Bipolar Disorder: Ghaemi SN

Ghaemi SN, Bauer M, Cassidy F, Malhi GS, Mitchell P, Phelps J, Vieta E, Youngstrom E, Anonymous00020. · Bipolar Disorder Research Program, Department of Psychiatry, Emory University, Atlanta, GA 30322, USA. · Bipolar Disord. · Pubmed #18199230 No free full text.

Abstract: The Diagnostic Guidelines Task Force of the International Society for Bipolar Disorders (ISBD) presents in this document and this special issue a summary of the current nosological status of bipolar illness, a discussion of possible revisions to current DSM-IV and ICD-10 definitions, an examination of the relevant literature, explication of areas of consensus and dissensus, and proposed definitions that might guide clinicians in the most valid approach to diagnosis of these conditions given the current state of our knowledge.

Ghaemi SN. · No affiliation provided · Am J Psychiatry. · Pubmed #18316425 links to  free full text

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Ghaemi SN. · No affiliation provided · Bipolar Disord. · Pubmed #18199231 No free full text.

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Ghaemi SN, Martin A. · No affiliation provided · Am J Psychiatry. · Pubmed #17267774 links to  free full text

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Ghaemi SN, Baldessarini RJ. · No affiliation provided · Psychother Psychosom. · Pubmed #17230046 No free full text.

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Goodwin FK, Ghaemi SN. · No affiliation provided · Am J Psychiatry. · Pubmed #14638572 links to  free full text

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Ghaemi SN, Soldani F. · No affiliation provided · Acta Psychiatr Scand. · Pubmed #12807370 No free full text.

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Koukopoulos A, Ghaemi SN. · Centro Lucio Bini, 42, Via Crescenzio, 00193 Rome, Italy. · Eur Psychiatry. · Pubmed #18789854 No free full text.

Abstract: In contemporary psychiatry, depression and mania are conceived as different entities. They may occur together, as in bipolar disorder, or they may occur separately, as in unipolar depression. This view is partly based on a narrow definition of mania and a rather broad definition of depression. Generally, depression is seen as more prominent, common, and problematic; while mania appears uncommon and treatment-responsive. We suggest a reversal: mania viewed broadly, not as simply episodic euphoria plus hyperactivity, but a wide range of excitatory behaviors; and depression seen more narrowly. Further, using pharmacological and clinical evidence, and in contrast to previous theories of mania interpreted as a flight from depression, we propose the primacy of mania hypothesis (PM): depression is a consequence of the excitatory processes of mania. If correct, current treatment of depressive illness needs revision. Rather than directly lifting mood with antidepressants, the aim would be to suppress manic-like excitation, with depression being secondarily prevented. Potential objections to, and empirical tests of, the PM hypothesis are discussed.

Wingo AP, Ghaemi SN. · Bipolar Disorder Research Program, Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Ga. 30322, USA. · J Clin Psychiatry. · Pubmed #18052572 No free full text.

Abstract: OBJECTIVE: Adult attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized and reported to frequently coexist with bipolar disorder. Concurrent diagnosis of adult ADHD and bipolar disorder remains controversial. In this study, we conducted a systematic review to examine the rates and diagnostic validity of the concept of comorbid adult ADHD and bipolar disorder. DATA SOURCES: MEDLINE, Embase, PsycInfo, and Cochrane databases were searched for articles published before March 30, 2007, using the keywords manic, bipolar, attention deficit hyperactivity, and adult. The computer search was supplemented with bibliographic cross-referencing. STUDY SELECTION: Exclusion criteria were studies with only pediatric subjects, childhood ADHD only but not adult ADHD, and either bipolar disorder or ADHD only, but not both; review articles, case reports; letters to the editor; and book chapters. Of the 262 citations found, 12 studies met our inclusion criteria. DATA EXTRACTION: Specific diagnostic validating criteria examined were phenomenology, course of illness, heredity, biological markers, and treatment response. There were 6 studies on comorbid rates, 4 on phenomenology, 3 on course of illness, 2 on heredity, none on biological markers, and 1 on treatment response. DATA SYNTHESIS: The proposed comorbid syndrome is fairly common (present in up to 47% of adult ADHD and 21% of bipolar disorder populations), with a more severe course of illness compared with that of bipolar disorder alone, and high rates of comorbidity with other psychiatric disorders. Its treatment appears to require initial mood stabilization. CONCLUSIONS: Comorbid adult ADHD and bipolar disorder has been insufficiently studied, with more emphasis on comorbidity rates and few data on course, neurobiology, heredity, and treatment. The diagnostic validity of adult ADHD/ bipolar disorder as a true comorbidity is not well-established on the basis of this equivocal and insufficient literature. More studies are greatly needed to further clarify its diagnostic validity and treatment approach.

Phelps JR, Ghaemi SN. · Co-Psych.com and PsychEducation.org, Corvallis, OR, USA. · J Affect Disord. · Pubmed #16529822 No free full text.

Abstract: OBJECTIVE: To examine the impact of assumptions about prevalence or prior clinical probability of bipolar disorder on the clinical performance (predictive values) of diagnostic screening tests. METHOD: Sensitivity and specificity data from four reports on two bipolar screening instruments (the Mood Disorders Questionnaire and the Bipolar Spectrum Diagnostic Scale) were used to calculate positive and negative predictive values at varying prevalence levels. Bayesian statistical concepts were employed. RESULTS: At low prevalence or low prior clinical probability, the sensitivity and specificity of the test have little impact on negative predictive value; the tests perform well, with low risk of false negatives. Similarly, at low prevalence or low prior clinical probability, positive predictive values are low regardless of which sensitivity and specificity data are used: the risk of false positives is substantial. CONCLUSIONS: At lower prevalence or prior probabilities, as in the community or primary care setting, these screening tests can rule out bipolarity (when patients have insight into their symptoms), but do not effectively rule it in. Clinicians' estimates of prior probability have as much, or in many cases more, impact on the clinical performance of the bipolar screening tools than the tests' sensitivity and specificity. To improve the performance of screening tools, the primary emphasis needs to be placed on improving clinicians' skill at recognizing clinical and historical features of bipolar diagnosis.

Henry C, Ghaemi SN. · Bipolar Disorder Research Program, Cambridge Hospital, Cambridge, MA, USA. · Psychopathology. · Pubmed #15305086 No free full text.

Abstract: Insight into illness is often impaired in psychosis and associated with poor prognosis, yet little is known about how to improve insight. After an examination of the conceptual background of insight, we review the limited empirical studies of this topic. Six studies of psychoeducation are mixed, though suggesting a possible benefit, especially with individualized interventions. In 2 studies of psychoanalytically oriented psychotherapy, and 1 of cognitive-behavioral psychotherapy, no beneficial effect on insight was notable. Two studies each of videotaped self-observation and antipsychotic medication reported improvement in insight. The possibility that atypical antipsychotics may be especially beneficial compared to traditional antipsychotics deserves further examination. We conclude that this literature suggests potentially useful options for clinicians, but further research is needed with better validated insight scales.

Ghaemi SN, Pardo TB, Hsu DJ. · Bipolar Disorder Research Program, Department of Psychiatry, Cambridge Health Alliance, Cambridge, Mass 02139, USA. · J Clin Psychiatry. · Pubmed #15242328 No free full text.

Abstract: In interpreting the maintenance literature for bipolar disorder, attention needs to be paid to important methodological issues. In this article, we initially examine the methodological topics that need to be considered, and we then examine the content of the evidence regarding maintenance treatments. Agents used in the long-term treatment of bipolar disorder possess varying degrees of supportive evidence. By consensus, the number of randomized studies and years of clinical experience with lithium mark it as the evidentially strongest long-term agent for bipolar disorder. Recent studies also demonstrate likely long-term benefit with lamotrigine, and possibly olanzapine. Although we possess fewer randomized data, some such evidence exists and, along with clinical experience, supports the likely long-term utility of valproate in the treatment of bipolar disorder as well. Some psychotherapies also may possess adjunctive maintenance efficacy.

Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. · Bipolar Disorder Research Program, Cambridge Hospital, Cambridge, MA and Harvard Medical School, Boston, MA 02139, USA. · Bipolar Disord. · Pubmed #14636365 No free full text.

Abstract: The 2002 American Psychiatric Association (APA) guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants. This change in comparison with previous APA guidelines has been criticized, especially from some groups in Europe. The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines. In this paper, we re-examine the argument put forward by the Munich group, and we demonstrate that indeed, conceptually and empirically, there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder, consistent with, and perhaps even more strongly than, the APA guidelines. This rationale is based on support for the following four propositions: (i) The risk of antidepressant induced mood-cycling is high, (ii) Antidepressants have not been shown to definitively prevent completed suicides and reduce mortality, whereas lithium has, (iii) Antidepressants have not been shown to be more effective than mood stabilizers in acute bipolar depression and have been shown to be less effective than mood stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood stabilizers, especially lithium and lamotrigine, have been shown to be effective in acute and prophylactic treatment of bipolar depressive episodes. We therefore draw three conclusions from this interpretation of the evidence: (i) There are significant risks of mania and long-term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15-20% of bipolar depressed patients).

Ghaemi SN, Soldani F, Hsu DJ. · Cambridge Health Alliance, Department of Psychiatry, Cambridge, MA 02139, USA. · Int J Neuropsychopharmacol. · Pubmed #12974998 No free full text.

Abstract: This Commentary summarizes findings from three other papers in this issue with recommendations for evidence-based treatment with lithium, anticonvulsants, antipsychotics, and antidepressants in bipolar disorder. We will also provide a summary of levels of evidence and examine two important methodological issues in assessing drug-induced mania: reliance on significance testing for assessment of side-effects, and limitations of randomized controlled trials (RCTs) for assessing frequency of side-effects. If a study is not specifically powered and designed to assess a side-effect, then no significance testing should be conducted, and side-effects should simply be reported as effect estimates and confidence intervals. Further, RCTs only establish a categorical response to a research question, i.e. whether or not something happens. The frequency of an event (treatment response, side-effects) is often more accurately assessed with observational studies.

Ghaemi SN, Ko JY, Goodwin FK. · Department of Psychiatry, Cambridge Hospital, 1493 Cambridge Street, Cambridge, MA 02139, USA. · Can J Psychiatry. · Pubmed #11926074 No free full text.

Abstract: The diagnosis and treatment of bipolar disorder (BD) has been inconsistent and frequently misunderstood in recent years. To identify the causes of this problem and suggest possible solutions, we undertook a critical review of studies concerning the nosology of BD and the effects of antidepressant agents. Both the underdiagnosis of BD and its frequent misdiagnosis as unipolar major depressive disorder (MDD) appear to be problems in patients with BD. Underdiagnosis results from clinicians' inadequate understanding of manic symptoms, from patients' impaired insight into mania, and especially from failure to involve family members or third parties in the diagnostic process. Some, but by no means all, of the underdiagnosis problem may also result from lack of agreement about the breadth of the bipolar spectrum, beyond classic type I manic-depressive illness (what Ketter has termed "Cade's Disease"). To alleviate confusion about the less classic varieties of bipolar illness, we propose a heuristic definition, "bipolar spectrum disorder." This diagnosis would give greater weight to family history and antidepressant-induced manic symptoms and would apply to non-type I or II bipolar illness, in which depressive symptom, course, and treatment response characteristics are more typical of bipolar than unipolar illness. The role of antidepressants is also controversial. Our review of the evidence leads us to conclude that there should be less emphasis on using antidepressants to treat persons with this illness.

Ghaemi SN, Lenox MS, Baldessarini RJ. · Consolidated Department of Psychiatry, Harvard Medical School, Boston, Mass, USA. · J Clin Psychiatry. · Pubmed #11488370 No free full text.

Abstract: OBJECTIVE: We sought to review research on use of antidepressants for long-term treatment of bipolar depression. METHOD: We conducted a computerized literature search of the MEDLINE, HealthStar, Current Contents, PsychInfo, and National Library of Medicine databases to identify studies involving antidepressant, anticonvulsant, or lithium use in bipolar disorder or manic-depressive illness published from 1966 through 2000. RESULTS: Only 7 blinded, controlled trials of long-term antidepressant treatment in bipolar disorders were found. The available information is not adequate to support the safety or effectiveness of long-term antidepressant treatment for bipolar depression, with or without mood-stabilizing cotherapy. CONCLUSION: Antidepressant treatment of bipolar depression is extraordinarily understudied. Controlled trials comparing specific antidepressants, particularly to compare mood-stabilizing agents given alone and combined with an antidepressant, are needed.

Sachs GS, Koslow CL, Ghaemi SN. · Massachusetts General Hospital, Consolidated Department of Psychiatry, Harvard Medical School, Boston 02114, USA. · Bipolar Disord. · Pubmed #11249803 No free full text.

Abstract: OBJECTIVES: The treatment of the depressed phase of bipolar disorder is understudied and remains a common clinical dilemma for clinicians. Compared to the manic phases, episodes of bipolar depression are more frequent and of longer duration, yet the literature on this problem is minimal. The few methodologically sound studies find that treatment effective for unipolar depression are also efficacious for bipolar depression. However, standard antidepressant agents may cause acute mania or a long-term worsening of bipolar illness. This paper reviews the available literature on the treatment of bipolar depression and offers recommendations for clinical management. METHODS: A literature search was conducted using keywords 'bipolar disorder', 'depression', 'drug therapy', 'antidepressants', 'lithium', and 'anticonvulsants'. RESULTS: If effectively treated by lithium, patients are spared the risk of antidepressant-induced mania. If lithium is not sufficient treatment for acute depression, the combination of lithium and a standard antidepressant appears to reduce the risk of affective switch, as well as the induction of a long-term rapid-cycling course. Additionally, tapering antidepressant medication after periods of sustained remission can be beneficial in limiting the risk of affective switch and acceleration of the cycle rate. CONCLUSIONS: Doctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided.

Ghaemi SN. · Consolidated Department of Psychiatry, Harvard Medical School, Cambridge Hospital, Mass, USA. · J Clin Psychiatry. · Pubmed #11154015 No free full text.

Abstract: Atypical neuroleptic agents are an excellent, safer, and more effective alternative to the widespread practice of maintenance adjunctive treatment with traditional neuroleptic agents in patients with bipolar disorder. Currently, a number of prospective studies are available with clozapine, risperidone, olanzapine, and quetiapine in the treatment of bipolar disorder. Most are short-term studies, although longer-term data are becoming available. Four double-blind studies of acute mania have been conducted with risperidone and olanzapine, leading to recent Food and Drug Administration approval for olanzapine in the indication of acute mania. Given the limited longer-term data, and the evidence for mostly adjunctive benefits with these agents, it seems unlikely that these agents will prove to be primary mood stabilizers in their own right. Nonetheless, they serve an important role as adjunctive treatments along with standard mood stabilizers in the rational polypharmacy of bipolar disorder. To date, differences in efficacy have not been established. However, differences in the side effect of weight gain may be even more relevant in bipolar disorder than in schizophrenia due to the need to use standard mood stabilizers that often potentiate such weight gain.

Ghaemi SN, Gaughan S. · Harvard Bipolar Research Program, Massachusetts General Hospital, Boston 02114, USA. · Harv Rev Psychiatry. · Pubmed #10824292 No free full text.

Abstract: Accumulating evidence suggests that at least some novel anticonvulsants may have mood-stabilizing properties. This paper reviews the literature for empirical studies of this topic. Lamotrigine has the most evidence in favor of its efficacy, with two double-blind studies in which it was more efficacious than placebo in the treatment of bipolar depression. However, it is associated with a 1/1000 risk of potentially fatal Stevens-Johnson syndrome. Gabapentin, although safe and well-tolerated, has been found in two double-blind studies not to be efficacious in treatment-refractory mania or refractory bipolar depression. Topiramate is currently supported only by naturalistic evidence of mild to moderate mood-stabilizing efficacy, but it has the advantage of often producing weight loss. Based on these data, lamotrigine may be effective, in monotherapy or as an adjunct, for treating depression in type I bipolar disorder, but suggestions regarding gabapentin and topiramate await further efficacy data. Most of the current findings derive from small, non-double-blind studies, and further research is required before clinicians can consider any of these agents to be mood stabilizers.

Ghaemi SN, Goodwin FK. · Center on Neuroscience, Medical Progress, and Society, Department of Psychiatry, George Washington University, Washington, DC, USA. · J Clin Psychopharmacol. · Pubmed #10440464 No free full text.

Abstract: Atypical antipsychotic agents seem to be effective treatments for bipolar disorder, especially as adjunctive treatments. They may be a safer and more effective alternative to the common practice of maintenance adjunctive treatment with traditional antipsychotic agents in patients with bipolar disorder. However, currently available research studies are limited methodologically mainly to open-label, uncontrolled designs. Further research is required before the definitive efficacy of these agents in bipolar disorder is established. If randomized or double-blind data support the open-label data reviewed here, atypical antipsychotic agents may possess an important role in the adjunctive treatment of bipolar disorder.

Ghaemi SN, Boiman EE, Goodwin FK. · Psychopharmacology Research Center, George Washington University, Washington, DC 20037, USA. · Biol Psychiatry. · Pubmed #9951560 No free full text.

Abstract: Since bipolar disorder is inherently a longitudinal illness characterized by recurrence and cycling of mood episodes, neurobiological theories involving kindlinglike phenomena appear to possess a certain explanatory power. An approach to understanding kindlinglike phenomena at the molecular level has been made possible by advances in research on second-messenger systems in the brain. The time frame of interest has shifted from the microseconds of presynaptic events to hours, days, months, and even years in the longer duration of events beyond the synapse--through second messengers, gene regulation, and synthesis of long-acting trophic factors. These complex interlocking systems may explain how environmental stress could interact over time with genetic vulnerability to produce illness. In its two sections, this paper will review an approach to understanding two major aspects of the neurobiology of bipolar disorder: kindling phenomena and second-messenger mechanisms. We will suggest that these two fields of research together help explain the biology of recurrence.

Dunn RT, Stan VA, Chriki LS, Filkowski MM, Ghaemi SN. · Psychopharmacology Research Program, Cambridge Health Alliance, Cambridge, MA, USA. · J Affect Disord. · Pubmed #18272230 No free full text.

Abstract: OBJECTIVE: To examine the efficacy and tolerability of aripiprazole treatment for acute bipolar depression. METHODS: A six-week prospective, nonrandomized, open label study was conducted in depressed bipolar outpatients (types I, II, and NOS), as diagnosed by DSM-IV criteria. Previous treatments were continued unchanged, and new treatments not permitted, except lorazepam up to 2 mg daily. Aripiprazole was dosed flexibly up to a maximum of 30 mg daily, based on tolerability and efficacy. Montgomery-Asberg Depression Rating Scale (MADRS) and Mania Rating Scale (MRS) scores were used to assess changes in mood symptoms. Side effect outcomes were measured. Data was analyzed using last observation carried forward methodology and Analysis of Variance. RESULTS: Twenty patients (15 men, 5 women) with bipolar disorder (10 type I, 7 type II, 3 type NOS) enrolled in the study. Mean endpoint dose was 13.6 mg/d+/-10.0 mg/d. Thirteen (65%) patients completed 6 weeks of treatment. MADRS and MRS scores significantly improved during treatment. 44% of patients who completed at least one week of treatment were considered responders, based on > or =50% decrease in MADRS scores from baseline. Side effect measures were mostly unchanged during treatment. CONCLUSION: Depressive symptoms improved in bipolar patients treated with open-label aripiprazole.

Ghaemi SN, Shirzadi AA, Klugman J, Berv DA, Pardo TB, Filkowski MM. · Bipolar Disorder Research Program, Department of Psychiatry, Emory University, Atlanta, GA 30322, United States. · J Affect Disord. · Pubmed #17586053 No free full text.

Abstract: OBJECTIVE: To assess the effectiveness and safety of zonisamide in bipolar disorder. METHODS: A chart review was conducted of naturalistic treatment with zonisamide in 35 outpatients meeting DSM-IV criteria for bipolar disorder (9 males, 26 females; mean +/- SD age = 29.2 +/- 12.7; 14 with bipolar disorder type I, 6 with bipolar disorder type II, and 14 with bipolar disorder not otherwise specified). Patients received zonisamide adjunctive therapy between January 1994 and December 2004. Treatment response was defined as a Clinical Global Impressions - Improvement (CGI-I) scale score of +2 (much improved) or + 3 (very much improved). RESULTS: Zonisamide was moderately to markedly effective in 9 subjects (26%). Indication for treatment included depressive (34.3%, [12/35]), manic/hypomanic (28.6%, [10/35]), or mixed (31.4%, [11/35]) symptoms. The mean zonisamide dose was 130 mg/d for a mean duration of treatment of 27.0 +/- 32.3 weeks. Sedation (25%, [4/16]) was the most common side effect; 19/35 (54.3%) reported no side effects. 17/35 (49%) patients terminated early, mostly due to adverse effects (6/35). Using a multivariable model, predictors of response, concurrent mood stabilizers, dose and bipolar subtype (bipolar type I > type II/NOS), were controlled for in this sample. CONCLUSIONS: In 35 persons with bipolar disorder taking standard mood stabilizers and other psychotropic agents, adjunctive zonisamide appears to have modest benefit in global improvement when added to a pre-existing complex medication regimen in patients with bipolar spectrum disorder. These pilot data support the need for larger studies to test the potential efficacy of zonisamide for treatment in mood disorders.

Ghaemi SN, Zablotsky B, Filkowski MM, Dunn RT, Pardo TB, Isenstein E, Baldassano CF. · Bipolar Disorder Research Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1365 Clifton Road, Atlanta, GA 30322, USA. · J Clin Psychopharmacol. · Pubmed #16855456 No free full text.

Abstract: OBJECTIVE: To examine the effectiveness and safety of zonisamide in the treatment of acute bipolar depression. METHODS: An open-label, prospective, nonrandomized, 8-week study conducted in bipolar outpatients (type I, type II, or not otherwise specified) with depressive symptoms. No patient was manic or mixed at study entry. Previous treatments were continued unchanged, but no new treatments were allowed. Montgomery Asberg Depression Rating Scale and the Mania Rating Scale from the Schedule of Affective Disorders and Schizophrenia-Change Version were used. RESULTS: Twenty patients (10 men, 10 women) with bipolar disorder (17 type I, 2 type II, 1 NOS), aged 38.1 +/- 8.81 years, received zonisamide at mean dose of 222.5 +/- 85.1 mg/d. Mean Montgomery Asberg Depression Rating Scale scores improved significantly from baseline to endpoint (mean difference = -8.4, 95% confidence interval [4.1, 12.6], P = 0.001). Ten patients (50%) terminated early due to adverse effects, mostly side effects including nausea/vomiting, cognitive impairment, and sedation. One patient experienced increased suicidal ideation, and one patient experienced hypomania. CONCLUSIONS: This study suggests improvement of depressive symptoms in this sample with 8 weeks of open-label zonisamide treatment.

Ghaemi SN, Hsu DJ, Rosenquist KJ, Pardo TB, Goodwin FK. · Bipolar Disorder Research Program, Department of Psychiatry, Emory University, 1365 Clifton Road, Building B, Suite 6100, Atlanta, GA 30322, USA. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #16412546 No free full text.

Abstract: OBJECTIVE: To examine, in a real-world clinical setting, the risk of extrapyramidal symptoms (EPS) with atypical neuroleptics in bipolar patients. METHODS: The authors assessed 51 individual patient trials of atypical neuroleptic agents (17 risperidone, 13 olanzapine, 11 quetiapine, 8 ziprasidone, and 2 aripiprazole) in 37 bipolar patients (type I or type II). Risk of EPS was assessed using the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, and the Simpson-Angus Scale. Mean duration of treatment was 25.5 weeks (range 3-107 weeks) and 60.8% of patients were female. RESULTS: 62.7% of trials resulted in moderate to severe EPS. EPS and discontinuation frequencies were similar between specific neuroleptic agents or between high potency (risperidone/ziprasidone/aripiprazole; 52.9%, 27/51 trials) and low potency (quetiapine/olanzapine; 47.1%, 24/51 trials) agents. In a multiple regression model adjusted for confounders, akathisia was less common with low potency agents. Younger age was associated with more akathisia. 31.4% (11/35) of trials discontinued due to side effects. 7.8% (4/51) of trials led to mild de novo tardive dyskinesia. CONCLUSIONS: Over one-half of bipolar patients experienced EPS in this real world clinical setting. This rate is much higher than the 5-15% range reported in clinical trials, suggesting potential problems with clinical trial generalizability.