Serotonin and working memory in mood disorder and healthy states: multi-cohort positron emission tomography study

Background Working memory deficits are common in mood disorders and severely affect everyday functioning. Serotonin (5-HT) signalling has been implicated in depression and is also involved in cognitive functioning. However, its relevance for working memory remains largely unexplored. Aims Using positron emission tomography (PET) brain imaging, we investigated the link between working memory and multiple 5-HT brain features in both healthy individuals and patients with mood disorders in a cross-sectional analysis of pooled data-sets. Method We used multiple linear regression to test the associations between working memory performance and 5-HT 1B receptor (5-HT_1BR) (healthy controls: 28), 5-HT 2A receptor (5-HT_2AR) (healthy controls: 116), 5-HT 4 receptor (5-HT₄R) (healthy controls: 97, patients: 98) and 5-HT transporter (5-HTT) (healthy controls: 137, patients: 12) PET binding in the frontal cortex. The frontal cortex was chosen as region of interest as it is critical for working memory functions. Results There was no association between working memory and 5-HT_1BR (p = 0.14), 5-HT_2AR (p = 0.99) or 5-HTT (p = 0.80) frontal cortex binding in healthy controls. For the 5-HT₄R, we observed a significant interaction effect of group status (p = 0.01), with patients showing a positive association (β = 6.51, p = 0.02) and healthy individuals showing no significant association (p = 0.16). Conclusions We found no evidence that key 5-HT receptor systems are associated with working memory performance in healthy individuals, but did observe a positive association for 5-HT₄R in patients with mood disorder. We speculate that although 5-HT neurotransmission markers may map onto working memory performance in the healthy state, pathologically altered 5-HT signalling may contribute to working memory deficits in mood disorders, possibly through downstream signalling and/or interactions with other neurotransmitter systems.