Bipolar Disorder: Keck PE

Keck PE, McIntyre RS, Shelton RC. · Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH, USA. · CNS Spectr. · Pubmed #18163039 links to  free full text

Abstract: Although certain aspects of bipolar disorder are well understood, there is a need for more information concerning management of acute bipolar depression, the effect of comorbid conditions, and long-term management of bipolar disorder. The outpatient presenting with bipolar disorder often presents with many of the key problems related to the long-term course of the disorder, including misdiagnosis and treatment non-adherence. Depressive symptoms are also prevalent during the course of bipolar disorder, with studies finding that depression can cause a low-grade "darkness" that longitudinally affects outpatients with bipolar disorder. These variable and persistent depressive symptoms may cause severe functional impairment and increased suicidality. Pharmacologic treatment of bipolar disorder typically includes anti-manic and mood-stabilizing medication. Although some studies find antidepressants have some positive effect, researchers have found that antidepressants, including selective serotonin reuptake inhibitors, when used as monotherapy or in conjunction with mood stabilizers, have little benefit for the treatment of bipolar disorder and may increase the likelihood of a switch into mania, hypomania, or mixed episodes. For long-term outpatient treatment, lamotrigine and lithium are proven to be highly effective. However, clinicians should also stress psychosocial treatment approaches, such as cognitive-behavioral therapy, as a principle of chronic disease management for long-term outpatients. Data on pharmacotherapy and psychosocial treatments are emerging, and clinicians should integrate these two treatment options into the standard of care. This expert roundtable supplement focuses on the treatment and management of the bipolar outpatient at risk for a depressive relapse as well as patients experiencing both acute and long-term symptoms of the disorder. Two case studies are presented to elucidate the best practices for the varying clinical states of bipolar disorder.

McIntyre RS, Keck PE. · No affiliation provided · Bipolar Disord. · Pubmed #17156151 No free full text.

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Keck PE. · No affiliation provided · BMJ. · Pubmed #14593007 links to  free full text

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Keck PE. · No affiliation provided · Biol Psychiatry. · Pubmed #11018214 No free full text.

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Keck PE, Kessler RC, Ross R. · University of Cincinnati College of Medicine, USA. · J Psychiatr Pract. · Pubmed #18677197 No free full text.

Abstract: The authors review the literature on the clinical and economic impact of unrecognized and inadequately treated bipolar disorder, highlighting the need to improve identification and treatment of this disabling disorder. Epidemiologic data on prevalence, diagnosis, and treatment of bipolar disorder (including subthreshold conditions) are presented, including data from the recent National Comorbidity Survey Replication. Clinical factors that contribute to misdiagnosis and resulting inappropriate treatment of bipolar disorder are reviewed as well as negative clinical consequences of such misdiagnosis and inappropriate treatment. The economic impact of underrecognized and inadequately treated bipolar disorder is discussed. The data provide empirical support for screening all patients diagnosed with depression for evidence of bipolar disorder before initiating treatment, to ensure that bipolar illness is not misdiagnosed and treated as unipolar mood disorder. Readers are referred to performance measures and treatment resources assembled by the STAndards for BipoLar Excellence (STABLE) Project to help clinicians screen more accurately for bipolar disorder.

Keck PE. · Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. · J Clin Psychiatry. · Pubmed #17201028 No free full text.

Abstract: Predictors of poor functional outcome in patients with bipolar disorder include psychiatric and medical comorbidity, interepisode subsyndromal symptoms, psychosis during manic or mixed episode, and low premorbid functioning. Cognitive dysfunction may also contribute to functional impairment. Psychosocial intervention has shown success in improving syndromal outcomes for people with bipolar disorder. Lithium, lamotrigine, olanzapine, and aripiprazole have all shown substantial improvements in relapse rates compared with placebo. Combination therapy with antipsychotics and antidepressants has also been shown to produce improvement in symptoms in people with bipolar disorder. However, limited evidence is available for the effects of these treatments on cognitive outcomes. This review discusses treatment strategies for the long-term management of bipolar disorder and functional outcome measures associated with these treatments.

Freeman MP, Hibbeln JR, Wisner KL, Davis JM, Mischoulon D, Peet M, Keck PE, Marangell LB, Richardson AJ, Lake J, Stoll AL. · Women's Mental Health Program, Department of Psychiatry, University of Arizona College of Medicine, Tucson 85724-5002, USA. · J Clin Psychiatry. · Pubmed #17194275 No free full text.

Abstract: OBJECTIVE: To determine if the available data support the use of omega-3 essential fatty acids (EFA) for clinical use in the prevention and/or treatment of psychiatric disorders. PARTICIPANTS: The authors of this article were invited participants in the Omega-3 Fatty Acids Subcommittee, assembled by the Committee on Research on Psychiatric Treatments of the American Psychiatric Association (APA). EVIDENCE: Published literature and data presented at scientific meetings were reviewed. Specific disorders reviewed included major depressive disorder, bipolar disorder, schizophrenia, dementia, borderline personality disorder and impulsivity, and attention-deficit/hyperactivity disorder. Meta-analyses were conducted in major depressive and bipolar disorders and schizophrenia, as sufficient data were available to conduct such analyses in these areas of interest. CONSENSUS PROCESS: The subcommittee prepared the manuscript, which was reviewed and approved by the following APA committees: the Committee on Research on Psychiatric Treatments, the Council on Research, and the Joint Reference Committee. CONCLUSIONS: The preponderance of epidemiologic and tissue compositional studies supports a protective effect of omega-3 EFA intake, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in mood disorders. Meta-analyses of randomized controlled trials demonstrate a statistically significant benefit in unipolar and bipolar depression (p = .02). The results were highly heterogeneous, indicating that it is important to examine the characteristics of each individual study to note the differences in design and execution. There is less evidence of benefit in schizophrenia. EPA and DHA appear to have negligible risks and some potential benefit in major depressive disorder and bipolar disorder, but results remain inconclusive in most areas of interest in psychiatry. Treatment recommendations and directions for future research are described. Health benefits of omega-3 EFA may be especially important in patients with psychiatric disorders, due to high prevalence rates of smoking and obesity and the metabolic side effects of some psychotropic medications.

Post RM, Altshuler LL, Frye MA, Suppes T, McElroy S, Keck PE, Leverich GS, Kupka R, Nolen WA, Grunze H. · Penn State College of Medicine, Hershey, PA, USA. · Curr Psychiatry Rep. · Pubmed #17162830 No free full text.

Abstract: In this article, we highlight recent Bipolar Collaborative Network data. We found that childhood-onset bipolar illness is common, often goes untreated for more than a decade, and carries a poor prognosis. During randomized studies of adjunctive medications in depression: 1) Venlafaxine showed higher switch rates than bupropion or sertraline; 2) Tranylcypromine was as well tolerated as lamotrigine; and 3) Modafinil was more effective than placebo. Finally, in treatment of overweight and obesity, topiramate and sibutramine showed equal efficacy but poor tolerability, and zonisamide data showed that it may be useful for mood and weight loss.

McElroy SL, Kotwal R, Keck PE. · Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA. · Bipolar Disord. · Pubmed #17156155 No free full text.

Abstract: 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.

McElroy SL, Kotwal R, Kaneria R, Keck PE. · Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0559, USA. · Bipolar Disord. · Pubmed #17042833 No free full text.

Abstract: 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.

Keck PE. · Department of Psychiatry, University of Cincinnati College of Medicine, and the General Clinical Research Center and Mental Health Care Line, Cincinnati Veterans Affairs Medical Center, Ohio 45267-0559, USA. · J Clin Psychiatry. · Pubmed #16965185 No free full text.

Abstract: Functional impairment is a problem for people with bipolar disorder. Predictors of poor functional outcome are psychiatric and medical comorbidity, interepisode subsyndromal symptoms, psychosis during a manic or mixed episode, and low premorbid functioning. Cognitive dysfunction may also be a contributory factor in functional impairment. Several psychosocial interventions designed for people with bipolar disorder have demonstrated success in improving syndromal outcomes, but the effects of psychosocial interventions on functioning and cognition have not been examined. Among pharmacologic interventions available for long-term treatment of bipolar disorder, there is a strong clinical trend away from monotherapy and toward combination therapy. Lithium, lamotrigine, olanzapine, and aripiprazole have all shown substantial improvements in relapse rates compared with placebo. Although some of these medications show superior results compared with the others in preventing the recurrence of either depressive or manic episodes, only anecdotal evidence exists regarding their effect on cognition. Combination therapy with antipsychotics or antidepressants has also been shown to produce better syndromal outcomes in people with bipolar disorder, but inadequate evidence is available on cognitive outcomes. Substantial information is needed regarding the prevalence and causes of cognitive dysfunction in bipolar disorder, the effects of existing treatments on cognition, and long-term treatments to improve cognition and functioning.

Patel NC, Keck PE. · University of Cincinnati, College of Pharmacy and Department of Psychiatry, College of Medicine, 3225 Eden Avenue, PO Box 670004, Cincinnati, OH 45267-0004, USA. · Expert Rev Neurother. · Pubmed #16893341 No free full text.

Abstract: Atypical antipsychotics have been increasingly shown to have efficacy in the treatment of various phases of bipolar disorder. Ziprasidone acts primarily through serotonergic and dopaminergic receptor antagonism, and exerts effects as an inhibitor of serotonin and norepinephrine reuptake. Ziprasidone exhibits dose proportional, linear changes in exposure and is hepatically metabolized primarily by aldehyde oxidase. In studies of patients with acute manic or mixed episodes, treatment with ziprasidone monotherapy or in combination with lithium, resulted in rapid symptom improvement and was generally well tolerated. Results from open-label extension studies of ziprasidone indicate continued improvement in manic symptoms. Preliminary data in pediatric patients with bipolar disorder also suggest it may be efficacious in this population. Ziprasidone is considered as a first-line treatment option in patients with bipolar manic or mixed episodes, with or without psychosis and displays a favorable side-effect profile.

Perlis RH, Welge JA, Vornik LA, Hirschfeld RM, Keck PE. · Bipolar Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. · J Clin Psychiatry. · Pubmed #16669715 No free full text.

Abstract: BACKGROUND: Randomized, controlled trials have demonstrated efficacy for atypical antipsychotics in the treatment of mania in bipolar disorder, either as monotherapy or adjunctive treatment. However, there are no published comparisons of individual atypical antipsychotics for mania. DATA SOURCES AND STUDY SELECTION: We conducted a systematic review and meta-analysis of randomized, placebo-controlled monotherapy and adjunctive therapy trials of atypical antipsychotics for acute bipolar mania. Studies published through 2004 were identified using searches of PubMed/MEDLINE with the search terms mania, placebo, and each of the atypical antipsychotics, limited to randomized, controlled clinical trials; review of abstracts from the 2003 meetings of the American College of Neuropsychiatry, American Psychiatric Association, and International Conference on Bipolar Disorder; and consultations with study investigators and representatives of pharmaceutical companies that market atypical antipsychotics. DATA EXTRACTION: Analyses were performed on the changes in Young Mania Rating Scale or Mania Rating Scale total scores from baseline to endpoint, using last observation carried forward and computing the difference in change scores between each drug and its corresponding placebo arm. A random-effects model with fixed drug effects was used to combine the studies and make comparisons of the antipsychotics to each other and to placebo. DATA SYNTHESIS: Data from 12 placebo-controlled monotherapy and 6 placebo-controlled adjunctive therapy trials involving a total of 4304 subjects (including 1750 placebo-treated subjects) with bipolar mania were obtained. Aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone all demonstrated significant efficacy in monotherapy (i.e., all confidence intervals exclude zero). However, after adjusting for multiple comparisons, pairwise comparisons of individual effects identified no significant differences in efficacy among antipsychotics. Magnitude of improvement was similar whether the antipsychotic was utilized as monotherapy or adjunctive therapy. CONCLUSIONS: The 5 newer atypical antipsychotics were all superior to placebo in the treatment of bipolar mania. For monotherapy and add-on therapy, cross-trial comparisons suggest that differences in acute efficacy between the drugs, if any, are likely to be small.

Keck PE, Strawn JR, McElroy SL. · Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, OH 45267-0559, USA. · J Clin Psychiatry. · Pubmed #16426111 No free full text.

Abstract: BACKGROUND: Anxiety disorders are among the most commonly co-occurring psychiatric syndromes with bipolar disorder. The presence of co-occurring anxiety disorders has important prognostic and treatment implications. METHOD: Using the PaperChase database augmented by a manual search of the literature, we identified 122 publications that consisted of reports regarding pharmacologic agents used in the treatment of bipolar disorder also assessing the efficacy of these agents in anxiety disorders, treatment studies of patients with comorbid bipolar disorder and specific anxiety disorders, and studies of novel antiepileptic agents in the treatment of anxiety symptoms or disorders. RESULTS: No randomized controlled trials have been conducted in patients with bipolar disorder and any co-occurring anxiety disorder. Among agents with antimanic or mood-stabilizing effects, evidence of efficacy from placebo-controlled trials exists for valproate in the treatment of panic disorder; lamotrigine, risperidone, and olanzapine in posttraumatic stress disorder; and risperidone, olanzapine, and quetiapine as adjunctive treatment in selective serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Antidepressants from virtually every class have efficacy in the treatment of most anxiety disorders but present the challenge of minimizing switch risk when used in conjunction with a moodstabilizer. Among novel antiepileptic agents without proven thymoleptic properties studied in randomized controlled trials in anxiety disorders, gabapentin and pregabalin had efficacy in the treatment of social anxiety disorder, and pregabalin in the treatment of generalized anxiety disorder. CONCLUSION: In the absence of controlled trials in patients with comorbid bipolar and anxiety disorders, the initial goals of treatment include mood stabilization and selection of thymoleptic agents with efficacy in the co-occurring anxiety disorder.

Keck PE. · Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267 0559, USA. · Bipolar Disord. · Pubmed #15948765 No free full text.

Abstract: Bipolar depression, the most common phase of bipolar disorder, causes significant morbidity and mortality. Traditional drugs such as lithium, lamotrigine or antidepressants each offer some clinical efficacy; however, efficacy can be limited and side effects are sometimes problematic. Thus there is a major unmet need for effective, well-tolerated agents for the treatment of bipolar depression. The atypical antipsychotics, with their proven efficacy against manic symptoms, are emerging as candidates for use against the depressive phase of bipolar disorder. Several studies have shown that some atypicals improve depressive symptoms in mixed episodes in patients with bipolar disorder; however, few studies have been performed in patients specifically with bipolar depressive episodes. In a randomized, placebo-controlled trial in patients with acute bipolar I depression, olanzapine monotherapy and an olanzapine-fluoxetine combination significantly improved Montgomery-Asberg Depression Rating Scale (MADRS) total scores compared with placebo (p < 0.001) with corresponding effect sizes (improvement of active treatment over placebo divided by pooled standard deviation) of 0.32 and 0.68, respectively. Importantly, there were no significant differences in rates of switch into mania among the three groups. Recent results from an 8-week, randomized placebo-controlled trial in patients with bipolar I and II disorder who were experiencing a bipolar depressive episode showed that quetiapine (300 and 600 mg/day) had significantly greater efficacy compared with placebo in improving the core symptoms of depression, including suicidal thoughts. Quetiapine significantly improved MADRS total scores compared with placebo (p < 0.001); effect sizes (improvement of quetiapine over placebo divided by pooled standard deviation) of 0.66 and 0.80 for 300 and 600 mg/day quetiapine, respectively, were observed. Both doses of quetiapine significantly improved symptoms of anxiety, sleep quality and global quality of life (all, p < 0.001 versus placebo). These initial findings suggest that atypical antipsychotics may prove to be important future treatments for patients with bipolar depression.

McElroy SL, Kotwal R, Keck PE, Akiskal HS. · Psychopharmacology Research Program, University of Cincinnati College of Medicine, P.O. Box 670559, 231 Bethesda Avenue, Cincinnati, OH 45267-0559, USA. · J Affect Disord. · Pubmed #15935230 No free full text.

Abstract: 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.

Keck PE. · Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. · J Clin Psychiatry. · Pubmed #15762829 No free full text.

Abstract: A key goal of the pharmacologic treatment of acute bipolar mania is rapid symptom improvement. Medications commonly used to attain this goal include lithium, several anticonvulsants, and both first- and second-generation antipsychotics. Second-generation antipsychotics, which are associated with substantially lower rates of extrapyramidal side effects than first-generation agents, are becoming a mainstay in the treatment of acute mania. Although their efficacy appears to be comparable, second-generation antipsychotics may differ in time to onset and in their side effect profiles. Therefore, selecting a second-generation antipsychotic requires consideration of how an agent's efficacy, onset of action, and adverse events profile influence its appropriateness for each patient.

Keck PE. · Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. · J Clin Psychiatry. · Pubmed #15554793 No free full text.

Abstract: Functional outcomes are more meaningful measures of response to treatment for bipolar disorder than are scores on various psychiatric rating scales (all of which have limitations) used to gauge improvement in symptoms. With the former approach, patients are considered to be in remission if they achieve normal or near-normal levels of functioning in occupational, family, and social settings. Sleep patterns are reliable indicators of whether a patient with bipolar disorder is likely to relapse or sustain remission in the near term. Regularly scheduled nightly sleep periods may help prevent rapid cycling in patients with mania, while perturbations in circadian rhythms may be early markers of impending relapse. Medications used to attain response and/or remission in maintenance therapy include lithium and valproate. The choice of mood stabilizer depends on the patient's symptoms, prior response to a mood stabilizer, and tolerance of the drug. For patients requiring additional therapy, combination regimens with mood stabilizers and atypical antipsychotics appear effective. Psychoeducation for patients and families and interpersonal psychotherapy also can help prolong remission.

Keck PE. · Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. · J Clin Psychiatry. · Pubmed #15242327 No free full text.

Abstract: Clinicians are faced with a diagnostic challenge when a bipolar patient reports breakthrough depressive symptomatology. Breakthrough depressive symptoms during treatment for a bipolar depressive episode may be a manifestation of recurrent bipolar depression or the emergence of a mixed episode. Treatment of recurrent bipolar depression and mixed episodes differs considerably, and antidepressant therapy during a mixed episode can worsen the episode and initiate or exacerbate rapid cycling. Therefore, accurate diagnosis and appropriate treatment are imperative to achieving a positive outcome. Research indicates that optimizing the current mood stabilizer therapy or adding another mood stabilizer may be the best treatment options for patients with a history of rapid cycling-in patients without a history of rapid cycling, adding an antidepressant to a mood stabilizer may be less risky and therefore a reasonable choice. Combination therapy with a mood stabilizer and an atypical antipsychotic may also be effective in managing bipolar depressive episodes.

McElroy SL, Kotwal R, Malhotra S, Nelson EB, Keck PE, Nemeroff CB. · Psychopharmacology Research and Eating Disorders and Obesity Research and Treatment Programs, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA. · J Clin Psychiatry. · Pubmed #15163249 No free full text.

Abstract: 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.

Keck PE, McElroy SL. · Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, PO Box 670559, Cincinnati, OH 45267, USA. · Psychopharmacol Bull. · Pubmed #15021862 links to  free full text

Abstract: Valproate is commonly used as a first-line agent for the treatment of acute bipolar I mania. Its efficacy in the treatment of acute mania has been established in randomized, controlled trials versus placebo, lithium, haloperidol, and olanzapine. Only preliminary data regarding the efficacy of valproate in acute bipolar depression are currently available. The efficacy of valproate in the maintenance treatment of bipolar disorder has not been definitively established but most evidence from randomized, controlled trials suggests that it may have comparable efficacy to lithium and olanzapine.The results of randomized, controlled trials of valproate in the treatment of bipolar disorder are reviewed along with their implications for clinical practice.

Keck PE, McElroy SL. · Division of Clinical Neuroscience, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA. · J Clin Psychiatry. · Pubmed #14728103 No free full text.

Abstract: BACKGROUND: Bipolar disorder, overweight, and obesity are each national public health problems. Overweight and obesity also appear to be related to mood disorders, and patients with bipolar disorder, in particular, may be at greater risk for overweight and obesity than individuals in the general population. This risk may be due to factors associated with the illness itself and/or with medications used to treat bipolar disorder. METHOD: We conducted a MEDLINE literature search of all English-language articles (1966-2002) using the keywords lithium, olanzapine, valproate, valproic acid, divalproex sodium, carbamazepine, lamotrigine, obesity, weight, and bipolar disorder. We augmented this search with manual review of relevant references. Our focus was on studies examining the prevalence of overweight and obesity in bipolar disorder, the risk and magnitude of weight gain associated with medications used to treat bipolar disorder, and the prevention and treatment of overweight and obesity in patients with bipolar disorder. RESULTS: Forty-five studies were reviewed. Patients with bipolar disorder appear to be at greater risk than the general population for overweight and obesity. Comorbid binge-eating disorder; the number of depressive episodes; treatment with medications associated with weight gain, alone or in combination; excessive carbohydrate consumption; and low rates of exercise appear to be risk factors for weight gain and obesity in patients with bipolar disorder. CONCLUSIONS: More research is required to identify the impact of specific risk factors for overweight and obesity in patients with bipolar disorder. These data could be used to develop better weight gain prevention and treatment programs for those with bipolar disorder. Therapeutic options include dietary counseling, use of mood stabilizers with lower propensities for weight gain, and combination pharmacotherapy with medications that have weight loss properties.

Post RM, Leverich GS, Altshuler LL, Frye MA, Suppes TM, Keck PE, McElroy SL, Kupka R, Nolen WA, Grunze H, Walden J. · Stanley Foundation Bipolar Network and Biological Psychiatry Branch, NIMH, NIH, DHHS, Bethesda, MD 20892-1272, USA. · Bipolar Disord. · Pubmed #14525551 No free full text.

Abstract: AIM AND METHODS: Selected recent findings of the Stanley Foundation Bipolar Network are briefly reviewed and their clinical implications discussed. RESULTS: Daily prospective ratings on the NIMH-LCM indicate a high degree of residual depressive morbidity (three times that of hypomania or mania) despite active psychopharmacological treatment with a variety of modalities including mood stabilizers, antidepressants, and benzodiazepines, as well as antipsychotics as necessary. The rates of switching into brief to full hypomania or mania during the use of antidepressants is described, and new data suggesting the potential utility of continuing antidepressants in the small group of patients showing an initial acute and persistent response is noted. Bipolar patients with a history of major environmental adversities in childhood have a more severe course of illness and an increased incidence of suicide attempts compared with those without. Preliminary open data suggest useful antidepressant effects of the atypical antipsychotic quetiapine, while a double-blind randomized controlled study failed to show efficacy of omega-3 fatty acids (6 g of eicosapentaenoic acid compared with placebo for 4 months) in the treatment of either acute depression or rapid cycling. The high prevalence of overweight and increased incidence of antithyroid antibodies in patients with bipolar illness is highlighted. CONCLUSIONS: Together, these findings suggest a very high degree of comorbidity and treatment resistance in outpatients with bipolar illness treated in academic settings and the need to develop not only new treatment approaches, but also much earlier illness recognition, diagnosis, and intervention in an attempt to reverse or prevent this illness burden.

Strakowski SM, Del Bello MP, Adler CM, Keck PE. · Department of Psychiatry, University of Cincinnati College of Medicine, PO Box 670559, Cincinnati, OH 45267-0559, USA. · Expert Opin Pharmacother. · Pubmed #12739998 No free full text.

Abstract: Atypical antipsychotic medications are widely used for the treatment of bipolar disorder. Most empirical support suggests that these medications are efficacious in the treatment of acute mania, but there is considerably less support for the utility of these drugs in other phases of bipolar disorder. However, it is likely that several of these drugs will demonstrate efficacy in relapse prevention, and perhaps antidepressant efficacy in bipolar disorder as more studies are conducted. Atypical antipsychotics offer different side effect profiles than older antipsychotics, which may be of benefit for some patients. Consequently, atypical antipsychotics provide an important treatment option for bipolar patients.

Keck PE, Nelson EB, McElroy SL. · Division of Psychopharmacology Research, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA. · Biol Psychiatry. · Pubmed #12706953 No free full text.

Abstract: The pharmacologic treatment of bipolar depression has not been well studied in randomized, controlled trials. Thus important clinical questions regarding the efficacy in bipolar depression of mood stabilizers, antidepressants, and new antiepileptic and atypical antipsychotic agents have been relatively unaddressed. Until recently there were few data regarding the degree to which mood stabilizers reduce the risk of switching associated with antidepressant treatment. Likewise, although treatment guidelines have often recommended limiting antidepressant exposure in the maintenance treatment of bipolar depression, the potential risks of depressive relapse after antidepressant discontinuation were largely unknown. We review here data from new randomized, controlled trials published or presented during the past 5 years regarding the efficacy of antidepressants, mood stabilizers, lamotrigine, and olanzapine in the acute and maintenance treatment of bipolar depression. We also review new studies clarifying the protective effect of coadministration of mood stabilizers from antidepressant-associated switching and the risk of depressive relapse when antidepressants are discontinued during maintenance treatment.