Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: a longitudinal brain imaging study

Abstract

Preclinical studies suggest that lithium may exert neurotrophic effects that counteract pathological processes in the brain of patients with bipolar disorder (BD). To describe and compare the course and magnitude of gray matter volume changes in patients with BD who are treated with lithium or valproic acid (VPA) compared to healthy comparison subjects, and to assess clinical relationships to gray matter volume changes induced by lithium in patients with BD, we conducted longitudinal brain imaging and clinical evaluations of treatment response in 22 mood-stabilizing and antipsychotic medications-naive patients with BD who were randomly assigned to either lithium or VPA treatment after baseline assessment. Fourteen healthy comparison subjects did not take any psychotropic medications during follow-up. Longitudinal data analyses of 93 serial magnetic resonance images revealed lithium-induced increases in gray matter volume, which peaked at week 10-12 and were maintained through 16 weeks of treatment. This increase was associated with positive clinical response. In contrast, VPA-treated patients with BD or healthy comparison subjects did not show gray matter volume changes over time. Results suggest that lithium induces sustained increases in cerebral gray matter volume in patients with BD and that these changes are related to the therapeutic efficacy of lithium.

Figure 1

Estimated gray and white matter volume changes for participants during 16 weeks of study period. (a) Trend lines of gray matter volume changes from baseline were fitted by use of quadratic mixed-effect regression modeling (blue line for Li-treated patients with BD, green line for VPA-treated patients with BD, and gray line for healthy comparison subjects). The trend of changes in gray matter volume in Li-treated patients with BD differed significantly from that in VPA-treated patients (p for interaction=0.02) and from that in healthy comparison subjects (p for interaction=0.001). Age, sex, and study site were included as covariates in these models. (b) Trend lines of white matter volume changes from baseline were fitted by use of linear mixed-effect regression modeling (blue line for Li-treated bipolar patients, green line for VPA-treated bipolar patients, and gray line for healthy comparison subjects). The trend of changes in white matter volume in Li-treated patients with BD did not differ from that in VPA-treated patients (p for interaction=0.99) and from that in healthy comparison subjects (p for interaction=0.18). Age, sex, and study site were included as covariates in these models. GM, gray matter; Li, lithium; VPA, valproic acid; WM, white matter. See online version for colour information.

Figure 2

Individual trajectories in gray and white matter volumes and their fitted trend lines for lithium-treated (a) and valproic acid-treated (b) bipolar disorder patients. Trend lines of gray matter volume changes from baseline were fitted by use of quadratic mixed-effect regression modeling (blue dotted line). White matter volume changes were fitted by use of linear mixed-effect regression modeling (gray dotted line). Age, sex, and study site were included as covariates in these models. GM, gray matter; ICV, intracranial volume; WM, white matter. See online version for colour information.