How do antidepressants work?

In 1954, trials of iproniazid for tuberculosis showed that the mood of some subjects improved during treatment. Iproniazid was found to inhibit monoamine oxidase activity and other drugs that replicated this effect turned out to have an antidepressant action. Monoamine oxidase was known to be involved in the breakdown of monoamine neurotransmitters in the brain and the theory that increases in serotonin activity were important in the treatment of depression was suggested by the finding that the antidepressant effect of MAOIs was enhanced by oral supplements of the serotonin precursor, tryptophan.

In 1958, trials of a tricyclic drug, imipramine, in schizophrenia, showed it to be of no help in the treatment of psychotic symptoms but to have an antidepressant effects in subjects with depressive symptoms. Imipramine was found to inhibit the reuptake of noradrenaline into presynaptic neurons, which suggested that noradrenaline was also involved in depression.

All the antidepressants developed since have an effect on either noradrenaline or serotonin, as illustrated in Figure 1. The relative effects of the monoamine reuptake inhibitors are shown in Figure 2. Some antidepressant drugs affect monoamines in novel ways, such as mirtazapine, which antagonises the presynaptic adrenergic autoreceptors that inhibit serotonin and noradrenaline release.

Fig. 1 Antidepressant drug action.

Fig. 2 Relative effects of monoamine reuptake inhibitors on serotonin (5HT) and noradrenaline (NA).

There is a problem with the theory that antidepressants work as a result of their effect on serotonin and noradrenaline. The levels of these monoamines in the synaptic cleft increase within a few hours of the first dose of reuptake inhibitors, whereas it usually takes one or two weeks of treatment before any antidepressant effect is apparent clinically. One explanation for this is that the therapeutic effect of antidepressants depends on a decrease in the sensitivity of some receptors, such as presynaptic serotonergic autoreceptors, that occurs gradually during the first few weeks of treatment. Alternatively, it may be that increases in monoamine transmission have secondary effects that help relieve depression, such as regulation of the hypothalamic pituitary axis, or production of neurotrophic factors that promote healing of damaged neurones.