Lithium and valproate affect subcortical brain volumes in individuals with bipolar disorder: Mega-analysis of 235...

The mega-analysis conducted by the ENIGMA Bipolar Disorder Working Group revealed significant volume increment effects of lithium on the hippocampus in individual with bipolar disorder. However, the study did not assess other medications and other subcortical regions.

Data of 235 individuals with bipolar disorder were taken from a mega-analysis conducted by the COCORO consortium in Japan. The effects of psychotropic prescriptions (lithium, valproate, antipsychotics, antidepressants, benzodiazepines) were assessed using a linear mixed-effects model with volumes of subcortical structures as dependent variables, and age, sex, intracranial volume, duration of illness, and psychotropic prescriptions as independent variables; the type of protocol was incorporated as a random effect.

Prescriptions of lithium was associated with larger left amygdala volume (Effect size (ES, Cohen's d) = 0.36, p = 0.001). Prescriptions of valproate was associated with smaller left amygdala volume (ES = -0.45, p = 0.001), and larger bilateral ventricle volumes (ES = 0.68, p < 0.001 (left), ES = 0.70, p < 0.001 (right)). Prescriptions of antipsychotics were associated with larger left globus pallidus volume (ES = 0.33, p = 0.014) and smaller left hippocampus volume (ES = -0.33, p = 0.024). Prescriptions of benzodiazepines were associated with smaller left lateral ventricle (ES = -0.40, p = 0.029). Prescriptions of antidepressants were associated with smaller right accumbens volume (ES = -0.22, p = 0.043), bilateral caudate volumes (ES = -0.38, p = 0.013 (left), ES = -0.25, p = 0.050 (right)) and right putamen volume (ES = -0.23, p = 0.024).

We confirmed the association between prescription of valproate and smaller amygdala and larger lateral ventricle volumes in a large sample for the first time. Large sample size, uniform data collection methodology, and robust statistical analysis are strengths of the current study.