Background: The hypothalamus is central to many hormonal and autonomous nervous system pathways. Emerging evidence indicates that these pathways may be disrupted in schizophrenia and bipolar disorder. Yet, few studies have examined the volumes of hypothalamic subunits in these patient groups. We compared hypothalamic subunit volumes in individuals with psychotic disorders to healthy controls. Study Design: We included 344 patients with schizophrenia spectrum disorders (SCZ), 340 patients with bipolar disorders (BPD) and 684 age-and-sex-matched healthy controls (CTR). Total hypothalamus and five hypothalamic subunit volumes were extracted from T1-weighted MRI using an automated Bayesian segmentation method. Regression models, corrected for age, age2, sex, and segmentation-based intracranial volume (sbTIV), were used to examine diagnostic group differences, interactions with sex, and associations with clinical symptoms, antipsychotic medication, antidepressants and mood stabilizers. Study Results: SCZ had larger volumes in the left inferior tubular subunit and smaller right anterior inferior, right anterior superior and right posterior hypothalamic subunits compared to CTR. BPD did not differ significantly from CTR for any hypothalamic subunit volume, however, there was a significant sex-by-diagnosis interaction. Analyses stratified by sex showed smaller right hypothalamus and right posterior subunit volumes in male patients, but not female patients, relative to same-sex controls. There was a significant association between BPD currently taking antipsychotic medication and the left inferior tubular subunits volumes. Conclusions: Our results show regional-specific alterations in hypothalamus subunit volumes in individuals with SCZ, with relevance to HPA-axis dysregulation, circadian rhythm disruption and cognition impairment.

OAA has received speaker's honorarium from Lundbeck and Sunovion and is a consultant for HealthLytix. IA has received speaker's honorarium from Lundbeck. The other authors report no conflicts of interest.

The work was supported by The Research Council of Norway (grant numbers 223273, 274359), the K. G. Jebsen Foundation (grant number SKGJ-MED-008), and Helse Sør-Øst RHF (grant numbers 2017-097, 2019-104, 2020-020).

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The TOP study was approved by the Regional Committees for Medical Research Ethics (REC) South East Norway. Data handling procedures were approved by the Norwegian Data Protection Authority (Datatilsynet) and data handling complied with GDPR regulations. The study was conducted in accordance with the Helsinki Declaration, and participants provided written informed consent.

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