Clinical implications of mechanisms of action of antidepressants

In 1965, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. In favour of this hypothesis was the observation that the antihypertensive drug reserpine, which depletes central and peripheral vesicular stores of catecholamines such as noradrenaline, can precipitate depression in patients in remission. The experimental drug α-methyl-paratyrosine that blocks the synthesis of noradrenaline and dopamine by inhibiting the rate-limiting enzyme tyrosine hydroxylase also precipitates depression in patients during remission. Such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression – more direct evidence is needed to substantiate the hypothesis. The most obvious approach would be to determine the concentration of noradrenaline and/or its major central metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brains of suicide victims. The problem with such post-mortem studies is that: (a) the precise diagnosis may be uncertain; (b) there is usually a considerable post-mortem delay before the brain is removed at autopsy; and (c) suicide is often committed by taking an overdose of alcohol together with drugs, which grossly affects central monoamine neurotransmitter function.