Preliminary evidence for increased frontosubcortical activation on a motor impulsivity task in mixed episode bipolar disorder.

BACKGROUND: Of all mood states, patients in mixed episodes of bipolar disorder are at the greatest risk for impulsive behaviors including attempted suicide. The aim of this study was to examine whether the neural correlates of motor impulsivity are distinct in patients with mixed mania. METHODS: Ten patients with bipolar disorder in a mixed episode (BP-M), 10 bipolar comparison participants in a depressed episode (BP-D), and 10 healthy comparison (HC) participants underwent functional MRI while performing a Go/No-Go task of motor impulsivity. RESULTS: Both patient groups had elevated, self-rated motor impulsiveness scores. The BP-M group also had a trend-level increase in commission errors relative to the HC group on the Go/No-Go task. While the full sample strongly activated a ventrolateral prefrontal-subcortical brain network, the BP-M group activated the amygdala and frontal cortex more strongly than the HC group, and the thalamus, cerebellum, and frontal cortex more strongly than the BP-D group. LIMITATIONS: This study is primarily limited by a relatively small sample size. CONCLUSIONS: Higher commission error rates on the Go/No-Go task suggest increased vulnerability to impulsive responding during mixed episodes of bipolar disorder. Moreover, the distinct pattern of increased brain activation during mixed mania may indicate a connection between behavioral impulsivity and a failure of neurophysiological "inhibition", especially in the amygdala.

Impulsivity across the course of bipolar disorder.

OBJECTIVE: To determine whether abnormalities of impulse control persist across the course of bipolar disorder, thereby representing potential state markers and endophenotypes. METHODS: Impulse control of 108 bipolar I manic or mixed patients was measured on three tasks designed to study response inhibition, ability to delay gratification, and attention; namely, a stop signal task, a delayed reward task, and a continuous performance task, respectively. Barrett Impulsivity Scale (BIS-11) scores were also obtained. Patients were then followed for up to one year and reassessed with the same measures if they developed depression or euthymia. Healthy comparison subjects were also assessed with the same instruments on two occasions to assess measurement stability. RESULTS: At baseline, bipolar subjects demonstrated significant deficits on all three tasks as compared to healthy subjects, consistent with more impulsive responding in the bipolar manic/mixed group. In general, performance on the three behavioral tasks normalized upon switching to depression or developing euthymia. In contrast, BIS-11 scores were elevated during mania and remained elevated as bipolar subjects developed depression or achieved euthymia. CONCLUSIONS: Bipolar I disorder patients demonstrate deficits on laboratory tests of various aspects of impulsivity when manic, as compared to healthy subjects, that largely normalize with recovery and switching into depression. However, elevated BIS-11 scores persist across phases of illness. These findings suggest that impulsivity has both affective-state dependent and trait components in bipolar disorder.

Characterizing impulsivity in mania.

OBJECTIVE: To determine whether specific aspects of impulsivity (response disinhibition, inability to delay gratification, inattention) differ between healthy and bipolar manic subjects, and whether these aspects of impulsivity were associated with each other and severity of affective symptoms. METHODS: Performance of 70 bipolar I manic or mixed patients was compared to that of 34 healthy subjects on three tasks specifically designed to study response inhibition, ability to delay gratification, and attention; namely, a stop signal task, a delayed reward task, and a continuous performance task, respectively. Correlations among tasks and with symptom ratings were also performed. RESULTS: Bipolar subjects demonstrated significant deficits on all three tasks as compared to healthy subjects. Performance on the three tasks was largely independent. Task performance was not significantly associated with the severity of affective symptom ratings. However, measures of response inhibition and attention were sensitive to medication effects. Differences in the delayed reward task were independent of medication effects or symptom ratings. During the delayed reward task, although bipolar patients made their choices more slowly than healthy subjects, they were significantly more likely to choose a smaller, but more quickly obtained reward. Moreover, performance on this task was not associated with performance on the other impulsivity measures. Manic patients showed more impulsive responding than mixed patients. CONCLUSIONS: Bipolar I manic patients demonstrate deficits on tests of various aspects of impulsivity as compared to healthy subjects. Some of these differences between groups may be mediated by medication effects. Findings suggested that inability to delay gratification (i.e., delayed reward task) was not simply a result of the speed of decision making or inattention, but rather that it reflected differences between bipolar and healthy subjects in the valuation of reward relative to delay.

High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebo-controlled monotherapy trial.

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of high-dose escitalopram in the treatment of binge-eating disorder (BED) associated with obesity. METHOD: Forty-four outpatients with BED by DSM-IV criteria and obesity were randomized to receive either escitalopram (N = 21) or placebo (N = 23) in a 12-week, double-blind, flexible dose (10-30 mg/day) study. RESULTS: In the primary analysis, escitalopram (mean dose 26.5 mg/day) and placebo had similar rates of reduction of binge episodes, binge days and obsessive-compulsive symptoms of BED. However, escitalopram was associated with statistically significant reductions in weight, body mass index (BMI), and global severity of illness scores. In a secondary analysis, escitalopram was associated with statistically significant reductions in frequency of binge episodes and binge days, weight, BMI and severity of illness, but not in obsessive-compulsive symptoms of BED. No changes in metabolic variables, including measures of ghrelin and leptin, were observed. High-dose escitalopram was well tolerated. CONCLUSION: High-dose escitalopram was not efficacious in reducing obsessive-compulsive symptoms of BED, but was efficacious in reducing weight and global severity of illness. No definitive conclusions about its efficacy in reducing binge-eating frequency could be drawn due to limitations related to statistical power.

Psychiatric and metabolic characteristics of childhood versus adult-onset obesity in patients seeking weight management.

The purpose of the study was to examine whether childhood-onset obesity differed from adult-onset obesity in lifetime prevalence of mood and eating disorders, and metabolic abnormalities, in currently obese adults seeking weight loss. A subgroup of childhood-onset obesity participants (N=44) was compared with a subgroup with adult-onset obesity (N=69) on a number of clinical and metabolic features. The results showed high lifetime prevalence rates of mood (78%) and eating (81%) disorders, and metabolic syndrome (45%), in the group as a whole. However, patients with childhood-onset obesity had a significantly higher lifetime prevalence of eating disorders in general, and of bulimia nervosa in particular, than patients with adult-onset obesity. Our results support findings of substantial comorbidity among obesity, mood and eating disorders, and metabolic syndrome in weight loss seeking populations. Early recognition and attention to eating and mood dysregulation, including, but not limited to binge eating disorder and bulimia nervosa, in some persons, might help reduce their lifetime risk for obesity.

Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial.

OBJECTIVE: Binge-eating disorder (BED) is associated with obesity. Atomoxetine is a highly selective norepinephrine reuptake inhibitor associated with weight loss. The purpose of this study was to evaluate atomoxetine in the treatment of BED. METHOD: In this 10-week, single-center, randomized, double-blind, placebo-controlled, flexible dose (40-120 mg/day) trial, outpatients with DSM-IV-TR BED received atomoxetine or placebo. The primary outcome measure was binge-eating episode frequency. The primary analysis of efficacy was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the effect measure. Patients were enrolled from September 2004 through October 2005. RESULTS: Compared with placebo (N = 20), atomoxetine (N = 20) was associated with a significantly greater rate of reduction in binge-eating episode frequency, as well as in binge day frequency, weight, body mass index, and scores on the Clinical Global Impressions-Severity of Illness scale, Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating obsession sub-scale, and Three Factor Eating Questionnaire hunger subscale. The mean (SD) atomoxetine daily dose at endpoint evaluation was 106 (21) mg/day. Four patients (N = 3 receiving atomoxe-tine, N = 1 receiving placebo) discontinued because of adverse events. The reasons for atomoxetine discontinuation were increased depressive symptoms (N = 1), constipation (N = 1), and nervousness (N = 1). CONCLUSION: Atomoxetine was efficacious and fairly well tolerated in the short-term treatment of BED. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00327834.

Comorbidity of eating disorders with bipolar disorder and treatment implications.

OBJECTIVES: To review the scientific evidence examining the comorbidity among eating disorders and bipolar disorder (BD). METHODS: We reviewed all published English-language studies addressing the comorbidity of anorexia nervosa, bulimia, bulimia nervosa, and binge eating disorder in patients with BD and studies of comorbidity of BD in patients with eating disorders. In addition, we discuss the pharmacologic treatment implications from reviewed studies of agents used in BD and eating disorders. RESULTS: Community and clinical population studies of the lifetime prevalence rates of eating disorders in patients with BD, and of BD in patients with eating disorders, particularly when subthreshold and spectrum manifestations of these disorders are included, indicate high rates of comorbidity among these illnesses. CONCLUSIONS: Pharmacologic treatment approaches to patients with BD and a co-occurring eating disorder require examination of the possible adverse effects of the treatment of each syndrome on the other and attempts to manage both syndromes with agents that might be beneficial to both.

Zonisamide in the treatment of binge eating disorder with obesity: a randomized controlled trial.

OBJECTIVE: Binge eating disorder (BED) is associated with obesity. Zonisamide is a novel antiepileptic drug associated with weight loss. The purpose of this study was to evaluate zonisa-mide in the treatment of BED associated with obesity. METHOD: In this 16-week, single-center, randomized, double-blind, placebo-controlled, flexible-dose (100-600 mg/day) trial, 60 outpatients with DSM-IV-TR BED received zonisamide (N = 30) or placebo (N = 30). The primary outcome measure was weekly frequency of binge eating episodes. The primary analysis of efficacy was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the effect measure. Patients were enrolled from September 5, 2003, through October 1, 2004. RESULTS: Compared with placebo, zonisamide was associated with a significantly greater rate of reduction in binge eating episode frequency (p = .021), body weight (p < .001), BMI (p = .001), and scores on the Clinical Global Impressions-Severity scale (p < .001), Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (p < .001), and Three Factor Eating Questionnaire disinhibition scales (p < .001). Plasma ghrelin concentrations increased with zonisamide but decreased with placebo (p = .001). The mean (SD) zonisamide daily dose at endpoint evaluation was 436 (159) mg/day. Twelve patients (N = 8 receiving zonisamide, N = 4 receiving placebo) discontinued because of adverse events. The most common reasons for discontinuing zonisamide were accidental injury with bone fracture (N = 2), psychological complaints (N = 2), and cognitive complaints (N = 2). CONCLUSION: Zonisamide was efficacious, but not well tolerated, in the short-term treatment of BED associated with obesity. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00221442.

Antidepressants and suicidal behavior in bipolar disorder.

Patients with bipolar disorder are at very high risk for suicidal ideation, non-fatal suicidal behaviors and suicide and are frequently treated with antidepressants. However, no prospective, randomized, controlled study specifically evaluating an antidepressant on suicidality in bipolar disorder has yet been completed. Indeed, antidepressants have not yet been shown to reduce suicide attempts or suicide in depressive disorders and may increase suicidal behavior in pediatric, and possibly adult, major depressive disorder. Available data on the effects of antidepressants on suicidality in bipolar disorder are mixed. Considerable research indicates that mixed states are associated with suicidality and that antidepressants, especially when administered as monotherapy, are associated with both suicidality and manic conversion. In contrast, growing research suggests that antidepressants administered in combination with mood stabilizers may reduce depressive symptoms in patients with bipolar depression. Further, the only prospective, long-term study evaluating antidepressant treatment and mortality in bipolar disorder, although open-label, found antidepressants and/or antipsychotics in combination with lithium, but not lithium alone, reduced suicide in bipolar and unipolar patients (Angst F, et al. J Affect Disord 2002: 68: 167-181). We conclude that antidepressants may induce suicidality in a subset of persons with depressive (and probably anxious) presentations; that this induction may represent a form of manic conversion, and hence a bipolar phenotype, and that lithium's therapeutic properties may include the ability to prevent antidepressant-induced suicidality.

Lithium augmentation of topiramate for bipolar disorder with comorbid binge eating disorder and obesity.

OBJECTIVE: To evaluate the effectiveness of lithium augmentation of topiramate on mood symptoms, binge eating behavior, and body weight in obese bipolar patients with binge eating disorder (BED) seeking weight management. METHOD: We conducted a naturalistic study of 12 consecutive outpatients with bipolar disorders, BED, and obesity who received lithium augmentation for mood instability during the course of topiramate-based pharmacotherapy for obesity and BED. Lithium was added to topiramate (mean dose 514 mg i.d.) and titrated to a mean dose of 1009 mg i.d. (mean plasma concentration 0.7 mmol/L). Treatment response was assessed by comparing changes in clinical severity scales for mood and eating disorders, weekly binge eating frequency, and weight for the 2 months before and the first 2 months during lithium treatment. RESULTS: A statistically significant improvement in global severity of mood symptoms was observed after as compared to before lithium augmentation. Statistically insignificant reductions in weight and in binge frequency and severity were also observed after lithium addition. CONCLUSION: Optimal weight loss treatment in obese patients with comorbid bipolar and BEDs may require stabilization of mood. The combination of lithium and topiramate may have a role in the management of this difficult-to-treat population.

Comorbidity of bipolar and eating disorders: distinct or related disorders with shared dysregulations?

BACKGROUND: The co-occurrence of bipolar and eating disorders, though of major clinical and public health importance, remains relatively unexamined. METHODS: In reviewing the literature on this comorbidity, we compared bulimia, anorexia nervosa, bulimia nervosa, binge eating disorders and bipolar disorders on phenomenology, course, family history, biology, and treatment response. RESULTS: Epidemiological studies show an association between subthreshold bipolar disorder and eating disorders in adolescents, and between hypomania and eating disorders, especially binge eating behavior, in adults. Of the clinical studies, most show that patients with bipolar disorder have elevated rates of eating disorders, and vice versa. Finally, the phenomenology, course, comorbidity, family history, and pharmacologic treatment response of these disorders show considerable overlap on all of these parameters. In particular, on phenomenologic grounds--eating dysregulation, mood dysregulation, impulsivity and compulsivity, craving for activity and/or exercise--we find many parallels between bipolar and eating disorders. Overall, the similarities between these disorders were more apparent when examined in their spectrum rather than full-blown expressions. LIMITATIONS: Despite an extensive literature on each of these disorders, studies examining their overlap across all these parameters are relatively sparse and insufficiently systematic. CONCLUSIONS: Nonetheless, the reviewed literature leaves little doubt that bipolar and eating disorders--particularly bulimia nervosa and bipolar II disorder--are related. Although several antidepressants and mood stabilizers have shown promise for eating disorders, their clinical use when these disorders co-exist with bipolarity is still very much of an art. We trust that this review will stimulate more rigorous research in their shared putative underlying psychobiologic mechanisms which, in turn, could lead to more rational targeted treatments.

Response of recurrent binge eating and weight gain to topiramate in patients with binge eating disorder after bariatric surgery.

BACKGROUND: The effectiveness of topiramate was evaluated in the treatment of recurrent binge eating and weight gain in patients with binge eating disorder (BED) and obesity who had undergone initially successful bariatric surgery. METHODS: The records of 3 consecutive patients with BED and obesity who presented to our clinic with recurrent binge eating and weight gain after undergoing initially successful bariatric surgery were reviewed. They were treated with topiramate for an average of 10 months. RESULTS: All three patients reported complete amelioration of their binge eating symptoms and displayed weight loss (31.7 kg in 17 months, 14.5 kg in 9 months, 2 kg in 4 months, respectively) in response to topiramate (mean dose 541 mg). CONCLUSION: Although anecdotal, these observations suggest that topiramate may be an effective treatment for patients with BED and obesity who experience recurrent binge eating and weight gain after initially successful bariatric surgery.

Are mood disorders and obesity related? A review for the mental health professional.

OBJECTIVE: We reviewed evidence regarding a possible relationship between mood disorders and obesity to better inform mental health professionals about their overlap. METHOD: We performed a MEDLINE search of the English-language literature for the years 1966-2003 using the following terms: obesity, overweight, abdominal, central, metabolic syndrome, depression, mania, bipolar disorder, binge eating, morbidity, mortality, cardiovascular, diabetes, cortisol, hypertriglyceridemia, sympathetic, family history, stimulant, sibutramine, antiobesity, antidepressant, topiramate, and zonisamide. We evaluated studies of obesity (and related conditions) in persons with mood disorders and of mood disorders in persons with obesity. We also compared studies of obesity and mood disorders regarding phenomenology, comorbidity, family history, biology, and pharmacologic treatment response. RESULTS: The most rigorous clinical studies suggest that (1). children and adolescents with major depressive disorder may be at increased risk for developing overweight; (2). patients with bipolar disorder may have elevated rates of overweight, obesity, and abdominal obesity; and (3). obese persons seeking weight-loss treatment may have elevated rates of depressive and bipolar disorders. The most rigorous community studies suggest that (1). depression with atypical symptoms in females is significantly more likely to be associated with overweight than depression with typical symptoms; (2). obesity is associated with major depressive disorder in females; and (3). abdominal obesity may be associated with depressive symptoms in females and males; but (4). most overweight and obese persons in the community do not have mood disorders. Studies of phenomenology, comorbidity, family history, biology, and pharmacologic treatment response of mood disorders and obesity show that both conditions share many similarities along all of these indices. CONCLUSION: Although the overlap between mood disorders and obesity may be coincidental, it suggests the two conditions may be related. Clinical and theoretical implications of this overlap are discussed, and further research is called for.

Zonisamide in the treatment of binge-eating disorder: an open-label, prospective trial.

BACKGROUND: Binge-eating disorder is characterized by recurrent episodes of uncontrollable overeating without compensatory weight-loss behaviors. It commonly co-occurs with obesity. Zonisamide is a novel antiepileptic drug associated with weight loss. The purpose of this study was to preliminarily assess zonisamide in the treatment of binge-eating disorder. METHOD: Fifteen outpatients with DSM-IV-TR binge-eating disorder were enrolled from Jan. 25, 2002, through Sept. 10, 2002, in an open-label, prospective, 12-week, flexible dose (100-600 mg/day) study of zonisamide. The primary outcome measure was binge-eating episode frequency. Secondary measures included binge day frequency, body mass index (BMI), weight, Clinical Global Impressions-Severity of Illness scale (CGI-S) scores, Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating (YBOCS-BE) scores, Three Factor Eating Questionnaire (TFEQ) scores, and Hamilton Rating Scale for Depression scores. Safety measures included adverse events, routine blood chemical and hematology laboratory values, urinalyses, plasma zonisamide levels, physical examination findings, and electrocardiograms. Outcome measures were analyzed by a repeated-measures random regression analysis using all data and an endpoint analysis using last observation carried forward. RESULTS: Eight subjects completed the 12 weeks of treatment. The mean (SD) zonisamide daily dose at endpoint evaluation was 513 (103) mg/day. Both the random regression and endpoint analyses found a highly significant decrease in binge-eating episode frequency, binge day frequency, BMI, weight, CGI-S scores, YBOCS-BE total scores, and TFEQ hunger and disinhibition scores (p <.0001 for all measures in both analyses except p =.001 for endpoint analysis of binge eating frequency, p =.0001 for endpoint analysis of TFEQ disinhibition, and p =.0008 for endpoint analysis of TFEQ hunger). The 7 subjects who discontinued zonisamide prematurely did so due to lack of response (N = 1), protocol non-adherence (N = 2), and adverse events (N = 4). CONCLUSION: Zonisamide was effective in reducing binge-eating frequency, severity of illness, and weight and was generally well tolerated in an open trial of binge-eating disorder. Controlled trials appear warranted.