Glutamatergic effects of divalproex in adolescents with mania: a proton magnetic resonance spectroscopy study.

OBJECTIVES: This study used proton magnetic resonance spectroscopy ((1)H MRS) to evaluate the in vivo effects of extended-release divalproex sodium on the glutamatergic system in adolescents with bipolar disorder, and to identify baseline neurochemical predictors of clinical remission. METHOD: Adolescents with bipolar disorder who were experiencing a manic or mixed episode (N = 25) were treated with open-label, extended-release divalproex (serum levels 85-125 µg/mL) and underwent (1)H MRS scanning at baseline (before treatment) and on days 7 and 28. Healthy comparison subjects (n = 15) also underwent (1)H MRS scanning at the same time points. Glutamate (Glu) and glutamate+glutamine (Glx) concentrations were measured in three voxels: anterior cingulate cortex (ACC), left ventrolateral prefrontal cortex (LVLPFC), and right ventrolateral prefrontal cortex (RVLPFC), and were compared between bipolar and healthy subjects. Within the bipolar subjects, Glu and Glx concentrations at baseline and each time point were also compared between remitters and nonremitters after divalproex treatment. RESULTS: At baseline, no differences in Glu or Glx concentrations between bipolar and healthy subjects were observed. Group (HC vs. BP) by time effects revealed an interaction for Glu in the ACC, and change over time effects for Glx were noted in the ACC in patients with bipolar disorder (increase from day 0 to day 7 and then a decrease from day 7 to day 28) but not in HC. Remitters had significantly lower baseline Glx concentrations in LVLPFC, and in remitters the change in LVLPFC Glu correlated with the change in YMRS score. CONCLUSIONS: Successful treatment of mania with divalproex may be predicted by lower baseline concentrations of Glx in the LVLPFC. In addition, in remitters, the degree of symptomatic improvement is related to the change in Glu concentrations in this region, suggesting that divalproex may work via modulation of the prefrontal glutamatergic system in youth with bipolar disorder.

Lithium treatment effects on Myo-inositol in adolescents with bipolar depression.

BACKGROUND: The neurochemical effects of lithium in adolescents with bipolar disorder largely are unknown. This study used proton magnetic resonance spectroscopy (1H MRS) to identify the in vivo effects of lithium on myo-inositol (mI) concentrations in adolescent bipolar depression. METHODS: Twenty-eight adolescents (12-18 years old) with bipolar I disorder, current episode depressed, received open-label lithium 30 mg/kg, adjusted to achieve serum levels of 1.0-1.2 mEq/L. The mI concentrations in the medial as well as the left and right lateral prefrontal cortices were measured at baseline, day 7, and day 42 of treatment. Changes in mI concentrations over time were analyzed. RESULTS: Significant main effects of time were observed for mI concentrations in the medial (p = .03) and right lateral (p = .05) prefrontal cortices. Baseline concentrations of mI were not significantly different from day 7 or day 42 concentrations. However, mI concentrations on day 42 were significantly higher than those on day 7 (p = .02) in both regions. CONCLUSIONS: This study demonstrates that prefrontal mI concentrations do not significantly change from baseline after acute and chronic lithium treatment in adolescents with bipolar depression. Further investigation of the effect of lithium on mI is warranted to better understand possible mechanisms by which lithium exerts antidepressant activity.

Open-label lithium for the treatment of adolescents with bipolar depression.

OBJECTIVES: To investigate the effectiveness and tolerability of lithium for the treatment of acute depression in adolescents with bipolar disorder. We hypothesized that patients receiving open-label treatment with lithium during a 6-week period would experience a statistically and clinically significant decrease in depressive symptoms and tolerate lithium treatment fairly well. METHOD: Twenty-seven adolescents (12-18 years old) with an episode of depression associated with bipolar disorder type I received open-label lithium 30 mg/kg (twice-daily dosing), which was adjusted to achieve a therapeutic serum level (1.0-1.2 mEq/L). Effectiveness measures included the Children's Depression Rating Scale-Revised (CDRS-R) and Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP). Adverse events were assessed weekly. RESULTS: Mean CDRS-R scores significantly decreased from baseline to endpoint (mean [SD] change = -25.5 (20.4); p < .001), resulting in a large effect size of 1.7. Response and remission rates (defined by a > or = 50% reduction in CDRS-R score from baseline to endpoint, and a CDRS-R score < or = 28 and a CGI-BP Improvement score of 1 or 2, respectively) were 48% and 30%. Side effects, which were generally mild to moderate in severity, included headache (74%), nausea/vomiting (67%), stomachache (30%), and abdominal cramps (19%). CONCLUSIONS: The findings of this study indicate that lithium may be effective and is relatively well tolerated for the treatment of an acute episode of depression in adolescents with bipolar disorder. Controlled studies of lithium in adolescent bipolar depression are needed.