The development of antidepressant medications has proceeded through several historical phases. The older antidepressants such as monoamine oxidase inhibitors and early tricyclic antidepressants were discovered largely by serendipity. While effective antidepressants, these medications affect a wide range of neurotransmitter systems and cause many undesirable side effects. Subsequently, psychopharmacologic research and development efforts focused upon identifying the neurochemical properties associated with the antidepressant actions of these medications and upon developing compounds with variations on their chemical structure.
As theories were developed about the neurotransmitter systems involved in depression (eg, the monoamines serotonin, norepinephrine, and dopamine), drug development techniques progressed in parallel, leading to the formation of compounds with targeted affinities for receptors involved in specific aspects of monoaminergic neurotransmission (eg, the selective serotonin reuptake inhibitors). The incidence of side effects were greatly reduced since these medications had less effect upon other types of receptors (eg, cholinergic, histaminic, alpha adrenergic).
Advances in the basic neurosciences have further elucidated the pathophysiology of depression and have expanded our view of the many neurotransmitter systems involved in affective illness. Current evidence suggests that the initial receptor and neurotransmitter effects of antidepressants lead to "downstream" changes in protein production at a cellular level; these changes in turn appear to influence elements of neuronal protection and synaptic plasticity . Modern psychopharmacologic research has capitalized on this information, leading to the development of "designer" antidepressants with effects on specific combinations of selected neurotransmitter and neuropeptide systems [2,3].
The pharmacology of MAO inhibitors is reviewed here. The pharmacology and use of selective serotonin reuptake inhibitors (SSRIs), heterocyclic, serotonin-norepinephrine reuptake inhibitors (SNRIs), other antidepressants, and the serotonin syndrome, are discussed separately. Switching and discontinuing antidepressants, and an overview of options for treatment in depression are also discussed separately. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects" and "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects" and "Serotonin-norepinephrine reuptake inhibitors (SNRIs): Pharmacology, administration, and side effects" and "Serotonin syndrome" and "Antidepressant medication in adults: Switching and discontinuing medication" and "Unipolar major depression in adults: Choosing initial treatment".)
MONOAMINE OXIDASE INHIBITORS
Monoamine oxidase inhibitors (MAOIs) were the first class of antidepressants in clinical use. They were discovered in 1952 after iproniazid (a derivative of the antibiotic isoniazid) was found to be ineffective for treating tuberculosis, but was a potent antidepressive agent . The next MAOI, tranylcypromine, was identified as an antidepressant after it proved to be ineffective as a nasal decongestant. What these two medications have in common is the property of irreversibly blocking monoamine oxidase, the enzyme responsible for the oxidative deamination of neurotransmitters such as serotonin, norepinephrine, and dopamine. This property is thought to be largely responsible for the MAOIs' antidepressant effects.