Role of Serotonin in the Neurobiology of Schizophrenia and Association with Negative Symptoms

Importance: The involvement of the serotonin system in the pathophysiology of schizophrenia has been proposed for over 60 years, but there has been no prior study to test if there is altered serotonin release in vivo in schizophrenia (to the authors' knowledge). Objective: To investigate serotonin release in vivo in schizophrenia and its association with negative symptoms. It was hypothesized a priori that frontal cortex serotonin release capacity would be lower in schizophrenia compared with healthy controls and that this would be associated with more severe baseline negative symptoms. Design, Setting, and Participants: This was a single-center case-control neuroimaging study conducted in London, UK. All participants had dynamic 90-minute [11C]Cimbi-36 positron emission tomography (PET) scans at baseline and 3 hours after oral administration of d-amphetamine 0.5mg/kg. Data were collected between 2015 and 2024. Participants included stable adult outpatients with DSM-5 schizophrenia (antipsychotic free or taking antipsychotics with negligible affinity for 5-hydroxytryptamine receptor 2A [5-HT2A] receptors) and healthy controls matched for age, sex, and body mass index. Main Outcomes and Measures: The primary neuroimaging outcome was the group difference in serotonin release capacity, prespecified as the percentage change in frontal cortex [11C]Cimbi-36 binding potential between the baseline and d-amphetamine scans. Results: A total of 54 individuals were included, 26 with DSM-5 schizophrenia (mean [SD] age, 33.3 [9.1] years, 16 male [62%]; 21 not taking antipsychotic medication [81%]) and 28 healthy controls (mean [SD] age, 32.0 [9.5] years, 19 male [68%]). Frontal cortex serotonin release was significantly greater in the group with schizophrenia compared with healthy controls (18.0%; 95% CI, 2.5%-33.6%; P =.02; Cohen d = 0.69). In schizophrenia, greater frontal cortex serotonin release was correlated with more severe baseline negative symptoms (Brief Negative Symptom Scale: Pearson r = 0.42; P =.04) and poorer functioning (Social Functioning Scale: Pearson r = -0.42; P =.04). Exploratory analyses showed significantly greater frontal cortex serotonin release in deficit schizophrenia, characterized by primary and enduring negative symptoms, compared with healthy controls (mean difference = 32.3%; FDR-corrected P value = 0.001; Cohen d = 1.10) and nondeficit schizophrenia (mean difference = 28.9%; FDR-corrected P value = 0.004; Cohen d = 0.89). These findings were all replicated in 21 individuals with schizophrenia not taking antipsychotic medication. Baseline cortical [11C]Cimbi-36 binding (indexing baseline cortical 5-HT2A receptor levels) was unaltered in schizophrenia. Conclusions and Relevance: This case-control study found that serotonergic dysfunction in the pathophysiology of schizophrenia was associated with negative symptoms, suggesting the regulation of serotonin release as a target to treat negative symptoms. Results of the exploratory analysis suggest particularly marked serotonergic dysfunction in the subgroup with deficit schizophrenia.