Monoamine Oxidase Inhibitors

For a more detailed discussion of this topic, see Monoamine Oxidase Inhibitors, Ch. 31.22, p. 3154, in Comprehensive Textbook of Psychiatry, 9th Edition.

Monoamine oxidase inhibitors (MAOIs) were introduced in the late 1950s as the first class of approved antidepressant drugs. The first of these drugs, isoniazid, was developed as a treatment for tuberculosis; the antidepressant properties were discovered by chance when some of the patients were observed to experience elevation of mood during treatment. Despite their effectiveness, prescription of MAOIs as first-line agents has always been limited by concern about the development of potentially lethal hypertension and the consequent need for a restrictive diet. Use of MAOIs declined further after the introduction of the selective serotonin reuptake inhibitors (SSRIs) and other new agents. They are now mainly relegated to use in treatment-resistant cases. Thus, the second-line status of MAOIs has less to do with considerations of efficacy than with concerns for safety. The currently available MAOIs include phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate), rasagiline (Azilect), moclobemide (Manerix), and selegiline (Eldepryl).

Two subsequent advances in the field of antidepressant MAOIs involve the introduction of a selective reversible inhibitor of MAO_A (RIMA), moclobemide (Manerix), in the early 1990s into most countries except the United States, and in 2005, the introduction of a transdermal delivery form of selegiline (Emsam) in the United States that is used for the treatment of parkinsonism. Other RIMA agents, including brofaromine (Consonar) and befloxatone, have not been submitted for registration despite favorable outcomes in clinical trials.

Pharmacologic Actions

Phenelzine, tranylcypromine, and isocarboxazid are readily absorbed after oral administration and reach peak plasma concentrations within 2 hours. Whereas their plasma half-lives are in the range of 2 to 3 hours, their tissue half-lives are considerably longer. Because they irreversibly inactivate MAOs, the therapeutic effect of a single dose of irreversible MAOIs may persist for as long as 2 weeks. The RIMA moclobemide is rapidly absorbed and has a half-life of 0.5 to 3.5 hours. Because it is a reversible inhibitor, moclobemide has a much briefer clinical effect after a single dose than do irreversible MAOIs.

The MAO enzymes are found on the outer membranes of mitochondria, where they degrade cytoplasmic and extraneuronal monoamine neurotransmitters such as norepinephrine, serotonin, dopamine, epinephrine, and tyramine. MAOIs act in the central nervous system (CNS), the sympathetic nervous system, the liver, and the gastrointestinal (GI) tract. There are two types of MAOs, MAO_A and MAO_B. MAO_A primarily metabolizes norepinephrine, serotonin, and epinephrine; dopamine and tyramine are metabolized by both MAO_A and MAO_B.

The structures of phenelzine and trancyclopyromine are similar to those of amphetamine and have similar pharmacologic effects in that they increase the release of dopamine and norepinephrine with attendant stimulant effects on the brain.

Therapeutic Indications

MAOIs are used for treatment of depression. Some research indicates that phenelzine is more effective than tricyclic antidepressants (TCAs) in depressed patients with mood reactivity, extreme sensitivity to interpersonal loss or rejection, prominent anergia, hyperphagia, and hypersomnia—a constellation of symptoms conceptualized as atypical depression. Evidence also suggests that MAOIs are more effective than TCAs as a treatment for bipolar depression.

Patients with panic disorder and social phobia respond well to MAOIs. MAOIs have also been used to treat bulimia nervosa, posttraumatic stress disorder, anginal pain, atypical facial pain, migraine, attention deficit disorder, idiopathic orthostatic hypotension, and depression associated with traumatic brain injury.

Trancyclomine is included as an effective option for treatment resistant depression in the STAR*D algorithm for the treatment of depressive disorders (see Appendix 1).

Precautions and Adverse Reactions

The most frequent adverse effects of MAOIs are orthostatic hypotension, insomnia, weight gain, edema, and sexual dysfunction. Orthostatic hypotension can lead to dizziness and falls. Thus, cautious upward tapering of the dosage should be used to determine the maximum tolerable dosage. Treatment for orthostatic hypotension includes avoidance of caffeine; intake of 2 L of fluid per day; addition of dietary salt or adjustment of antihypertensive drugs (if applicable); support stockings; and in severe cases, treatment with fludrocortisone (Florinef), a mineralocorticoid, 0.1 to 0.2 mg a day. Orthostatic hypotension associated with tranylcypromine use can usually be relieved by dividing the daily dosage.

Insomnia can be treated by dividing the dose, not giving the medication after dinner, and using trazodone (Desyrel) or a benzodiazepine hypnotic if necessary. Weight gain, edema, and sexual dysfunction often do not respond to any treatment and may warrant switching to another agent. When switching from one MAOI to another, the clinician should taper and stop use of the first drug for 10 to 14 days before beginning use of the second drug.

Paresthesias, myoclonus, and muscle pains are occasionally seen in persons treated with MAOIs. Paresthesias may be secondary to MAOI-induced pyridoxine deficiency, which may respond to supplementation with pyridoxine, 50 to 150 mg orally each day. Occasionally, persons complain of feeling drunk or confused, perhaps indicating that the dosage should be reduced and then increased gradually. Reports that the hydrazine MAOIs are associated with hepatotoxic effects are
relatively uncommon. MAOIs are less cardiotoxic and less epileptogenic than are the tricyclic and tetracyclic drugs.

The most common adverse effects of the RIMA moclobemide are dizziness, nausea, and insomnia or sleep disturbance. RIMAs cause fewer GI adverse effects than do SSRIs. Moclobemide does not have adverse anticholinergic or cardiovascular effects, and it has not been reported to interfere with sexual function.

MAOIs should be used with caution by persons with renal disease, cardiovascular disease, or hyperthyroidism. MAOIs may alter the dosage of a hypoglycemic agent required by diabetic persons. MAOIs have been particularly associated with induction of mania in persons in the depressed phase of bipolar I disorder and triggering of a psychotic decompensation in persons with schizophrenia. MAOIs are contraindicated during pregnancy, although data on their teratogenic risk are minimal. MAOIs should not be taken by nursing women because the drugs can pass into the breast milk.

Tyramine-induced Hypertensive Crisis

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