Depression as a spreading neuronal adjustment disorder

The outlines of a theory of the pathophysiology of depression are presented. The classic monoamine theory of depression as well as its more recent elaborations suggests that a deficit in monoamine neurotransmitters in the synaptic cleft is the primary cause of depression. We suggest that the primary defect emerges in the regulation of firing rates in brainstem monoaminergic neurons, which brings about a decrease in the tonic release of neurotransmitters in their projection areas, an increase in postsynaptic sensitivity and, concomitantly, exaggerated responses to acute increases in presynaptic firing rate and transmitter release. We propose that the initial defect involves, in particular, the noradrenergic innervation from the locus coeruleus, which in turn leads to dysregulation of 5-HT-ergic and dopaminergic neurotransmission.