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People with bipolar I disorder experience an illness course marked by potentially disastrous manic episodes, disabling depressive episodes, and functional impairment. A frequent obstacle to wellness in these individuals is nonadherence to treatment. Long-acting injectable (LAI) antipsychotics have the potential to address nonadherence and thereby increase patients' chances at sustained recovery and normal psychosocial functioning. LAI formulations of 2 second-generation antipsychotics-aripiprazole monohydrate and risperidone-have received approval from the US Food and Drug Administration as monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder in adult patients. In a recent roundtable meeting, a panel of 4 experts discussed the use of these medications in bipolar I disorder. This Academic Highlights summarizes their discussion, which included the impact of functional impairment, the potential benefits of employing an LAI antipsychotic at earlier stages of bipolar illness, and the characteristics of patients who may be good candidates for treatment with an LAI antipsychotic.

Objective A nominal group process followed by a modified Delphi method was used to survey expert opinions on best practices for tardive dyskinesia (TD) screening, diagnosis, and treatment and to identify areas lacking in clinical evidence. Participants A steering committee of 11 TD experts met in nominal group format to prioritize questions to be addressed and identify core bibliographic materials and criteria for survey panelists. Of 60 invited experts, 29 (23 psychiatrists and 6 neurologists) agreed to participate. Evidence A targeted literature search of PubMed (search term: tardive dyskinesia) and recommendations of the steering committee were used to generate core bibliographic material. Inclusion criteria were as follows: (1) review articles, meta-analyses, guidelines, or clinical trials; (2) publication in English between 2007 and 2017; (3) > 3 pages in length; and (4) publication in key clinical journals with impact factors ≥ 2.0. Of 29 references that met these criteria, 18 achieved a score ≥ 5 (calculated as the number of steering committee votes multiplied by journal impact factor and number of citations divided by years since publication) and were included. Consensus process Two survey rounds were conducted anonymously through electronic media from November 2017 to January 2018; responses were collected, collated, and analyzed. Respondent agreement was defined a priori as unanimous (100%), consensus (75%-99%), or majority (50%-74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥ 4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with 75% agreement (unless feedback suggested further investigation). Conclusions Consensus was reached that (1) a brief, clinical assessment for TD should be performed at every clinical encounter in patients taking antipsychotics; (2) even mild movements in 1 body area may represent possible TD; (3) management requires an overall evaluation of treatment, including reassessment of antipsychotics and anticholinergics as well as consideration of vesicular monoamine transporter 2 (VMAT2) inhibitors; and (4) informed discussions with patients/caregivers are essential.

OBJECTIVE To examine the effects of treatment on functioning impairments and quality of life and assess baseline functioning and employment status as predictors of treatment response in symptomatic individuals from the Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (Bipolar CHOICE) study. METHOD Bipolar CHOICE was an 11-site, 6-month randomized effectiveness study comparing lithium to quetiapine, each with adjunctive personalized treatments (APTs). We examined post hoc (1) the effects of treatment on functioning, (2) how changes in functioning differed between treatment responders and nonresponders, and (3) whether functioning and employment status mediated treatment response in 482 participants with DSM-IV-TR bipolar I or II disorder from September 2010 to September 2013. RESULTS Treatment was associated with significant improvements in functioning and quality of life, regardless of treatment group (P values < .0001). Responders showed greater improvements in quality of life (Quality of Life Enjoyment and Satisfaction Questionnaire P values < .05) and functioning (Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool P values < .05) than nonresponders. Unemployed or disabled participants at baseline had significantly greater illness severity at baseline than employed participants (P values < .05). Over the study duration, employed participants reported greater improvements in physical health and quality of life in leisure activities than both unemployed and disabled participants (P values < .05). Individuals who saw greater improvement in functioning and quality of life tended to show greater improvements in depressive and anxiety symptoms (P values ≤ .0001), as well as overall illness severity (P values < .001). Early (8 weeks) and very early (4 weeks) clinical changes in mood symptoms predicted changes in functioning and quality of life at 6 months (P values < .001). CONCLUSIONS Prior disability status was associated with a worse treatment response and prospective illness course. Results implicate functioning and employment status as important markers of illness severity and likelihood of recovery in bipolar disorder, suggesting that interventions that target functional impairment may improve outcomes. TRIAL REGISTRATION ClinicalTrials.gov identifier for the Bipolar CHOICE study: NCT01331304.

Rhythm disruption is a hallmark of bipolar disorder.1 Multiple models have been proposed to explain the disruptions in rhythms associated with bipolar disorder.2-15 While no consensus has been reached on the direction of these disturbances, an integrating concept is that, rather than there being a stable change In the absolute timing of the circadian clock, there is am inherent instability in the circadian timing system and therefore an increased sensitivity toward temporal disorganization of physiologic rhythms In patients with affective dlsorders.16 In support of this concept are several studies that report a wide variability In the phases of circadian rhythms In patients suffering from bipolar disorder.12-15 Actigraphy has previously been used to assess sleep, activity, and circadian variables in bipolar disorder.5,17,18 Findings from these studies support the concept that there is a loss of rhythmicity in those suffering from the Ulness. Disturbances in the levels of locomotor activity are common in both manic and depressive phases of bipolar dlsorder.17 Bipolar subjects show less locomotor activity when depressed and greater locomotor activity when manlc.5,17 Bipolar subjects have also demonstrated less stable circadian activity patterns, a greater fragmentation of activity, and a greater variabiUty In 24-hour rhythm when compared to controls.18 Previous studies were designed to compare the differences in activity patterns and rhythms between bipolar patients and healthy controls or assessed activity levels in specific mood states. The aim of this study was to test the relationships between mood state and rhythm disturbances as measured via actigraphy in bipolar disorder by assessing the correlations between manic and depressive symptoms as measured via Young Mania Rating Scale (YMRS) and 30-item Inventory of Depressive Symptoms, Clinician-Rated scale (IDS-C-30) scores and the actigraphlc measurements of rhythm the 24-hour autocorrelation coefficient and circadian quotient. We hypothesized an association between greater severity of affective symptoms and a decrease in the circadian rhythmicity of activity. We also hypothesized that mania would have a greater Impact on rhythm disturbances than would depression.

BACKGROUND Early predictors of response and remission in pediatric mania are lacking, requiring further study. METHODS This was a post hoc analysis of a 3-week, randomized, placebo-controlled trial of olanzapine conducted between November 2002 and May 2005 in 161 adolescents aged 13-17 years who were diagnosed with a DSM-IV acute manic or mixed episode of bipolar I disorder. Data from the olanzapine arm were analyzed to investigate the predictive power of early response or early nonresponse (≥25% or < 25% reduction in Young Mania Rating Scale [YMRS] score, respectively) at week 1 for ultimate response or nonresponse (≥ 50% or < 50% reduction in YMRS score, respectively) and for remission (YMRS total score ≤ 12 [standard definition] or ≤ 8 [stringent definition]) at week 3. Correlates of early response and ultimate response were examined in multivariable regression models. RESULTS By week 1, 69.2% of olanzapine-treated adolescents (n = 104, 2.5-20.0 mg/d) achieved early response, and 49.0% reached ultimate response at week 3. Patients with early response and early nonresponse were similar regarding baseline variables except higher scores for sleep and thought content were found with early response (P < .05) and higher olanzapine doses with early nonresponse (P < .01). At week 3, early response was associated with significantly greater improvements in YMRS, Clinical Global Impressions-Severity of Illness scale (both P < .001), and Overt Aggression Scale scores (P = .024). Adverse events were similar in patients with early response and early nonresponse, except for higher AIMS scores for patients with early nonresponse (P = .036). Early response significantly predicted ultimate response (OR = 5.61, P < .001; sensitivity = 86.3, specificity = 47.2, positive predictive value = 61.1, negative predictive value = 78.1). Significantly more early response than early nonresponse patients achieved ultimate response (61.1% vs 21.9%, P < .001) and remission defined by YMRS score ≤ 12 (45.8% vs 12.5%, P < .001) and YMRS score ≤ 8 (33.3% vs 3.1%, P < .001). In multivariable analyses, among other variables, early response remained an independent correlate of ultimate response and remission. CONCLUSIONS In acute pediatric manic or mixed episodes, early response to olanzapine at week 1 was strongly associated with ultimate response and remission at week 3, while absence of early response predicted the unlikely success of further treatment. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00050206.

This 6-week, randomized, double-blind, placebo-controlled trial used simultaneous depression and mania criteria to compare a single mood stabilizer, divalproex, with and without adjunctive olanzapine in patients with bipolar I disorder experiencing acute mixed episodes.Two hundred two adults, aged 18 to 60 years, who met DSM-IV-TR criteria for bipolar disorder with a current mixed episode and had been taking divalproex foror=14 days at levels of 75 to 125 microg/mL with inadequate efficacy (21-item Hamilton Depression Rating Scale [HDRS-21] and Young Mania Rating Scale [YMRS] scoresor=16) were randomly assigned to olanzapine 5 to 20 mg/d versus placebo augmentation. HDRS-21, YMRS, Clinical Global Impressions for Bipolar Disorder (CGI-BP), hospitalizations, concomitant medications, and adverse events were assessed. Comparisons included changes in both HDRS-21 and YMRS (primary outcome measure), time to partial response and time to response, CGI-BP improvement, hospitalizations, and safety (secondary outcome measures). The study was conducted from December 2006 to February 2008.Mean (SD) baseline HDRS-21 and YMRS scores were 22.2 (4.5) and 20.9 (4.4), respectively, with 59% female and 51% white subjects. Mean +/- SE score changes from baseline across the 6-week treatment period for adjunctive olanzapine (n = 100) versus adjunctive placebo (n = 101) arms, respectively, were -9.37 +/- 0.55 versus -7.69 +/- 0.54, P = .022, on the HDRS-21 and -10.15 +/- 0.44 versus -7.68 +/- 0.44 P.001, on the YMRS. Mean +/- SE score changes from baseline to last observation carried forward for CGI-BP measures were -1.34 +/- 0.11 for adjunctive olanzapine versus -1.06 +/- 0.11 for adjunctive placebo, P = .056. Time to partial response (or=25% HDRS-21 and YMRS decreases, median 7 versus 14 days) and time to response (or=50% HDRS-21 and YMRS decreases, median 25 versus 49 days) were significantly shorter with adjunctive olanzapine. Increases in weight (total andor=7%) and fasting blood glucose were significantly greater with adjunctive olanzapine.Adjunctive olanzapine yielded greater and earlier reduction of manic and depressive symptoms in mixed-episode patients with inadequate response to at least 2 weeks of divalproex.clinicaltrials.gov Identifier: NCT00402324.

Since stability of DSM-IV diagnoses of disorders with psychotic features requires validation, we evaluated psychotic patients followed systematically in the McLean-Harvard International First Episode Project.We diagnosed 517 patients hospitalized in a first psychotic illness by SCID-based criteria at baseline and at 24 months to assess stability of specific DSM-IV diagnoses.Among 500 patients (96.7%) completing the study, diagnoses remained stable in 77.6%, ranking as follows: bipolar I disorder (96.5%)schizophrenia (75.0%)delusional disorder (72.7%)major depressive disorder (MDD), severe, with psychotic features (70.1%)brief psychotic disorder (61.1%)psychotic disorder not otherwise specified (NOS) (51.5%)schizophreniform disorder (10.5%). Most changed diagnoses (22.4% of patients) were to schizoaffective disorder (53.6% of changes in 12.0% of subjects, from psychotic disorder NOSschizophreniaschizophreniform disorder = bipolar I disorder most recent episode mixed, severe, with psychotic featuresMDD, severe, with psychotic featuresdelusional disorderbrief psychotic disorderbipolar I disorder most recent episode manic, severe, with psychotic features). Second most changed diagnoses were to bipolar I disorder (25.9% of changes, 5.8% of subjects, from MDD, severe, with psychotic featurespsychotic disorder NOSbrief psychotic disorderschizophreniform disorder). Third most changed diagnoses were to schizophrenia (12.5% of changes, 2.8% of subjects, from schizophreniform disorderpsychotic disorder NOSbrief psychotic disorder = delusional disorder = MDD, severe, with psychotic features). These 3 categories accounted for 92.0% of changes. By logistic regression, diagnostic change was associated with nonaffective psychosisauditory hallucinationsyouthmale sexgradual onset.Bipolar I disorder and schizophrenia were more stable diagnoses than delusional disorder or MDD, severe, with psychotic features, and much more than brief psychotic disorder, psychotic disorder NOS, or schizophreniform disorder. Diagnostic changes mainly involved emergence of affective symptoms and were predicted by several premorbid factors. The findings have implications for revisions of DSM and ICD.

To evaluate the efficacy and safety of olanzapine, divalproex, and placebo in a randomized, double-blind trial in mild to moderate mania (DSM-IV-TR criteria).The study was conducted from October 2004 to December 2006. A total of 521 patients from private practices, hospitals, and university clinics were randomly assigned to olanzapine (5-20 mg/day), divalproex (500-2500 mg/day), or placebo for 3 weeks; those completing continued with a 9-week double-blind extension. Efficacy (mean change in Young Mania Rating Scale [YMRS] total score was the primary outcome) and safety were assessed.After 3 weeks of treatment, olanzapine-treated (N = 215) and placebo-treated (N = 105) patients significantly differed in YMRS baseline-to-endpoint total score change (p = .034; least squares [LS] mean: -9.4 and -7.4, respectively). Such changes were not significantly different between olanzapine vs. divalproex (N = 201) or divalproex vs. placebo. After 12 weeks of treatment, olanzapine- and divalproex-treated patients significantly differed in YMRS baseline-to-endpoint changes (p = .004; LS mean: -13.3 and -10.7, respectively). Of observed cases, 35.4% (35/99; 3 weeks) to 57.1% (28/49; 12 weeks) had valproate plasma concentrations lower than the recommended valproate therapeutic range, but these patients' YMRS scores were lower than those of patients with valproate concentrations above/within range. Compared with divalproex, after 12 weeks, olanzapine-treated patients had significant increases in weight (p.001) and in glucose (p.001), triglyceride (p = .003), cholesterol (p = .024), uric acid (p = .027), and prolactin (p.001) levels. Divalproex-treated patients had significant decreases in leukocytes (p = .044) and platelets (p.001) compared with olanzapine after 12 weeks of treatment. The incidence of potentially clinically significant weight gain (/= 7% from baseline) was higher with olanzapine than with divalproex (3-week: p = .064, 6.4% vs. 2.7%; 12-week: p = .002, 18.8% vs. 8.5%; respectively).Olanzapine was significantly more efficacious than placebo but not divalproex at 3 weeks and significantly more efficacious than divalproex at 12 weeks. Olanzapine-treated patients had significantly greater increases in weight and in glucose, cholesterol, triglyceride, uric acid, and prolactin levels than divalproex-treated patients.clinicaltrials.gov Identifier: NCT00094549.

OBJECTIVE To identify symptoms associated with suicidality in bipolar I disorder patients, and to assess suicide risk during treatment with olan-zapine in combination with lithium or divalproex. METHOD We used data from a study (conducted from September 1997 to October 2000) in which DSM-IV bipolar I manic or mixed-episode patients who were partially responsive to at least 2 weeks of lithium or dival-proex monotherapy prior to study entry were randomly assigned to augmentation therapy with olanzapine (5-20 mg/day) or placebo. Among mixed-episode patients with residual suicidality (Hamilton Rating Scale for Depression-item 3 [HAM-D-3] score of 1 or above) at randomization to cotherapy, we identified items in the Young Mania Rating Scale, Positive and Negative Syndrome Scale, and Barnes Akathisia Rating Scale that correlated with HAM-D-3 scores. We used factor analysis of correlated items to identify symptom domains associated with suicidality ratings and assessed changes in symptom factors and HAM-D-3 scores during 6 weeks of combination therapy with olanzapine versus placebo. RESULTS In 58 mixed-episode patients, mean +/- SD HAM-D-3 scores averaged 1.36 +/- 0.55 after at least 2 weeks of initial mood stabilizer monotherapy prior to study entry. Factors associated with the HAM-D-3 appeared to represent somatic discomfort, agitated depression, and psychotic features. Combination therapy with olanzapine (N = 36) versus placebo (N = 22) differentially reduced HAM-D-3 scores by 58% versus 29% (p < .05) within 1 week, and all 3 associated symptom factors within 2 weeks by averages of 31% versus 12% (p < .05). CONCLUSIONS Suicidality in adult, mixed-episode, bipolar I disorder patients was associated with somatic discomfort, agitated depression, and psychosis. Overall, these findings suggest that the addition of an atypical antipsychotic-antimanic agent in some bipolar disorder patients may help to reduce suicidal ideation.

Background Previous research on pharmacotherapy with conventional antipsychotics has suggested that patients with affective disorders have higher rates of treatment-emergent extrapyramidal symptoms (EPS) than patients with schizophrenia. It is not known whether this differential vulnerability holds true for treatment with atypical antipsychotics such as olanzapine. The present analysis retrospectively examined olanzapine clinical trial data for incidence of treatment-emergent EPS in patients with either schizophrenia or bipolar disorder. Method Study participants were 4417 patients meeting DSM-III or DSM-IV criteria for either schizophrenia or bipolar mania participating in olanzapine clinical trials through July 31, 2001. Data were pooled across haloperidol-controlled trials and separately across placebo-controlled trials. Measures of EPS included rates of treatment-emergent EPS adverse event by type (i.e., dystonic, parkinsonian, or residual), Simpson-Angus Scale score mean change, rates of treatment-emergent parkinsonism, and rates of anticholinergic use. Results Consistent with prior research, haloperidol-treated patients with bipolar disorder appeared to be more vulnerable to the development of EPS than those with schizophrenia. However, olanzapine-treated patients with bipolar disorder were no more likely to develop EPS than those with schizophrenia. Conclusion Results support previous research regarding conventional antipsychotics and suggest that olanzapine therapy does not increase the risk of EPS for patients with bipolar disorder.

INTRODUCTION Bipolar disorder outcome worsens as number of manic episodes increases, suggesting that prevention of recurrent episodes early during the disorder could improve patient prognosis. We investigated treatment efficacy in prevention of mood episodes in patients subgrouped by number of prior manic episodes. METHOD This study was a post hoc analysis of data from a multicenter, double-blind, 12-month clinical trial of relapse/recurrence in 431 initially euthymic patients with at least 2 prior manic/ mixed episodes and a DSM-IV diagnosis of bipolar I disorder randomly assigned to olanzapine (5-20 mg/day) or lithium (serum concentration 0.6 to 1.2 mEq/L). Data were collected between August 1999 and June 2002. Patients were subcategorized by illness stage according to number of prior manic/mixed episodes-early stage: 2 prior episodes (N = 53, lithium; N = 48, olanzapine), intermediate stage: 3 to 5 prior episodes (N = 80, lithium; N = 98, olanzapine), and later stage: more than 5 prior episodes (N = 81, lithium; N = 71, olanzapine)-and were evaluated for rates of relapse/recurrence. RESULTS There were significant effects for treatment (p < .001) and illness stage (p = .006) but no significant interaction (p = .107) on rate of manic/mixed relapse/recurrence. Rates of manic/ mixed relapse/recurrence for olanzapine versus lithium were 2.1% versus 26.4% (p = .008), 13.3% versus 23.8% (p = .073), and 23.9% versus 33.3% (p = .204) for early-, intermediate-, and later-stage groups, respectively. There was no significant effect for treatment (p = .096) or illness stage (p = .731) for depressive relapse/recurrence. CONCLUSIONS Early-stage (but not intermediate-or later-stage) patients had a significantly lower rate of relapse/recurrence of manic/mixed episodes with olanzapine compared to lithium. Thus, olanzapine maintenance therapy may be particularly effective early in the course of bipolar illness.

Introduction: Rapid-cycling (RC) bipolar disorder patients experience high levels of morbidity, typically respond unsatisfactorily to available treatments. and, so, require additional studies of novel treatments. We report on the first controlled study comparing acute and continuous clinical outcomes in RC and non-RC manic patients treated with olanzapine. Method: We analyzed data pooled from 2 placebo-controlled, double-blind, 3- to 4-week trials of olanzapine in mania (N = 254), 1 with an open-label extension up to 1 year (N = 113) and controlled supplementation with lithium or fluoxetine as needed, to compare demographic, clinical, and outcome measures between RC and non-RC subgroups of 254 DSM-IV bipolar I manic subjects. Results: RC (N = 90, 35%) versus non-RC subjects (N = 164, 65%) were younger at intake (p = .02), less often psychotic (p

Background Early course in contemporary, clinically treated, nonaffective psychotic disorders other than schizophrenia remains incompletely defined. Methods We prospectively, repeatedly, and systematically assessed 114 patients hospitalized for a first episode of DSM-IV-TR nonaffective psychotic illness for ≥ 2 years (1989-1996) using structured (Structured Clinical Interview for DSM-III-R, Patient Edition; Clinical Global Impressions scale; Scale for the Assessment of Negative Symptoms; Scale for the Assessment of Positive Symptoms; and the expanded version of the Brief Psychiatric Rating Scale) and unstructured (best-estimate procedure, life charting) naturalistic follow-up procedures and survival analysis. Results Duration of untreated psychosis (22 ± 38 months) was longest with schizophrenia. Within 2 years, syndromal remission sustained for ≥ 8 weeks (recovery) was attained by 75 subjects (65.8%); median latency to syndromal recovery was 9.4 (95% CI, 5.7-13.3) weeks and was shorter with cycloid features, initial diagnosis of brief psychosis or schizophreniform disorder, and shorter initial hospitalization. Functional recovery within 2 years was achieved by 28 of 68 subjects (41.2%), more often without initial mood-psychomotor instability or homicidal ideation. New episodes occurred in 52 of 114 subjects (45.6%) and were more likely with less affective flattening, younger age, and white race. Median time to new episodes (43.7 [27.9-70.6] weeks) was earlier with initial first-rank auditory hallucinations, substance abuse, and functional nonrecovery. Diagnosis changed to other nonaffective, schizoaffective, or affective disorders within 2 years in 62 of 108 cases (57.4%). Conclusions Three-quarters of patients presenting in first lifetime, nonaffective psychotic episodes achieved recovery within 2 years, but only 41% returned to baseline functioning, and nearly half experienced new episodes. Patients with schizophrenia had the longest duration of untreated psychosis. A majority changed diagnosis, indicating instability of some DSM psychotic-disorder diagnoses.

Background Bipolar disorder is among the 10 most disabling medical conditions worldwide. While lithium has been used extensively for bipolar disorder since the 1970s, second-generation antipsychotics (SGAs) have supplanted lithium since 1998. To date, no randomized comparative-effectiveness study has compared lithium and any SGA. Method Within the duration of the study (September 2010-September 2013), participants with bipolar I or II disorder (DSM-IV-TR) were randomized for 6 months to receive lithium (n = 240) or quetiapine (n = 242). Lithium and quetiapine were combined with other medications for bipolar disorder consistent with typical clinical practice (adjunctive personalized treatment [APT], excluding any SGA for the lithium + APT group and excluding lithium or any other SGA for the quetiapine + APT group). Coprimary outcome measures included Clinical Global Impressions-Efficacy Index (CGI-EI) and necessary clinical adjustments, which measured number of changes in adjunctive personalized treatment. Secondary measures included a full range of symptoms, cardiovascular risk, functioning, quality of life, suicidal ideation and behavior, and adverse events. Results Participants improved across all measures, and over 20% had a sustained response. Primary (CGI-EI, P = .59; necessary clinical adjustments, P = .15) and secondary outcome changes were not statistically significantly different between the 2 groups. For participants with greater manic/hypomanic symptoms, CGI-EI changes were significantly more favorable with quetiapine + APT (P = .02). Among those with anxiety, the lithium + APT group had fewer necessary clinical adjustments per month (P = .02). Lithium was better tolerated than quetiapine in terms of the burden of side effects frequency (P = .05), intensity (P = .01), and impairment (P = .01). Conclusions Despite adequate power to detect clinically meaningful differences, we found outcomes with lithium + APT and quetiapine + APT were not significantly different across 6 months of treatment for bipolar disorder. Trial registration ClinicalTrials.gov identifier for the Bipolar CHOICE study: NCT01331304.

OBJECTIVE: To determine the use of antipsychotics during and following inpatient treatment of patients with a first-episode of mania. METHOD: The 198 subjects available for analysis were 129 consecutively hospitalized first-episode manic patients and 69 nonaffective psychotic patients assessed at admission and at 6-month follow-up postdischarge. Comparisons between the groups were made on frequency, type, and doses of antipsychotics prescribed during and after hospitalization in relation to clinical status. RESULTS: First-episode manic patients were given lower mean +/- SD daily doses of antipsychotics than nonaffective psychotic patients at discharge (163 +/- 132 mg chlorpromazine equivalents [CPZe] vs. 224 +/- 167 mg CPZe, p = .0102), at 6-month follow-up (109 +/- 167 mg CPZe vs. 260 +/- 178 mg CPZe; p = .0001), and if recovered (110 +/- 174 mg CPZe vs. 265 +/- 207 mg CPZe, p = .0014). At 6-month follow-up, 31 (24%) of 129 manic and 24 (35%) of 69 nonaffective psychotic patients continued to receive antipsychotics (NS). There was no difference between the groups in the time to discontinuation of antipsychotic agents. The mean time to drug discontinuation in manic patients was 98 days. CONCLUSION: (1) Antipsychotic doses at discharge and at 6-month follow-up were much lower in manic than in nonaffective psychotic patients, although there was no significant difference in the proportion of patients who continued to receive them 6 months after discharge. (2) The time to discontinuation was independent of clinical outcome. In those who discontinued the antipsychotic agent, the time to discontinuation was more rapid in the manic group than in the nonaffective psychotic patients.

Background Divalproex sodium has been reported to be better tolerated than valproic acid. To our knowledge, no study has examined whether significant differences in the tolerability and efficacy exist between these preparations in psychiatric patients. The objective of the present study was to compare the tolerability and efficacy of divalproex sodium with those of valproic acid in psychiatric inpatients. Method Information gathered retrospectively from the medical records of 150 patients treated with divalproex sodium was compared with that of 150 patients treated with valproic acid. These medical records were photocopied, and any mention of divalproex sodium or valproic acid treatment was concealed. A series of demographic and clinical characteristics were compared. Results Patients treated with divalproex sodium compared with patients treated with valproic acid were less likely to have gastrointestinal side effects (14.7% vs. 28.7%, p = .003), specifically anorexia (6.0% vs. 14.7%, p = .012), nausea or vomiting (6.7% vs. 16.7%, p = .007), and dyspepsia (11.3% vs. 22.0%, p = .013). Divalproex sodium-treated patients compared with valproic acid-treated patients were less likely to have discontinued their medication because of side effects (4.0% vs. 12.7%, p = .0066). Twelve (63.2%) of 19 patients who discontinued valproic acid because of gastrointestinal side effects were subsequently treated with divalproex sodium, of whom only 2 continued to have gastrointestinal side effects. There were no differences in efficacy between the 2 drugs. Conclusion Divalproex sodium was better tolerated than valproic acid in inpatients with a variety of diagnoses and taking concomitant medications. Patients treated with divalproex sodium compared with patients treated with valproic acid were less likely to experience gastrointestinal side effects and to have discontinued their medication because of an adverse event.

OBJECTIVE Post hoc mediator/moderator analyses were designed to identify risk factors and their relationships in predicting relapse in olanzapine- or lithium-treated bipolar patients with an index manic or mixed episode. The aim was to identify moderators that precede and influence other variables to affect relapse and mediators that explain how or why a second variable affects relapse. METHOD We examined DSM-IV-diagnosed bipolar I disorder patients who met symptomatic remission criteria of an index manic or mixed (6.3%) episode after acute (6-12 weeks), open-label, combined therapy with olanzapine (5-20 mg/d; mean dose = 13.5 mg/d) plus lithium (300-1,800 mg/d; mean dose = 1,003.3 mg/d) followed by double-blind randomization to lithium (n = 214) or olanzapine (n = 217) for up to 52 weeks. The study started on August 5, 1999, and finished on June 14, 2002. Mediator/moderator analyses with α cut at .05 were used to understand how variables work together to impact rate of relapse. RESULTS For lithium-treated patients, variables identified for relapse were country of residence, smoking status, previous episode history, and previous lithium use. For olanzapine-treated patients, risk factors included smoking status, previous episode history, amount of time patients had a 21-Item Hamilton Depression Rating Scale (HDRS-21) score ≤ 8 at pre-randomization, and HDRS-21 score at randomization. For lithium-treated patients, no mediators/moderators were identified among relapse variables. For olanzapine-treated patients, several baseline variables--such as previous number of mood episodes (manic or depressive)--operate through severity of depressive symptoms prior to remission (mediator) to affect relapse rate. On the other hand, the effect of the patient's pre-remission depressive symptoms on outcome is moderated by the polarity of the first episode, whether manic, depressive, or mixed. CONCLUSIONS Mediators and moderators may provide valuable information in the treatment planning of patients with bipolar disorder and potentially influence treatment outcomes.

OBJECTIVE To evaluate early improvement associated with atypical antipsychotic treatment as a predictor of later response or remission among patients experiencing an acute manic or mixed episode without psychotic features. METHOD A post hoc analysis was performed on data from a 3-week, randomized, double-blind clinical trial of olanzapine (N = 147) or risperidone (N = 127) to treat inpatients aged 18-70 years meeting DSM-IV criteria for bipolar I disorder. Early improvement, measured as percent change (≥ 25% and ≥ 50% cut points) in the Young Mania Rating Scale (YMRS) total score, was assessed after 2 days and 1 week of treatment. Receiver operating characteristic curves, sensitivity and specificity, and positive and negative predictive values were calculated to determine whether early improvement predicted endpoint (week 3) response or remission. The study was conducted from July 2001 through June 2002. RESULTS Among 234 patients with ≥ 25% reduction in YMRS total score at week one, 167 (71.4%) responded and 121 (51.7%) remitted at endpoint. Of the 40 patients with < 25% improvement, 25% (n = 10) responded and 5% (n = 2) remitted at endpoint. A total of 157 patients had a ≥ 50% reduction in week 1 YMRS total score, of whom 132 (84.1%) responded and 101 (64.3%) remitted at endpoint. Of the 117 patients with < 50% improvement, 45 (38.5%) responded and 22 (18.8%) remitted at endpoint. CONCLUSIONS Improvement in manic or mixed symptoms at week 1 appears to be a good predictor of treatment outcome. Patients not having sufficient improvement (< 25% reduction in YMRS score) were less likely to reach response or remission by week 3. Patients who achieved response by week 1 (≥ 50% reduction in YMRS score) were likely to remain responders at endpoint. These data suggest the potential to assess benefit in the treatment of manic or mixed symptoms within 1 week of initiating olanzapine or risperidone.

Because clinical and biologic research and optimal clinical practice require stability of diagnoses over time, we determined stability of ICD-10 psychotic disorder diagnoses and sought predictors of diagnostic instability.Patients from the McLean-Harvard International First-Episode Project, conducted from 1989 to 2003, who were hospitalized for first psychotic illnesses (N = 500) were diagnosed by ICD-10 criteria at baseline and 24 months, on the basis of extensive prospective assessments, to evaluate the longitudinal stability of specific categorical diagnoses and predictors of diagnostic change.Diagnostic stability averaged 90.4%, ranking as follows: schizoaffective disorder (100.0%)mania with psychosis (99.0%)mixed affective episode (94.9%)schizophrenia (94.6%)delusional disorder (88.2%)severe depressive episode with psychotic symptoms (85.2%)acute psychosis with/without schizophrenia symptoms = unspecified psychosis (all 66.7%)acute schizophrenia-like psychosis (28.6%). Diagnoses changed by 24 months of follow-up to schizoaffective disorder (37.5%), bipolar disorder (25.0%), schizophrenia (16.7%), or unspecified nonorganic psychosis (8.3%), mainly through emerging affective features. By logistic regression, diagnostic change was associated with Schneiderian first-rank psychotic symptoms at intakelack of premorbid substance use.We found some psychotic disorder diagnoses to be more stable by ICD-10 than DSM-IV criteria in the same patients, with implications for revisions of both diagnostic systems.

OBJECTIVE To characterize response profiles of olanzapine/fluoxetine combination therapy in treatment-resistant depression (TRD) and to investigate predictive relationships of early improvement with olanzapine/fluoxetine combination for subsequent response/remission during the acute phase of treatment. METHOD Results were pooled from 5 outpatient studies comparing oral olanzapine/fluoxetine combination, fluoxetine, or olanzapine for a maximum of 8 weeks in patients with TRD who had at least 1 historical antidepressant treatment failure during the current episode and who failed a prospective antidepressant therapy during the study lead-in period. Mean Montgomery-Asberg Depression Rating Scale (MADRS) total and core mood items scores from the 8-week evaluation period were compared across treatment groups. Positive and negative predictive values (PPVs, NPVs) were computed from olanzapine/fluoxetine combination-treated patients demonstrating response and remission based on whether they demonstrated early improvement. RESULTS Mean olanzapine/fluoxetine combination MADRS score reductions were significantly greater than fluoxetine by week 0.5 and olanzapine by week 1. Significantly more olanzapine/fluoxetine combination patients demonstrated MADRS onset of response compared with fluoxetine and olanzapine patients (P < .001 for both MADRS total and core mood items). In olanzapine/fluoxetine combination patients, 38.1% exhibited MADRS total score response versus 26.9% of fluoxetine patients (P < .001) and 22.2% of olanzapine patients (P < .001). NPVs for MADRS total and core mood items response and remission ranged from 85.7% to 92.1%; PPVs ranged from 29.9% to 45.1%. CONCLUSIONS Olanzapine/fluoxetine combination is superior to fluoxetine and olanzapine in producing early improvement in patients with TRD. The absence of early improvement is highly predictive for overall response failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00035321.

Objective: The objective of this study was to compare the 3-year course of schizophrenia between persons with tardive dyskinesia (TD) and persons without TD on multiple outcome measures. Method: Data were drawn from a large, prospective, naturalistic study of persons treated for schizophrenia-spectrum disorders (DSM-IV criteria) in the United States, conducted between July 1997 and September 2003. Treatment outcomes were assessed at enrollment and at 12, 24, and 36 months postenrollment using measures of symptoms, functioning, productivity, activity, and quality of life. Participants who had TD at enrollment (fulfilling Schooler-Kane criteria, N = 637) were compared with those who did not (N = 1538) on clinical and functional measures at enrollment and across the 3 years of follow-up. Additional analyses examined those with persistent TD compared to those without persistent TD. Results: With adjustment for known correlates of TD, participants with TD compared to those without TD had significantly more severe psychopathology, were less likely to experience symptom remission, had more severe extrapyramidal side effects, and had lower levels of quality of life and functioning, lower productivity, and fewer activities (all p

OBJECTIVE To compare olanzapine and risperidone in the treatment of nonpsychotic acute manic or mixed episodes. METHOD This 3-week, randomized, controlled, double-blind, parallel multicenter study compared olanzapine (5-20 mg/day; N = 165) and risperidone (1-6 mg/day; N = 164) among hospital inpatients who met DSM-IV criteria for bipolar I disorder, manic or mixed episode, without psychotic features. The study was conducted at 30 sites in the United States between July 2001 and June 2002. The primary outcome measure was the mean change in the Young Mania Rating Scale (YMRS) total score. Secondary measures included the 21-item Hamilton Rating Scale for Depression (HAM-D-21), the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions-Bipolar Version (CGI-BP) severity of illness scale, and the Cognitive Test for Delirium (CTD). Quality of life (Short Form Health Survey [SF-12]), psychological well-being (Psychological General Well-Being [PGWB] inventory), and sexual functioning were also compared. RESULTS Mean modal doses for olanzapine and risperidone were 14.7 mg/day and 3.9 mg/day, respectively. Between treatments, there was no difference in mean change in the YMRS, MADRS, CTD, PGWB, or SF-12 measures or in remission or response rates. Significantly more olanzapine-treated patients completed the study compared with risperidone patients (78.7% vs. 67.0%; p = .019). Olanzapine-treated patients had greater HAM-D-21 (p = .040) and CGI-BP (p = .026) score improvement across the study. Olanzapine-treated patients experienced greater elevations in liver function enzymes (p < .05) and increase in weight (2.5 kg vs. 1.6 kg; p = .004), while risperidone-treated patients were more likely to experience prolactin elevation (51.73 ng/mL vs. 8.23 ng/mL; p < .001) and sexual dysfunction (total score increase of 1.75 vs. 0.64; p = .049). CONCLUSION Both olanzapine and risperidone treatment yielded similar improvements in mania. The olanzapine group had significantly greater improvements in secondary measures of severity and depressive symptoms and better study completion rates but experienced more weight gain.

Background: This study examined patterns of medication compliance and reasons for noncompliance among patients with bipolar disorder and substance use disorder. Method: Forty-four patients with current bipolar disorder and substance use disorder were administered a structured interview regarding lifetime compliance with prescribed psychotropic medications. Results: Patients who were prescribed both lithium and valproate were significantly (p = .03) more likely to report full compliance with valproate than with lithium. Side effects were the most common reason for lithium noncompliance, but were not cited as a reason for valproate non-compliance. Also, a common pattern of noncompliance among patients prescribed benzodiazepines, neuroleptics, and tricyclic antidepressants was the use of more medication than prescribed. Conclusion: Valproate may have greater acceptability than lithium among patients with bipolar disorder and substance use disorder. Clinicians should also be aware that these patients may take higher doses of medication than prescribed.

OBJECTIVE Olanzapine-fluoxetine combination has shown efficacy in the acute treatment of depressive episodes in patients with bipolar I disorder. The present analyses examined the efficacy and safety of longer term treatment with olanzapine-fluoxetine combination or olanzapine monotherapy in a 6-month open-label extension study. METHOD 376 patients with DSM-IV bipolar I disorder, depressed, who completed an acute trial entered the open-label study and received 1 week of olanzapine monotherapy (5-20 mg/day). At all subsequent visits, patients could choose between olanzapine monotherapy or olanzapine-fluoxetine combination (6/25, 6/50, or 12/50 mg/day). Three treatment groups were defined retrospectively according to the medication course taken from week 1: olanzapine, olanzapine-fluoxetine combination, or switched. The efficacy measures were the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Bipolar Version, and Young Mania Rating Scale. The study was conducted from July 2000 to May 2002. RESULTS Among patients who started in remission, MADRS total scores did not change significantly from baseline to endpoint in the olanzapine-fluoxetine combination (0.8) or olanzapine (0.3) groups, but increased slightly in the switched (2.3, p = .02) group. For patients who started in nonremission, MADRS total scores decreased significantly in all groups (olanzapine-fluoxetine combination: -5.7, p = .001; olanzapine: -11.6, p = .004; switched: -6.4, p = .015). The majority of patients who entered the study in nonremission achieved remission (MADRS total score < or = 12) during the trial (olanzapine-fluoxetine combination: 66.7%, olanzapine: 64.7%, switched: 62.5%). The overall rate of depressive relapse was 27.4%, and the overall incidence of mania emergence was 5.9%. CONCLUSIONS The present findings suggest that long-term treatment with olanzapine-fluoxetine combination may be a useful option for the management of depressive symptoms and carries a low risk of mania emergence.

BACKGROUND Body weight increase during long-term treatment with olanzapine in schizophrenia patients is well documented, but weight gain and its association with other medical measures are less well evaluated in bipolar disorder patients. METHOD We analyzed data from a 3-week, randomized, placebo-controlled trial of olanzapine for acute mania in DSM-IV bipolar I patients, followed by open continuation treatment with olanzapine up to a year. We examined factors associated with increased body mass index (BMI), including ratings of clinical change and selected physiologic measures. RESULTS Among 113 subjects treated with olanzapine for a mean +/- SD of 28.6 +/- 19.9 weeks, BMI increased from a baseline mean of 28.8 +/- 6.2 kg/m(2), by 7.9 +/- 10.8% (p < .001), into the obese range (31.0 +/- 6.1 kg/m(2)). Initial BMI change (first 3 weeks of drug exposure) predicted final BMI increases (Spearman rank correlation r(s) = 0.32, p < .001). History of longer illness (p = .006) and lifetime substance abuse (p = .02) were associated with below-median BMI increases. BMI increased much more among 40 subjects achieving symptomatic recovery than in the 73 who did not (by 11.9 +/- 13.2% vs. 5.3 +/- 7.7%; p = .004), with correspondingly longer olanzapine exposure (44.7 +/- 11.8 vs. 19.7 +/- 17.7 weeks; p < .001) at similar doses. On average, serum cholesterol increased 4.8 times more (17.5% vs. 3.6%) and endpoint cholesterol levels were newly 240 mg/dL or greater 3.6 (95% CI = 1.5 to 8.0) times more frequently in subjects with above-median BMI gain, who also experienced significantly larger increases in systolic and diastolic blood pressure, pulse rates, and nonfasting serum glucose than low-BMI-gain subjects. CONCLUSIONS Weight gain associated with long-term olanzapine treatment for mania was common, substantial, time-dependent, predicted by initial increases, and temporally associated with significant changes in cardiovascular and metabolic measures in bipolar I patients with prolonged illness and already-high basal BMI. An association of weight gain with favorable clinical response probably reflects longer olanzapine treatment.

As the authors point out, failed psychopharmacologic randomized controlled trials are common but poorly understood. In the companion article,2 the authors describe the analyses from computer-based assessments to examine the impact of eligibility criteria in more detail. The major finding was that, on the basis of computer assessments, nearly two-thirds of randomized subjects failed to meet at least 1 protocol-specified eligibility criterion. As the authors indicate, the enrollment of ineligible subjects may contribute to the failure of acute psychopharmacologic efficacy studies. Computer assessments may no doubt not only control rater bias but also influence the responses of subjects of investigation. As the authors recognize, the study does not measure the benefits of the site monitoring system nor does it establish that computer assessments of any of the eligibility criteria are superior to those of a well-trained site-based rater. A key message is that we need to improve the validity and reliability in the way we establish eligibility criteria and symptom severity. Possible solutions to this problem include improving the training of site raters and using central raters through videoconferencing or with the assistance of computer-generated ratings. The authors’ results provide valuable information to improve the design of clinical trials. The fact that, according to the computer assessment, close to two-thirds of patients did not meet eligibility criteria for diagnosis and symptom severity is concerning—such a large proportion of subjects in any study would lead to biased assessments. Failing to find a difference when one exists or finding spurious differences is concerning. The presented data suggest that a better signal detection will be reached when the eligibility of subjects is established with highest possible confidence, which, in this case, was achieved with the help of computer-administered assessments. Advantages of computer-administered ratings may include consistency of metrics across subjects of investigation and sites, but this system may also miss information that can be captured only by well-trained clinician raters. To summarize, we applaud the publication of negative/ failed data, but, more importantly, we value the attempt to find solutions to deal with challenges that contribute to the failure of clinical trials with psychotropic agents. By improving our clinical trial methodology, we will be able to find better and safer treatments for our patients.

Background: Olanzapine has demonstrated efficacy in the treatment of acute mania in 2 double-blind, placebo-controlled trials. We describe the results of the open-label extension from one of these trials. Method: In a 3-week, double-blind study of patients with DSM-IV bipolar I disorder, olanzapine was superior to placebo for the treatment of acute manic symptoms. Of the 139 patients who entered the double-blind phase of the 3-week study, 113 patients continued into the 49-week open-label extension. Efficacy measurements including the Young Mania Rating Scale (YMRS), the 21-item Hamilton Rating Scale for Depression (HAM-D-21), the Clinical Global Impressions scale-Bipolar Version, and the Positive and Negative Syndrome Scale and safety measurements including the Simpson-Angus scale, the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale were completed throughout. The analysis considered all treatment results, starting with the first olanzapine dose. Adjunctive lithium and fluoxetine were allowed during the open-label extension. Results: The mean length of olanzapine treatment was 6.6 months, with a mean modal dose of 13.9 mg/day. A significant mean improvement in the YMRS total score, baseline to endpoint (-18.01, p

In controlled studies of patients with schizophrenia, the atypical antipsychotic olanzapine has been shown to be more effective in the treatment of positive and negative symptoms compared with haloperidol at doses of 10 mg/day. However, little is known about the efficacy of olanzapine in patients with psychotic mood disorders. The purpose of this study was to assess the efficacy of olanzapine in the treatment of these psychotic mood disorders in comparison with nonaffective psychotic disorders and to identify clinical factors associated with olanzapine response.In a naturalistic setting, by reviewing medical records, we assessed response to olanzapine and factors associated with response to olanzapine in 150 consecutive patients newly treated with the drug at a nonprofit academic psychiatric hospital.Patients displaying a moderate-to-marked response to olanzapine were more likely to be younger; be female; receive a diagnosis of bipolar disorder; and have a shorter duration of illness, shorter length of stay prior to olanzapine, and longer duration of trial.Olanzapine may be a useful alternative or adjunctive treatment for patients with bipolar disorder.

Background The possibly limited adverse effects of risperidone encourage interest in its use in geriatric patients. Method Medical records of 122 hospitalized psychogeriatric patients (> or = 65 years old) newly treated with risperidone were reviewed and scored for indications, doses, and effects of this novel neuroleptic. Results Subjects (83 women, 39 men), mean +/- SD age = 76.5 +/- 6.8 years (range, 65-95), were given risperidone for agitation or psychosis associated with dementia (53%), a major mood disorder (29%), or other disorders (18%). Most (77%) were also medically ill and received other psychotropic (76%) or cardiovascular agents (70%). Daily doses of risperidone averaged 1.6 +/- 1.1 mg (range, 0.25-8.0) (0.025 mg/kg body wt.); 78% received 2.0 mg. Risperidone appeared to be effective in 85% of cases, but 18% were discontinued due to intolerability (11%) or inefficacy (7%). Adverse events occurred in 32% of the patients (36% of those discontinued). These adverse events included hypotension (29%) or symptomatic orthostasis (10%), cardiac arrest (1.6%) with fatality (0.8%), and extrapyramidal effects (11%) or delirium (1.6%). Benefits were associated with younger age and male gender, but not risperidone dose. Adverse effects were associated with cardiovascular disease and its treatment, cotreatment with an SRI antidepressant or valproate, and relatively rapid dose increases. Conclusion Risperidone appeared to be effective and may be safe for many elderly psychiatric patients with comorbid medical conditions provided that doses are low and increased slowly. Particular caution is advised in the presence of cardiovascular disease or cotreatment with other psychotropic agents.

Background: Treatment-emergent mania is a potential risk when patients with bipolar disorder are treated with antidepressant agents. These subanalyses compare treatment-emergent mania rates in bipolar I depressed patients treated with olanzapine, placebo, or olanzapine/fluoxetine combination. Method: In this 8-week, double-blind investigation, patients with bipolar I depression (DSM-IV criteria) (N = 833, baseline Montgomery-Asberg Depression Rating Scale total score ≥ 20) were randomly assigned to olanzapine (5-20 mg/day, N = 370), placebo (N = 377), or olanzapine/fluoxetine combination (6/25, 6/50, or 12/50 mg/day; N = 86). Treatment-emergent mania was evaluated with the Young Mania Rating Scale (YMRS), the Clinical Global Impressions-Bipolar Edition (CGI-BP) Severity of Mania scale, and adverse events records. Results: Overall rates of study discontinuation due to mania were low and not significantly different among the therapy groups (p =.358). Incidence of treatment-emergent mania (defined as a YMRS score < 15 at baseline and ≥ 15 at any subsequent visit) did not differ significantly among therapy groups (olanzapine 5.7%, placebo 6.7%, olanzapine/fluoxetine combination 6.4%; p =.861). Subjects receiving olanzapine or olanzapine/fluoxetine combination had greater mean decreases in YMRS scores than those receiving placebo (p