Does serotonin matter in depression?

Serotonin (5-HT) neurons constitute a tiny fraction of neurons in the brain (300 000 out of a billion neurons in human brain [0.03%]), yet they send projections to virtually all regions of the brain. 1 The 5-HT system has been the target of multiple therapeutic drugs, like selective serotonin reuptake inhibitors (SSRIs), approved to treat major depressive disorder by the US Food and Drug Administration since 1987 2 and with indications for several mental health conditions including anxiety, compulsions and eating disorders. 3 More recently, psychedelic drugs targeting 5-HT receptors have been receiving attention for their behavioural actions, which are powerful yet variable among individuals. 4 It is perhaps because of this breadth of actions that it has been difficult to define how 5-HT modulates specific brain regions to alter behaviour. The underlying complexity of the serotonin system can lead to contradictory findings, as argued by Moncrieff and colleagues. 5 Yet, as discussed in this editorial, through consideration of how the 5-HT system works and the limitations of methods used we can also understand why different groups may obtain different or even contradictory results. Moncrieff and colleagues 5 present a systematic umbrella review of studies reviewing different aspects of 5-HT related to depression. Unfortunately, the umbrella approach tends to muddy the waters. A good example is the inconsistent association of lower regional 5-HT 1A receptor levels with depression. 6–9 Without knowing the specifics of the probe (antagonist v. agonist 10 ), method (positron emission tomography [PET] v. postmortem), 7 use of a reference region compared with arterial input (e.g., in PET 9 ) and regions affected (e.g., presynaptic v. postsynaptic 5-HT 1A that have