Serotonin and depression - a riposte to Moncrieff et al. (2022)

In their recently published systematic "umbrella" review, Moncrieff and colleagues conclude that there is no consistent evidence that depression is caused by decreased serotonin activity in the central nervous system (CNS). However, this paper - which was extensively publicized and received a lot of attention on the social media - can cause misunderstandings, since the serotonin hypothesis of depression in its original form (i.e. reduced serotonin activity in the CNS = depression) formulated more than 50 years ago has been considered outdated for several decades. It has long been known that depression is a heterogeneous disorder not only genetically, clinically and biologically but also from a pharmacotherapeutic perspective. The decreased activity of serotonin, which undoubtedly plays an essential role in the pathogenesis of depression, is characteristic of only a subgroup of depressed subjects whose clinical picture is mostly dominated by intensified negative emotions, agitation, anxiety, insomnia, decreased appetite, self-blame and suicidality and these individuals are primarily responsive to SSRIs. By contrast, depression cases with reduced positive affects (characterized by anhedonia, anergia, inhibition and reduced cognitive functions) are mainly caused by a disturbance in the metabolism of dopamine and/or noradrenaline. These patients are primarily responsive to dual-action (e.g. SNRI) antidepressants. Results of serotonin and catecholamine (dopamine, noradrenaline) depletion studies also suggest that that the dysregulation of serotonin and dopamine/noradrenaline in the CNS is characteristic of different subgroups of depressed patients. In addition to the serotonergic, dopaminergic and noradrenergic systems, many other neurotransmitter systems (e.g. cholinergic, glutamatergic, GABAergic) and other mechanisms (e.g. neuroinfl ammation) have also been proven to play a role in the development of the disorder. Knowledge of the data presented in our publication is important since the simplistic interpretation by Moncrieffetal. of the role of serotonin in the pathogenesis of depression may undermine confidence in SSRIs in many patients. (Neuropsychopharmacol Hung 2022; 24(3): 120-125).