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

AI Summary

No association between working memory and 5-HT1BR, 5-HT2AR or 5-HTT frontal cortex binding in healthy controls.
Significant group interaction for 5-HT4R; positive association with working memory in patients with mood disorder but not in healthy individuals.
Findings suggest pathologically altered serotonin signalling may contribute to working memory deficits in mood disorders via downstream signalling or other neurotransmitter interactions.

AI Summary

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-HT1BR) (healthy controls: 28), 5-HT 2A receptor (5-HT2AR) (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. 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.

Basic summary

BJPsych Open. 2026 May 25;12(3):e146. doi: 10.1192/bjo.2026.11045.

ABSTRACT

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.

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.

PMID:42179183 | DOI:10.1192/bjo.2026.11045

Document this CPD