Enhanced Prefrontal Function With Pharmacotherapy on a Response Inhibition Task in Adolescent Bipolar Disorder

In adolescent bipolar disorder (ABD), inattention, impulsivity and behavioral dis-inhibition are prominent and persist even after achieving mood stability.4 The frontostriatal circuitry that supports motor response inhibition has been shown to be affected in ABD.5 Appropriate goals of treatment, therefore, are to aim for mood stabilization, reducing motor response inhibition problems, and reversing the related frontostriatal deficits in ABD. Lamotrigine is one such medication that is used to stabilize mood in ABD6 and adult bipolar disorder (BD)7;8 due to its glutamatergic attenuating function that is believed to have the potential to improve cognitive function related to motor response inhibition problems.9–11 There is preliminary evidence from two fMRI studies indicating that lamotrigine may enhance brain circuitry function in bipolar disorder.6;12 In a study of patients with ABD performing an affective task requiring the rating of emotions in pictures, reduction in depressive symptoms was correlated with decreased right amygdala activation over an 8-week period.6 In an adult study of euthymic bipolar patients performing an “N back” working memory task, greater activation in the left medial prefrontal cortex (MPFC) and bilateral pregenual anterior cingulate cortex (ACC) was observed after 6 weeks of treatment with lamotrigine.12 Methodological limitations in these studies include a short treatment period and lack of demonstration of greater improvement in brain function after treatment in patients relative to matched healthy controls (HC) retested over a similar time period. This control group is essential for interpreting change over time as representing a drug treatment effect rather than a benefit from practice effects with the task or the scanning experience. Further, meta-analysis of studies of response inhibition in HC has demonstrated increased activity in the right prefrontal cortex.13 The task of response inhibition is complex and multifactorial with attention, perceptual discrimination, and motor executive control. Response suppression involves a situation that is highly stereotyped, requiring repetitive responses with little deliberation, except when an unusual event occurs in the midst of this routine task with clear stimulus-response requirements. This effort is shown to deploy dorsal, ventral, and medial PFC regions in HC.13–15 It was also shown that in ABD poor performance on voluntary motor response inhibition tasks is related to the high degree of impulsivity and inattention5 with underlying frontostriatal disturbances.5;16;17 Patients with adult BD, relative to HC, have also shown decreased activation in the orbitofrontal cortex during response suppression.18 Therefore, the primary aim of the current study is to evaluate the differences between ABD and HC in the domain of neurobehavioral deficits in frontostriatal circuitry that support the ability to voluntarily suppress behavioral responses. Our aim is to see if pharmacotherapy can reverse the frontostriatal circuitry dysfunction in ABD. Our pharmacotherapy consists of second generation antipsychotics (SGAs) for acute mania followed by lamotrigine for continued mood stabilization. We did not use SGAs for maintenance treatment due to high risk for metabolic side effects if prescribed for long-term treatment,19 in addition to our interest in determining the beneficiary effects of lamotrigine for optimal symptomatic recovery and cognitive function. We designed a Response Inhibition Task to probe the neural circuitry supporting “stopping process and motor inhibition.” We administered this task at baseline and after 14 weeks to HC and to ABD patients, who were acutely ill and unmedicated at baseline and at 14 weeks after mood stabilization with pharmacotherapy. The concept underlying this task is to compare the process of motor response inhibition to motor execution in ABD patients compared to HC, rather than examining response inhibition in the context of a pre-potent tendency to respond.20 This is an important first step in clarifying the basic neural circuits for motor inhibition versus execution in these patients. To this end, we contrasted blocks of trials that mainly required motor inhibition (Stop trials) to blocks of trials that mainly required motor action (Go trials). We predicted that there would be differences in prefrontal activation between the ABD subjects and HC at baseline. We hypothesized that lamotrigine, by virtue of pharmacological effects on prefrontal and striatal systems, would reverse the dysfunction in these regions that are believed to contribute to behavioral control deficits in ABD.