Antidepressant and Antimanic Medications: Monoamine Oxidase Inhibitors
The MAOIs are some of the earliest developed antidepressant drugs. The initial enthusiasm that followed their discovery in the late 1950s was tempered by reports of serious side effects that relegated them to drugs of last resort. MAOIs have been associated with serious adverse events, including hypertensive crisis, lethal reactions with SSRIs, and delirium with meperidine, and less severe reactions reported with other opiate agonists such as morphine and partial agonists such as buprenorphine, butorphanol, and pentazocine. Hepatotoxicity, which was seen with the first MAOI drugs, appears to be very uncommon with the currently used MAOIs. Although they are free of anticholinergic side effects, these drugs commonly cause insomnia, daytime somnolence, clinically significant hypotension and orthostatic hypotension, anorgasmia, weight gain, myoclonus, and pedal edema. The hydrazine MAOIs (phenelzine and isocarboxazid) are associated with pyridoxine (B6) deficiency in up to 7% of subjects.
MAOIs inhibit the primary enzyme responsible for degradation of monoamines, resulting in increased synaptic levels. Two forms of MAO exist in the CNS: type A (MAO-A) and type B (MAO-B). MAO-A metabolizes NE, serotonin, DA, and tyramine, whereas MAO-B metabolizes DA and tyramine but has no effect on NE or serotonin. Selective MAO-B inhibitors such as l-deprenyl, which is used in the treatment of Parkinson’s disease, are relatively ineffective for depression.
The earliest developed MAOIs (phenelzine, tranylcypromine, and isocarboxazid) are all irreversible inhibitors of both the A and B forms of the MAO enzyme. Each molecule of drug permanently inactivates one enzyme molecule. Before enzyme activity can be restored, new enzyme must be synthesized. The level of MAO activity, therefore, is a balance between MAOI drug level and rate of enzyme synthesis. It can take up to 2 weeks from the time that an irreversible MAOI drug is discontinued until full MAO activity returns.
Irreversible MAOIs have been studied extensively with regard to their antidepressant properties, and all are clearly effective in the treatment of MDE. They may be more effective in the treatment of MDE with atypical features (mood reactivity, weight gain or increased appetite, hypersomnia, leaden paralysis, interpersonal rejection sensitivity) than other antidepressant medications (Davidson 1992). MAOIs alone appear not to be as effective in the treatment of patients with MDE with psychotic features. Because of potential side effects, these drugs continue to be second- and third-line agents, seldom being used first in treatment-naive patients.
Antidepressant dosages of tranylcypromine and isocarboxazid are 20-60 mg/day, and those of phenelzine are 30-90 mg/day. Clinical studies have shown that antidepressant activity is related to degree of inhibition of plasma MAO, with patients who show less than 80% inhibition responding less frequently. Some studies have used higher than the usual recommended doses to achieve sufficient inhibition of the enzyme and have demonstrated antidepressant effects in patients who did not respond to lower doses.
A new category of drugs, selective reversible inhibitors of MAO-A (RIMAs), has been developed. Moclobemide and brofaromine are examples of drugs in this category that are currently in phase III clinical trials. These drugs are less likely to cause hypertensive reactions because of their reversible type of inhibition. When MAO is irreversibly inhibited, compounds such as tyramine cause increased levels of NE or serotonin, and this increased NE or serotonin is not metabolized, which leads to an increased response. Reversible MAOIs can be displaced from the enzyme by the natural transmitter. Tyramine-induced release of NE and serotonin leads to the displacement of reversible MAOIs, resulting in metabolism of the transmitters by MAO and thereby causing less response.
Although the initial clinical trials of RIMAs were promising, none of these drugs may be introduced into the United States market. RIMAs should theoretically be safer and more tolerable than standard MAOIs, but, unfortunately, early reports of relatively high incidence of some side effects have tempered enthusiasm for them. Moclobemide has been reported to cause high rates of stimulant-like side effects such as agitation, insomnia, restlessness, “aggressivity,” and “mild mania-like symptoms,” as well as altered perceptions and depersonalization (Fahy 1993). It has also been reported to interact with cimetidine and meperidine (Amrein et al. 1992) as well as clomipramine. In some of these interactions and in overdose, there were hypermetabolic symptoms including hyperthermia, hypertension, agitation, coma, and muscle rigidity—the so-called serotonin syndrome (Amrein et al. 1992; Myrenfors et al. 1993).
Antidepressant and Antimanic Medications
Combined Medication and Psychotherapy
Treatment-Resistant Mood Disorders
Treatment of Mood Disorders in the Medically Ill Patient
Strategies and Tactics in the Treatment of Depression
Revision date: July 8, 2011
Last revised: by Andrew G. Epstein, M.D.