Enhanced prefrontal function with pharmacotherapy on a response inhibition task in adolescent bipolar disorder

Abstract

Objective: The aim of the current study is to determine whether pharmacotherapy normalizes cognitive circuitry function supporting voluntary behavioral inhibition in adolescent bipolar disorder.

Method: Healthy controls and unmedicated patients with DSM-IV adolescent bipolar disorder in manic, mixed, or hypomanic episodes were matched on demographics and IQ (n = 13 per group; mean age = 14.4 ± 2.4 years). Functional magnetic resonance imaging studies were performed at baseline and after 14 weeks, during which time patients with adolescent bipolar disorder were treated initially with second-generation antipsychotics (SGAs) followed by lamotrigine monotherapy. The primary outcome measure was a Response Inhibition Task, which involved a planned motor response, already "on the way" to execution, that had to be voluntarily inhibited by the subjects in the trials in which a stop signal was presented. There were 6 blocks, each with a predominant rate of either "go" or "stop" trials. The study was conducted from June 2006 through July 2009.

Results: All patients showed significant improvement (P < .001) in both the manic and depressive symptoms from baseline. Behavioral data showed that accuracy improved over 14 weeks in patients and healthy controls. Significant time by group interaction effects for the difference between stop versus go blocks showed greater increases of activation in prefrontal (left inferior and middle frontal gyri and medial frontal gyrus bilaterally) and temporal (left superior temporal gyrus and right middle temporal gyrus) regions and greater decreases in activation in right putamen and bilateral thalamus at follow-up in the adolescent bipolar disorder group than in healthy controls. Increased ventrolateral prefrontal cortex function was related to clinical treatment response.

Conclusions: Treatment with SGAs followed by lamotrigine monotherapy enhanced prefrontal and temporal lobe activity during a Response Inhibition Task demonstrating the reversal of disorder-relevant neural circuitry dysfunction in patients with adolescent bipolar disorder. Patient performance was not slowed down with this treatment regimen.

Trial registration: clinicaltrials.gov Identifier: NCT00176228.

© Copyright 2010 Physicians Postgraduate Press, Inc.

Figures

Figure 1. Stop and Go Trials in Response Inhibition Task

Appearance of airplane must be followed by immediate response in a Go trial; and must stop from responding when airplane is replaced by man with the stop sign’ in a Stop trial.

Figure 2. Lamotrigine Treatment Effects

PANEL I: Pictures A, B and C shows post-treatment activation relative to pre-treatment for Stop vs. Go Condition in patients with Adolescent Bipolar Disorder (ABD). Red indicates increased activation post-treatment relative to pre-treatment and blue indicates increased activation pre-treatment relative to post-treatment (not shown here) PFC = prefrontal cortex; Pregen/Subgen ACC = pregenual/subgenual anterior cingulate cortex; PCC = posterior cingulate cortex; Ven Striat= Ventral Striatum. PANEL II: Pictures D and E show lamotrigine treatment effects over time on brain function in patients with ABD vs. Healthy Controls. Red indicates increased activation in patients with ABD relative to HC; and blue indicates increased activation in HC relative to patients with ABD for Stop vs. Go Condition over the 14 week period.