Depression: 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.

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.

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, 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.

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.

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.

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.

Keck PE, McElroy SL. · Program Psychopharmacology Research, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA. · J Clin Psychiatry. · Pubmed #12625800 No free full text.

Abstract: Historically, the pharmacologic treatment of bipolar depression has not been well studied. New data are beginning to emerge regarding the efficacy of new medications and the use of combinations of mood stabilizers and antidepressants in acute and long-term treatment of bipolar depression. We reviewed data from recent randomized, controlled trials of mood stabilizers and antidepressants in the treatment of bipolar depression and naturalistic studies examining the risk of switching and depressive relapse with ongoing antidepressant treatment.

Keck PE, McElroy SL. · Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0559, USA. · J Affect Disord. · Pubmed #12507749 No free full text.

Abstract: This review considers the definition of the term 'mood-stabilizer' in the context of new pharmacological agents for the treatment of bipolar disorder. Three definitions of a mood-stabilizer are described and the available data from randomized, double-blind, controlled trials for putative mood-stabilizers studied in the treatment of different aspects of bipolar disorder (mania, mixed states, depression, maintenance) are reviewed. No available agent meets the criteria for a comprehensive mood-stabilizer, although lithium comes the closest.

Suppes T, Dennehy EB, Swann AC, Bowden CL, Calabrese JR, Hirschfeld RM, Keck PE, Sachs GS, Crismon ML, Toprac MG, Shon SP, Anonymous00056. · Department of Psychiatry The University of Texas Southwestern Medical Center Dallas, 75390-9070, USA. · J Clin Psychiatry. · Pubmed #12004801 No free full text.

Abstract: BACKGROUND: The process and outcome of a consensus conference to develop revised algorithms for treatment of bipolar disorder to be implemented in the public mental health system of Texas are described. These medication algorithms for bipolar disorder are an update of those developed for the Texas Medication Algorithm Project, a research study that tested the clinical and economic impact of treatment guidelines for major psychiatric illnesses treated in the Texas public mental health system (Texas Department of Mental Health and Mental Retardation [TDMHMR]). METHOD: Academic clinicians and researchers, practicing clinicians in the TDMHMR system, administrators, advocates, and consumers participated in a consensus conference in August 2000. Participants attended presentations reviewing new evidence in the pharmacologic treatment of bipolar disorder and discussed the needs of consumers in the TDMHMR system. Principles were enumerated, including balancing of evidence for efficacy, tolerability, and safety in medication choices. A set of 7 distinct algorithms was drafted. In the following months, a subcommittee condensed this product into 2 primary algorithms. RESULTS: The panel agreed to 2 primary algorithms: treatment of mania/hypomania, including 3 pathways for treatment of euphoric symptoms, mixed or dysphoric symptoms, and psychotic symptoms; and treatment of depressive symptoms. General principles to guide algorithm implementation were discussed and drafted. CONCLUSION: The revised algorithms are currently being disseminated and implemented within the Texas public mental health system. The goals of the Texas initiative include increasing the consistency of appropriate treatment of bipolar disorder, encouraging systematic and optimal use of available pharmacotherapies, and improving the outcomes of patients with bipolar disorder.

Charney DS, Nemeroff CB, Lewis L, Laden SK, Gorman JM, Laska EM, Borenstein M, Bowden CL, Caplan A, Emslie GJ, Evans DL, Geller B, Grabowski LE, Herson J, Kalin NH, Keck PE, Kirsch I, Krishnan KR, Kupfer DJ, Makuch RW, Miller FG, Pardes H, Post R, Reynolds MM, Roberts L, Rosenbaum JF, Rosenstein DL, Rubinow DR, Rush AJ, Ryan ND, Sachs GS, Schatzberg AF, Solomon S, Anonymous00188. · Division of Intramural Research Programs, National Institute of Mental Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. · Arch Gen Psychiatry. · Pubmed #11879164 No free full text.

Abstract: A consensus conference on the use of placebo in mood disorder studies consisted of expert presentations on bioethics, biostatistics, unipolar depression, and bipolar disorder. Work groups considered evidence and presented statements to the group. Although it was not possible to write a document for which there was complete agreement on all issues, the final document incorporated input from all authors. There was consensus that placebo has a definite role in mood disorder studies. Findings of equivalence between a new drug and standard treatment in active control studies is not evidence of efficacy unless the new drug is also significantly more effective than placebo. Add-on studies in which patients are randomized to standard therapy plus the investigational drug or standard therapy plus placebo are especially indicated for high-risk patients. Mood disorders in elderly and pediatric patients are understudied, and properly designed trials are urgently needed. Research is needed on the ethical conduct of studies to limit risks of medication-free intervals and facilitate poststudy treatment. Patients must fully understand the risks and lack of individualized treatment involved in research.

Keck PE, McElroy SL, Arnold LM. · Department of Psychiatry, Biological Psychiatry Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. · Med Clin North Am. · Pubmed #11349478 No free full text.

Abstract: Bipolar disorder (manic-depressive illness) is a common, recurrent, and severe psychiatric disorder that affects 1% to 3% of the US population. The illness is characterized by episodes of mania, depression, or mixed states (simultaneously occurring manic and depressive symptoms). Bipolar disorder frequently goes unrecognized and untreated for many years without clinical vigilance. New screening tools have been developed to assist physicians in making the diagnosis. Fortunately, several medications are now available to treat the acute mood episodes of bipolar disorder and to prevent further episodes with maintenance treatment.

Dunayevich E, Keck PE. · Clinical Psychobiology Program, Department of Psychiatry, University of Cincinnati, PO Box 670559, Cincinnati, OH 45267-0559, USA. · Curr Psychiatry Rep. · Pubmed #11122970 No free full text.

Abstract: Psychotic symptoms are common in both the manic and depressive phases of bipolar disorder. More than half of patients with bipolar disorder will experience psychotic symptoms in their lifetime. Grandiose delusions are the most common type of psychotic symptom, but any kind of psychotic symptom, including thought disorder, hallucinations, mood-incongruent psychotic symptoms, and catatonia can present as part of a manic episode. Psychotic symptoms suggest poor prognosis when they occur in the absence of affective symptoms. However, psychotic symptoms can mask affective symptoms and make the distinction between manic-depressive illness and other psychiatric disorders difficult, especially in minorities. Careful assessment of prior psychiatric history, family history, and treatment response can aid in the differentiation of affective disorders with psychotic features from psychotic disorders.

Keck PE, Welge JA, McElroy SL, Arnold LM, Strakowski SM. · Biological Psychiatry Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA. · Biol Psychiatry. · Pubmed #10773184 No free full text.

Abstract: Randomized, double-blind, placebo-controlled, parallel group clinical trials have been the standard methodology for establishing the efficacy of new treatments for patients with bipolar disorder in manic, mixed, or depressive episodes. We examine the placebo response rate in acute treatment trials of acute mania (and mixed states) and bipolar depression. Also addressed are potential variables associated with placebo response, strategies to minimize placebo response, the optimum duration of placebo-controlled acute treatment trials, possible alternatives to the use of placebo, and the ramifications of these issues with regard to the design of studies in children, adolescents, and older adults with bipolar disorder.

Keck PE, McElroy SL, Strakowski SM, Soutullo CA. · Department of Psychiatry, University of Cincinnati College of Medicine, Ohio 45267-0559, USA. · J Clin Psychiatry. · Pubmed #10739329 No free full text.

Abstract: Psychosis occurs commonly in patients with mood disorders and has traditionally been treated with typical antipsychotics. Exposure to typical antipsychotics poses a risk for the emergence of tardive dyskinesia. Atypical antipsychotics may have advantages over typical agents in the treatment of patients with mood disorders complicated by psychotic features. The studies of typical and atypical antipsychotics in the treatment of mood disorders were reviewed. Similarly, studies regarding the risk of tardive dyskinesia from typical and atypical agents in patients with mood disorders were surveyed. Typical and atypical antipsychotics appear to be comparably effective in the treatment of acute mania. Limited data regarding these medications in psychotic depression are available. Advantages of atypical antipsychotics include, for most agents, minimal extrapyramidal and prolactin effects, inherent thymoleptic activity, and lower rates of tardive dyskinesia. Atypical antipsychotics appear to have a number of advantages over typical agents in the treatment of patients with psychotic mood disorders.

Keck PE, Strakowski SM, McElroy SL. · Department of Psychiatry, University of Cincinnati College of Medicine, Ohio 45267-0559, USA. · J Clin Psychiatry. · Pubmed #10724127 No free full text.

Abstract: Depressive symptoms and syndromal depression commonly occur in patients with schizophrenia. Schizophrenia is also associated with aggression directed at self and others. For this article, the available literature regarding the efficacy of clozapine, risperidone, olanzapine, quetiapine, and ziprasidone in the treatment of depression, hostility, and suicidality in patients with schizophrenia was reviewed. These studies suggest that atypical antipsychotics may exert therapeutic effects on depression and hostility as well as psychosis and that clozapine and olanzapine may reduce suicidality in patients with schizophrenia. These therapeutic actions appear to represent additional advantages of atypical antipsychotics compared with standard agents.

Keck PE, Mintz J, McElroy SL, Freeman MP, Suppes T, Frye MA, Altshuler LL, Kupka R, Nolen WA, Leverich GS, Denicoff KD, Grunze H, Duan N, Post RM. · Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine and the Mental Health Care Line, Cincinnati, Ohio 45267-0559, USA. · Biol Psychiatry. · Pubmed #16814257 No free full text.

Abstract: BACKGROUND: The results of pilot trials suggest that omega-3 fatty acids may have efficacy in the treatment of mood symptoms in bipolar disorder. METHODS: We conducted a 4-month, randomized, placebo-controlled, adjunctive trial of ethyl-eicosapentanoate (EPA) 6 g/day in the treatment of bipolar depression and rapid cycling bipolar disorder. Subjects were receiving mood-stabilizing medications at therapeutic doses or plasma concentrations. The measures of efficacy were early study discontinuation, changes from baseline in depressive symptoms (Inventory for Depressive Symptomology total score) and in manic symptoms (Young Mania Rating Scale total score), and manic exacerbations ("switches"). We also measured side effects and bleeding time, a biomarker of drug action. RESULTS: Overall, there were no significant differences on any outcome measure between the EPA and placebo groups. CONCLUSIONS: This study did not find overall evidence of efficacy for adjunctive treatment with EPA 6 g/day in outpatients with bipolar depression or rapid cycling bipolar disorder.

Potkin SG, Keck PE, Segal S, Ice K, English P. · Neuropsychiatric Center, University of California-Irvine, 101 City Drive South, Bldg. 3, Orange, CA 92868-3298, USA. · J Clin Psychopharmacol. · Pubmed #16012271 No free full text.

Abstract: BACKGROUND: In an earlier 21-day, placebo-controlled trial, ziprasidone was efficacious in improving symptoms of mania and was well tolerated. To confirm these results, a similarly designed 21-day trial was conducted. METHODS: Inpatients with bipolar I disorder, manic or mixed, were randomized to ziprasidone (40 to 80 mg BID) or placebo. Efficacy rating scales were derived from the Schedule for Affective Disorders and Schizophrenia-Change Bipolar Scale (SADS-CB). SADS-CB-derived Mania Rating Scale (MRS) total score was the primary efficacy parameter. Secondary SADS-CB-derived efficacy parameters included Manic Syndrome and Behavior and Ideation Subscales, Hamilton Depression Rating Scale (HAM-D), and the Montgomery Asberg Depression Rating Scale (MADRS). The Clinical Global Impression-Severity Scale (CGI-S), the Global Assessment of Functioning (GAF), and the Positive and Negative Syndrome Scale (PANSS) were also assessed. RESULTS: Sixty-five placebo and 137 ziprasidone patients were evaluable for efficacy. Baseline-to-endpoint mean changes in MRS scores were -11.1 for ziprasidone and -5.6 for placebo (all patients, last observation carried forward [LOCF]; P < 0.01). Ziprasidone produced significantly greater improvements in Manic Syndrome (P < or = 0.01) and Behavior and Ideation Subscales (P < or = 0.001), CGI-S score, (P < or = 0.001), PANSS Total (P < or = 0.01) and Positive Subscale (P < or = 0.001) scores, and GAF (P < or = 0.001). With ziprasidone, significant improvements were observed from Day 2 onward for MRS and CGI-S at all time points except Day 4 for MRS. Treatment-related discontinuations due to adverse events were 5.8% for ziprasidone and 1.5% for placebo (P = 0.20). CONCLUSIONS: Ziprasidone was well tolerated, rapidly efficacious, and superior to placebo in improving symptoms and global illness severity in these inpatients with acute bipolar mania, both manic and mixed episodes.

Calabrese JR, Keck PE, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, Cutler AJ, McCoy R, Wilson E, Mullen J. · University Hospitals of Cleveland and Case University School of Medicine, 11400 Euclid Ave., Suite 200, Cleveland, OH 44106, USA. · Am J Psychiatry. · Pubmed #15994719 links to  free full text

Abstract: OBJECTIVE: There is a major unmet need for effective options in the treatment of bipolar depression. METHOD: Five hundred forty-two outpatients with bipolar I (N=360) or II (N=182) disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 8 weeks of quetiapine (600 or 300 mg/day) or placebo. The primary efficacy measure was mean change from baseline to week 8 in the Montgomery-Asberg Depression Rating Scale total score. Additional efficacy assessments included the Hamilton Depression Rating Scale, Clinical Global Impression of severity and improvement, Hamilton Anxiety Rating Scale, Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: Quetiapine at either dose demonstrated statistically significant improvement in Montgomery-Asberg Depression Rating Scale total scores compared with placebo from week 1 onward. The proportions of patients meeting response criteria (> or =50% Montgomery-Asberg Depression Rating Scale score improvement) at the final assessment in the groups taking 600 and 300 mg/day of quetiapine were 58.2% and 57.6%, respectively, versus 36.1% for placebo. The proportions of patients meeting remission criteria (Montgomery-Asberg Depression Rating Scale < or =12) were 52.9% in the groups taking 600 and 300 mg/day of quetiapine versus 28.4% for placebo. Quetiapine at 600 and 300 mg/day significantly improved 9 of 10 and 8 of 10 Montgomery-Asberg Depression Rating Scale items, respectively, compared to placebo, including the core symptoms of depression. Treatment-emergent mania rates were low and similar for the quetiapine and placebo groups (3.2% and 3.9%, respectively). CONCLUSIONS: Quetiapine monotherapy is efficacious and well tolerated for the treatment of bipolar depression.