced nonfatal hyperpyrexia, hypertension, tachycardia, confusion, and seizures; most reported cases of hyperpyretic crises, severe seizures, or death occurred following overdosage or parenteral administration of one or both drugs. Although the mechanism has not been clearly established, these reactions resemble serotonin syndrome and may be caused by excessive serotonergic activity in CNS. (See Drug Interactions: Drugs Associated with Serotonin Syndrome.)

CNS Depressants

Several manufacturers caution that MAO inhibitors may be additive with, or may potentiate the action of, CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol. CNS depressants should be administered cautiously to patients receiving MAO inhibitors in order to avoid excessive sedation and acute hypotension; a reduction in dosage of the CNS depressant agent(s) may be necessary. One manufacturer recommends that, if emergency surgery is necessary in a patient receiving an MAO inhibitor, the dose of opiate, sedative, analgesic, and other premedication be reduced to one-fourth to one-fifth the usual dose.

Meperidine

Meperidine should not be used in patients receiving MAO inhibitors since severe, generally immediate reactions, including excitation, sweating, rigidity, and hypertension, suggestive of serotonin syndrome, have occurred. Circulatory collapse and death have also occurred following administration of a single dose of meperidine in some patients receiving an MAO inhibitor.

Dextromethorphan

Concomitant use of MAO inhibitors and dextromethorphan (ingested as a lozenge) has been reported to cause brief episodes of psychosis or bizarre behavior.103,104 Cases of apparent serotonin syndrome, including at least 2 fatalities, have been reported in patients receiving concurrent MAO inhibitor and dextromethorphan therapy. Dextromethorphan preparations should not be used in patients receiving an MAO inhibitor.

Bupropion

Studies in animals using phenelzine have shown that the acute toxicity of bupropion is enhanced by the MAO inhibitor.152 Concomitant use of an MAO inhibitor and bupropion is contraindicated, and it is suggested that at least 14 days elapse between discontinuance of MAO inhibitor therapy and initiation of bupropion therapy.103,152

Anesthetics

The hypotensive and CNS depressant effects of general anesthetics may be exaggerated in patients receiving MAO inhibitors. Since inhibition of monoamine oxidase may persist for several days following discontinuance of therapy, some manufacturers suggest that MAO inhibitors be discontinued for at least 7-14 days prior to elective surgery to allow time for recovery of enzymatic activity before general anesthetics are used. If emergency surgery is necessary in a patient receiving an MAO inhibitor, the dose of the general anesthetic should be carefully adjusted.

Patients receiving MAO inhibitors should not be given cocaine or local anesthetics that contain sympathomimetic vasoconstrictors, since hypertension may result.

Because MAO inhibitors may potentiate the hypotensive effect of local anesthetics used in spinal anesthesia, these agents should be used with caution in patients receiving MAO inhibitors.

Disulfiram

MAO inhibitors should probably be used with caution in patients receiving disulfiram. In one study in animals receiving large intraperitoneal doses of disulfiram and the d - or l -isomer of tranylcypromine, severe toxicity, including seizures and death, occurred. However, in other studies in animals receiving large oral doses of disulfiram and racemic tranylcypromine, no adverse interaction was reported.

Diuretics and Hypotensive Agents

In general, MAO inhibitor antidepressants should not be administered concomitantly with diuretics or hypotensive agents since a marked hypotensive effect may occur.

Drugs with Anticholinergic Activity

Some manufacturers state that anticholinergic antiparkinsonian drugs should be used with caution in patients receiving MAO inhibitors, since severe reactions have reportedly occurred when these drugs were used concurrently; however, additional information is needed to determine the clinical importance of this potential interaction. It also should be considered that MAO inhibitors may prolong and intensify some anticholinergic effects (e.g., dryness) of antihistamines.

Acute Toxicity

Manifestations

In general, overdosage of monoamine oxidase (MAO) inhibitors may be expected to produce effects that are extensions of common adverse reactions. Patients with early or mild intoxication may experience drowsiness, dizziness (sometimes severe), ataxia, headache (sometimes severe), insomnia, restlessness, anxiety, and irritability. Other reported effects associated with severe overdosage include mental confusion, incoherence, tachycardia, rapid and irregular pulse, hypotension, coma, seizures, respiratory depression, hyporeflexia or hyperreflexia, fever, diaphoresis (sometimes perfuse and associated with cool, clammy skin), precordial pain, and shock. A few patients have developed hypertension, which rarely may be associated with twitching or myoclonic fibrillation of skeletal muscles and with hyperpyrexia, sometimes progressing to generalized rigidity and coma. In addition, trismus and opisthotonus have been reported to occur in some patients. Hyperactivity with marked agitation may occur. Signs and symptoms following acute overdosage may be delayed for 12-24 hours. Although signs and symptoms usually resolve within 3-4 days, they may persist for up to 2 weeks in some patients. Careful observation of patients for at least 1 week after overdosage is generally recommended.

Treatment

Treatment of MAO inhibitor overdosage generally involves symptomatic and supportive care; there is no specific antidote for intoxication. In acute overdosage, the stomach should be emptied immediately by inducing emesis or by gastric lavage with instillation of charcoal slurry. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Hemodialysis, peritoneal dialysis, and charcoal hemoperfusion may be of value in cases of massive overdosage, but data are insufficient to recommend the routine use of these procedures in MAO inhibitor overdosage.103

Because of the potential for interactions with other drugs, extreme caution should be used in the management of patients following MAO inhibitor overdosage. Conservative measures to maintain normal body temperature (e.g., external cooling), respiration, and blood pressure and to correct fluid and electrolyte abnormalities have generally been successful. Appropriate therapy (e.g., volume expansion) should be instituted if hypotension occurs; however, administration of pressor amines (e.g., norepinephrine) may be of limited value and should be used with caution, since the hypertensive effects of these agents may be potentiated by MAO inhibitors (see Sympathomimetic Agents and Catecholamine-releasing Agents under Drug Interactions: Food and Drugs Associated with Hypertensive Crisis). Appropriate therapy should be instituted if severe hypertension (i.e., hypertensive crisis) occurs. For the management of hypertensive crisis, see Hypertensive Crisis under Cautions: Cardiovascular Effects. Signs and symptoms of CNS stimulation, including seizures, should be treated with diazepam. Appropriate therapy should be instituted if excessive sedation occurs. Phenothiazines and CNS stimulants should be avoided (see Sympathomimetic Agents and Catecholamine-releasing Agents under Drug Interactions: Food and Drugs Associated with Hypertensive Crisis). Evaluation of liver function is recommended at the time of overdosage and for 4-6 weeks following recovery.

Chronic Toxicity

Although MAO inhibitors are not usually associated with dependence and addiction, drug dependence has occurred in some patients receiving tranylcypromine doses substantially in excess of the usual therapeutic range.104 Some of these patients had a history of previous substance abuse.104 Following discontinuance of the drug, symptoms of withdrawal, including restlessness, anxiety, depression, confusion, hallucinations, headache, weakness, and diarrhea have occurred.104 A withdrawal syndrome also has been reported to occur infrequently after abrupt discontinuance of phenelzine.103 In reported cases, signs and symptoms of withdrawal ranging from vivid nightmares with agitation to frank psychosis and seizures have been evident within 24-72 hours after phenelzine was discontinued; the syndrome generally responds to reinitiation of MAO inhibitor therapy followed by cautious downward titration and discontinuance.103

Pharmacology

The discovery of monoamine oxidase (MAO) inhibitors resulted from a search for derivatives of isoniazid (isonicotinic acid hydrazide) with antitubercular activity. During clinical trials with these hydrazine derivatives, a rather consistent beneficial effect of mood elevation was noted in depressed patients with tuberculosis receiving the drugs. Iproniazid, the first derivative synthesized, was found to be too toxic (principally hepatotoxicity) at the dosage level required for antitubercular activity. Although its antidepressant effect was still pronounced at lower dosage, toxicity was also eventually observed at the lower dosage level and use of iproniazid was finally discontinued. However, the antidepressant activity of iproniazid prompted a search for other MAO inhibitors and resulted in the synthesis of several agents, both hydrazine and nonhydrazine compounds, that were relatively less toxic than iproniazid.

Monoamine oxidase, an enzyme found mainly in nerve tissue and in the liver and lungs, catalyzes the oxidative deamination of various amines, including epinephrine, norepinephrine, dopamine, and serotonin (5-HT). There appear to be at least 2 isoforms of monoamine oxidase, monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B), with differences in substrate preference, inhibitor specificity, tissue distribution, immunologic properties, and amino acid sequence. MAO-A substrates include serotonin; MAO-B substrates include phenylethylamine. Tyramine, epinephrine, norepinephrine, and dopamine are substrates for both MAO-A and MAO-B. Inhibition of monoamine oxidase results in increased concentrations of these amines. Currently available MAO inhibitor antidepressants (phenelzine, tranylcypromine) are considered nonselective inhibitors of MAO. Phenelzine binds irreversibly to monoamine oxidase; tranylcypromine binds reversibly to the enzyme. Selective inhibitors of monoamine oxidase-A (e.g., clorgiline) are being investigated. Rasagiline162 , safinamide,170 and selegiline127 are considered selective MAO-B inhibitors and are used for the symptomatic treatment of parkinsonian syndrome. (See Rasagiline Mesylate 28:36.32, see Safinamide Mesylate 28:36.32, and see Selegiline Hydrochloride 28:36.32.)

Although the precise mechanism of antidepressant action of MAO inhibitors is unclear, it has been suggested that the increase in free serotonin and norepinephrine and/or alterations in other amine concentrations within the CNS are mainly responsible for the antidepressant effect of the drugs. Although this concept offers a useful working hypothesis, it should be remembered that definite proof of the mode of action of MAO inhibitors is lacking. Attempts have been made to correlate inhibition of platelet monoamine oxidase (a possible index of a drug's effect on brain monoamine oxidase) with therapeutic effect; preliminary evidence suggests that a dose-related effect of phenelzine on platelet monoamine oxidase correlates with a beneficial effect on mood in depressed patients.

MAO inhibitors may cause hypotension or hypertension, probably by the same mechanism of action. The reduction in blood pressure induced by MAO inhibitors is mainly an orthostatic (postural) effect; reduction in supine blood pressure is minimal in most patients. Although the precise mechanism of hypotensive action of MAO inhibitors is not fully understood, it has been postulated that this paradoxical effect may result from gradual accumulation of false neurotransmitters (phenylethylamines) in peripheral adrenergic neurons. Phenylethylamines (e.g., tyramine) are usually oxidatively deaminated in the GI tract and liver; however, inhibition of monoamine oxidase in the GI tract and liver may result in substantial systemic absorption of these indirect-acting amines. Gradual accumulation of octopamine in the adrenergic neurons may result from MAO inhibition in the neurons with subsequent alternate hydroxylation of tyramine to octopamine. It has been suggested that octopamine gradually displaces norepinephrine from storage granules. Stimulation of norepinephrine release may result in release of some norepinephrine and some octopamine, the latter amine having minimal activity at α- or β-adrenergic receptors. Thus, gradual MAO inhibitor-induced displacement of norepinephrine from adrenergic neurons may result in a functional block of sympathetic neurotransmission. Similarly, MAO inhibitors may cause severe hypertension when foods containing large amounts of tyramine are ingested. (See Drug Interactions: Food and Drugs Associated with Hypertensive Crisis.) Following systemic absorption of large amounts of tyramine, there may be a rapid, massive displacement and release of norepinephrine from adrenergic neurons resulting in severe hypertension. It has been suggested that selective inhibitors of monoamine oxidase-B (e.g., rasagiline, selegiline) may be less likely than nonselective MAO inhibitors to cause hypertension; however, hypertensive reactions have been reported rarely with selegiline at recommended doses as a result of dietary influences.

MAO inhibitors interfere with the hepatic metabolism of many drugs and may potentiate the actions of such agents as general anesthetics, barbiturates, morphine, alcohol, corticosteroids, and atropine. (See Drug Interactions.)

The pharmacologic effects of MAO inhibitors are cumulative; a latent period of a few days to several months may occur before the onset of antidepressant or hypotensive activity, and effects may persist for up to 3 weeks following discontinuance of therapy.

Chemistry

Monoamine oxidase (MAO) inhibitors are a chemically heterogeneous group of drugs that can block oxidative deamination of naturally occurring monoamines. Various MAO inhibitors have been found to have antidepressant action (e.g., isocarboxazid, iproniazid, phenelzine, tranylcypromine); however, the only MAO inhibitors currently commercially available in the US for use as antidepressant agents are phenelzine and tranylcypromine.

Based on their structure, MAO inhibitors can be classified as hydrazines (e.g., phenelzine) and nonhydrazines (e.g., tranylcypromine). Although no longer used clinically, the prototype hydrazine MAO inhibitor is iproniazid. (See Pharmacology.) MAO inhibitors also can be classified according to their ability to selectively or nonselectively inhibit monoamine oxidase. (See Pharmacology.)

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