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.

Impulsivity in adolescents with bipolar disorder and/or attention-deficit/hyperactivity disorder and healthy controls as measured by the Barratt Impulsiveness Scale.

OBJECTIVE: To compare the type and degree of impulsivity among adolescents with bipolar disorder (BD), adolescents with attention-deficit/hyperactivity disorder (ADHD), and healthy comparison subjects using the Barratt Impulsiveness Scale, Version 11 (BIS-11). METHODS: Manic adolescents with BD (n=31), adolescents with ADHD (n=30), and healthy subjects (n=25) completed the BIS-11, a 30-item, self-report scale with three subscales (cognitive, motor, and nonplanning). The BIS-11 total and subscale scores were compared among groups. We also examined associations among the BIS-11, Young Mania Rating Scale and co-occurring disruptive behavioral disorders (DBDs) within the BD group. RESULTS: Total and each subscale scores were significantly higher for the BD group than for the healthy controls (p<0.05). The total scores and the cognitive and motor subscale scores were significantly higher for the ADHD group than for the healthy control group (p<0.05). However, there was no statistically significant difference between the nonplanning subscale scores of the ADHD group and the healthy control group (p>0.05). There were no significant differences between the BD and ADHD groups or between the BD groups with and without ADHD. The BD patients with DBDs (i.e., oppositional defiant disorder or conduct disorder) scored significantly higher on the motor subscale than did BD patients without DBDs. There were no statistically significant associations between the Young Mania Rating Scale and BIS-11 scores within the BD group. CONCLUSION: Our findings suggest that impulsivity is elevated in adolescents with BD as well as adolescents with ADHD, except for nonplanning impulsivity, which was not significantly different between adolescents with ADHD and the healthy comparison group. This may suggest that nonplanning impulsivity is relatively specific to adolescents with BD. Additionally, our data indicate that elevations in impulsivity, as measured by the BIS-11, may be independent of symptoms severity and, therefore, may be a stable, trait-related component of BD.

Preventative strategies for early-onset bipolar disorder: towards a clinical staging model.

Bipolar disorder is a chronic and typically recurring illness with significant psychosocial morbidity. Although the aetiological factors that contribute to the onset of mania, and by definition bipolar I disorder, are poorly understood, it most commonly occurs during the adolescent period. Putative risk factors for developing bipolar disorder include having a first-degree relative with a mood disorder, physical/sexual abuse and other psychosocial stressors, substance use disorders, psychostimulant and antidepressant medication exposure and omega-3 fatty acid deficiency. Prominent prodromal clinical features include episodic symptoms of depression, anxiety, hypomania, anger/irritability and disturbances in sleep and attention. Because prodromal mood symptoms precede the onset of mania by an average of 10 years, and there is low specificity of risk factors and prodromal features for mania, interventions initiated prior to onset of the disorder (primary prevention) or early in the course of the disorder (early or secondary prevention) must be safe and well tolerated upon long-term exposure. Indeed, antidepressant and psychostimulant medications may precipitate the onset of mania. Although mood stabilizers and atypical antipsychotic medications exhibit efficacy in youth with bipolar I disorder, their efficacy for the treatment of prodromal mood symptoms is largely unknown. Moreover, mood stabilizers and atypical antipsychotics are associated with prohibitive treatment-emergent adverse effects. In contrast, omega-3 fatty acids have neurotrophic and neuroprotective properties and have been found to be efficacious, safe and well tolerated in the treatment of manic and depressive symptoms in children and adolescents. Together, extant evidence endorses a clinical staging model in which subjects at elevated risk for developing mania are treated with safer interventions (i.e. omega-3 fatty acids, family-focused therapy) in the prodromal phase, followed by pharmacological agents with potential adverse effects for nonresponsive cases and secondary prevention. This approach warrants evaluation in prospective longitudinal trials in youth determined to be at ultra-high risk for bipolar I disorder.

Selegiline transdermal system: a novel treatment option for major depressive disorder.

BACKGROUND: The use of monoamine oxidase inhibitors has declined owing to the risk of hypertensive crisis following the consumption of tyramine-rich foods and the consequent need for dietary tyramine restriction. However, owing to their superior efficacy in treating depression, continued efforts have been made to develop more selective and reversible monoamine oxidase inhibitors. Oral selegiline, at low doses, is a selective monoamine oxidase B (MAO-B) inhibitor, but at higher doses it loses its selectivity and can potentially interact with tyramine. Unfortunately, antidepressant effects of selegiline have been observed only at higher doses. The selegiline transdermal system was developed to deliver sustained selegiline blood concentrations sufficient to selectively inhibit MAO-A and MAO-B in the brain, producing antidepressant effects, without substantially inhibiting MAO-A in the gastrointestinal tract, thereby reducing the risk of hypertensive crisis. OBJECTIVES: This article reviews the basic pharmacology, as well as efficacy and safety data of selegiline transdermal system for the treatment of depression. CONCLUSIONS: Selegiline transdermal system is safe and effective in treating major depressive disorder at the dose range of 6 - 12 mg/24 h, without the need for dietary precautions at the 6 mg/24 h dose. No cases of hypertensive crisis were reported in clinical trials, even without dietary restrictions.

Pharmacologic treatment of pediatric bipolar disorder.

Bipolar disorder (BPD) is being diagnosed with increasing frequency in the pediatric population as the phenomenology of this disorder is becoming more clearly delineated. Early diagnosis and treatment of pediatric BPD is important to minimize psychosocial disability and improve prognosis. Traditional mood stabilizers and atypical antipsychotic agents are frequently used to treat BPD in youth, and there are emerging data to support their use in this population. This article provides a review of the literature on appropriate pharmacologic treatment strategies for BPD in children and adolescents. The complex treatment issues of comorbid BPD and attention deficit/hyperactivity disorder also are addressed.