Revisiting the role of raphe and serotonin in neuropsychiatric disorders

The monoaminergic hypothesis of depression posits that this illness results from a deficit in serotonin (5-HT), noradrenaline, and dopamine signaling in the brain. Of these monoamines, the serotonergic system has been the one most strongly implicated in the pathophysiology and treatment of mood disorders. Although this relationship has not been proven, many findings indirectly support this hypothesis: (a) a subgroup of depressed patients have a very marked reduction of the concentration of 5-HT in plasma (Sarrias et al., 1987) and of its metabolite, 5-hydroxyindoleacetic acid, in the cerebro-spinal fluid (Asberg et al., 1976) that may reflect decreased serotonergic transmission in the brain; (b) most prescribed antidepressant drugs increase serotonergic transmission in the long term; (c) a clinical study showed that in 50% of depressed patients that responded to selective 5-HT reuptake inhibitors (SSRIs) (see Fig. 1), de-pressive symptoms relapsed after depletion of the 5-HT precursor tryptophan (Delgado et al., 1999); (d) recent preclinical investigations have reported that an intact serotonergic system is required for an antidepressant response to experimental treatments such as deep brain stimulation or ketamine (Hamani et al., 2010; Gigliucci et al., 2013); and (e) optogenetic activation of the pre-frontal cortex projection to the dorsal raphe (DR) nucleus produces antidepressant-like effects in rodents (Covington et al., 2010; Warden et al., 2012). Therefore, there is evidence that deficits in serotonergic transmission are associated with at least some depressive states and a poor response to antidepressant drugs (Sachs et al., 2015), whereas the activation of 5-HT neurons in the DR evokes an antidepressant response.