Treatment of Major Depression: Monoamine Oxidase Inhibitors

Monoamine Oxidase Inhibitors

Iproniazid, originally developed for the treatment of tu-berculosis, exhibited mood-elevating properties during clinical trials in tuberculosis patients with depression. The distinguishing biochemical feature between iproni-azid and other chemically similar antituberculosis com-pounds was the ability of the former to inhibit MAO. Thus, a series of hydrazine and non–hydrazine-related MAOI agents was synthesized and tested for antide-pressant properties. Three MAOI agents are approved in the United States for use in major depression: isocar-boxazid (Marplan), phenelzine (Nardil), and tranyl-cypromine (Parnate).

The MAOIs are as effective as the heterocyclic anti-depressants and the newer agents, such as the SSRIs. However, at least two forms of life-threatening toxicity (hepatotoxicity and dietary tyramine–induced hyper-tensive crisis ) have been associated with their chronic use. For this reason, the MAOIs are not considered first-line agents in the treatment of depression. They are gen-erally reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants. However, a new transdermal formulation of selegiline undergoing clinical trials demonstrates antidepressant efficacy without concerns of liver toxicity or dietary tyramine-induced hypertension.

Mechanism of Action

Monoamine oxidase exists in the human body in two molecular forms, known as type A and type B. Each of these isozymes has selective substrate and inhibitor characteristics. Neurotransmitter amines, such as norep-inephrine and serotonin, are preferentially metabolized by MAO-A in the brain. MAO-B is more likely to be in-volved in the catabolism of human brain dopamine, al-though dopamine is also a substrate for MAO-A.

Isocarboxazid, phenelzine, and tranylcypromine are irreversible nonselective inhibitors of both MAO-A and MAO-B. However, it appears that inhibition of MAO-A, not MAO-B, is important to the antidepres-sant action of these agents.

Therapeutic efficacy by selective MAO-A inhibitors (such as clorgyline or moclobemide) in major depres-sions strongly suggests that MAO inhibition at central serotonin or norepinephrine synapses or both is re-sponsible for the antidepressant properties of these agents. However, since complete MAO-A inhibition is achieved clinically within a few days of treatment, while the antidepressant effects of these drugs are not ob-served for 2 to 3 weeks, suggests that additional actions must be involved.

In a manner similar to that of the TCAs and SSRIs, MAOIs are known to induce adaptive changes in the CNS synaptic physiology over 2 to 3 weeks. These changes result in both down-regulation of synaptic transmission mediated through noradrenergic α- and β- adrenoceptors and up-regulation or enhancement of synaptic transmission at serotonin synapses (5HT_1A-receptors). This action on serotonin neurotransmission is the result of desensitized somatodendritic autorecep-tors responsible for the regulation of the firing rate of serotonin-containing neurons of the forebrain. Accordingly, these neurons fire at elevated rates, releas- ing large quantities of serotonin into the synapse. This serotonin is protected from degradation by inhibition of synaptic MAO-A. It is believed that the development of these physiological changes at norepinephrine and serotonin synapses, which parallel the time delay asso-ciated with the antidepressant properties of the MAOIs, is the mechanism of action for these agents in the treat-ment of major depression.

Adverse Effects

The potential for toxicity that is associated with the ad-ministration of the MAOIs restricts their use in major depression. Hepatotoxicity is likely to occur with iso-carboxazid or phenelzine, since hydrazine compounds can cause damage to hepatic parenchymal cells. This is true particularly for patients identified as slow acetyla-tors  of hydrazine compounds. For-tunately, the incidence of hepatotoxicity is low with the available agents.

A greater concern is the potentially lethal cardio-vascular effects that can occur in patients who do not comply with their dietary restrictions. Patients who take a MAOI should not eat food rich in tyramine or other biologically active amines. Normally, these amines are rapidly metabolized by MAO-A during gastric absorp-tion by the mucosal cells of the intestinal wall and by MAO-A and MAO-B during passage through the liver parenchyma. If both isozymes of MAO are inhibited, el-evated circulating levels of tyramine will be free to in-teract with the sympathetic noradrenergic nerve termi-nals innervating cardiac and vascular smooth muscle tissue to produce a pressor effect . In these conditions, tyramine can cause an acute elevation in blood pressure, sometimes leading to a hypertensive crisis. Cheeses, wine, and a whole host of other foods rich in tyramine must be avoided. A number of other bothersome side effects, such as tremors, orthostatic hy-potension, ejaculatory delay, dry mouth, fatigue, and weight gain, are common at therapeutic doses of MAOIs (Table 33.2).

Drug Interactions

Serious hypertension can occur with concomitant ad-ministration of over-the-counter cough and cold med-ications containing sympathomimetic amines. When switching from a MAOI to another antidepressant, such as a SSRI, a drug-free period of 2 weeks is required to allow for the regeneration of tissue MAO and elimina-tion of the MAOI. When switching from an antidepres-sant, such as an SSRI, to a MAOI, sufficient time should be allowed for the SSRI to be cleared from the body (at least 5 half-lives) before starting the MAOI. Special note should be taken of fluoxetine’s long half-life, re-quiring at least 5 weeks after discontinuation of fluoxe-tine at a 20-mg dose and longer at higher doses, before initiation of MAOI therapy. Coadministration of a MAOI and an SSRI or venlafaxine can overstimulate the serotonin receptors in the brainstem and spinal cord (serotonin syndrome), which can be lethal. Serotonin syndrome consists of a constellation of psychiatric, neu-rological, and cardiovascular symptoms that may in-clude confusion, elevated or dysphoric mood, tremor, myoclonus, incoordination, hyperthermia, and cardio-vascular collapse.