Mechanism of Action

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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 involved in the catabolism of human brain dopamine, although 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 depressions strongly suggests that MAO inhibition at central serotonin or norepinephrine synapses or both is responsible 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 observed 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 a- and (3-adrenoceptors and up-regulation or enhancement of synaptic transmission at serotonin synapses (5HT1A-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 associated with the antidepressant properties of the MAOIs, is the mechanism of action for these agents in the treatment of major depression.

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