Altered Brain Tissue Volumes With Valproate Treatment for Schizophrenia

Journal article

Schizophrenia is a debilitating psychiatric condition that affects ≈0.5% of the global population. Some people with schizophrenia do not respond to first‐line antipsychotics and are prescribed clozapine; this is termed treatment‐resistant schizophrenia (TRS). When clozapine is ineffective for patients with TRS, and concomitant antipsychotics or mood stabilisers are required, this is termed ultra‐TRS (UTRS). Patients with UTRS are often prescribed augmentation therapy with mood stabilisers such as valproate to relieve residual symptoms. However, to date, the relationship between valproate and brain structure in people with schizophrenia has not been well described. Using magnetic resonance imaging, we found significant decreases in whole brain and white matter volumes in participants taking valproate compared to those taking clozapine without valproate. Further analyses revealed hypertrophy of grey matter in the cerebellum. This research indicates that using valproate augmentation in people with schizophrenia may alter white matter volumes and fractional anisotropy (FA) and grey matter density in the cerebellum and brainstem when compared to those receiving clozapine.

Authors: Cawood, T; Harrison, OK; McIlwain, M; Kydd, RR; Russell, BR

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Journal of the Royal Society of New Zealand
• Volume: 56
• Issue: 2
• Article number: e70034
• Publication date: 2026-03-23
• Acceptance date: 2026-01-22
• DOI: 10.1002/snz2.70034
• EISSN: 1175-8899
• ISSN: 0303-6758
• Language: English
• Keywords: valproate; clozapine; tissue volume estimation; diffusion weighted imaging; schizophrenia; voxel based morphometry; treatment‐resistance