Antidepressants

Severe emotional disorders, generally termed the affective psychoses, are those in which the patient is severely disabled because of long-lasting depression accompanied by weight loss, sleeplessness, and often by contemplation of suicide; in such cases a family history of similar depression is often found. This severe form of depression accounts for a large number of admissions to psychiatric hospitals each year. Chemotherapy and electroshock therapy have significantly improved and subsequently stabilized mood in affected patients.

In 1957 imipramine emerged as the first therapeutically useful antidepressant. An accidental discovery led to the finding that the drug iproniazid caused some patients to become extremely euphoric and hyperactive by inhibiting monoamine oxidase, a liver and brain enzyme that normally breaks down norepinephrine and other monoamines. Drugs that were better at blocking the activity of this enzyme were even more effective in evoking euphoria. Shortly thereafter, the monoamine oxidase inhibitors, as they were later called, were introduced for the treatment of depression.

The most useful of the imipramine-like compounds all share the basic three-carbon ring structures of the early antipsychotic antihistaminic drugs, and for this reason they have been named tricyclic antidepressants. Clinically useful tricyclic drugs almost all inhibit the active re-uptake of the monoamines norepinephrine, serotonin, and sometimes dopamine into the presynaptic neuron. Inhibiting the active re-uptake of the monoamines allows them to remain in contact longer with their postsynaptic receptors. This mechanism seems to support the hypothesis that depression is due to altered monoamine transmission because, by allowing the accumulation of the monoamine neurotransmitters, me antidepressant corrects a deficiency in the monoamine transmitter pathway. The activity of monoamine oxidase inhibitors also supports this concept since their ability to relieve depression is based on their actions to inhibit the enzyme that breaks down the monoamines. Ten to 14 days are typically required to produce significant improvement in a depressed patient, even though these drugs almost completely block monoamine re-uptake or the catabolic actions of monoamine oxidase enzyme within hours after treatment begins. The reason for this delay is not known.

Patients with affective psychosis have unpredictable spontaneous remissions, which makes it impossible to conclude firmly that the antidepressant drug was responsible for the recovery. Monoamine oxidase inhibitors are known to be more effective than placebos but less effective in general than the tricyclic compounds. Important complications of these drugs are the increased sensitivity of the sympathetic nervous system and cardiac irregularities.