19.01.2 Neurochemistry of Depression and the Monoamine Theory

The major neurotransmitters thought to be involved in depression are the monoamines, most likely noradrenaline and serotonin.

Serotonin and noradrenaline are diffusely projecting neurotransmitters in the central nervous system, projecting from the brainstem raphe nuclei and locus coeruleus, respectively, to key brain regions such as the prefrontal cortex, limbic system and hypothalamus. Consequently, these neurotransmitters regulate behaviours such as cognition, vigilance, emotion and stress responses.

The ‘monoamine theory of depression’ was first postulated in 1965 to suggest that depression is caused by a functional deficit of monamines in specific brain regions. This claim was based on pharmacological evidence that reserpine (from Rauwolfia serpentina) disrupts monoamine storage and causes depression, and that known antidepressant drugs augment the monoamine systems to increase available transmitters and ameliorate symptoms of depression. Nevertheless, monoamine levels are augmented straight away while the symptoms of depression take weeks to diminish. Moreover, it is shown that the delayed therapeutic effect of antidepressants coincides with monoamine receptor downregulation.

The monoamine theory was thus revised in the 1980’s to suggest that the hyponoradrenergic/hyposerotoninergic state that is postulated to occur in depression leads to hypperresponsiveness of the adrenergic and serotoninergic receptors in certain parts of the brain. Accordingly, the action of antidepressants is to increase synaptic levels of noradrenaline and serotonin to normal, while downregulating “hyperresponsive” receptors to reinstate normal neuronal activities, accounting for the delayed therapeutic action of these drugs.