Efficacy of adjunctive aripiprazole in major depressive disorder: a pooled response quartile analysis and the predictive value of week 2 early response.

OBJECTIVE: To assess varying levels of response to aripiprazole adjunctive to standard antidepressant therapy (ADT) and the predictive value of an early response for a sustained response. METHOD: This post hoc analysis of 3 similarly designed randomized, double-blind, placebo-controlled phase 3 studies investigated the efficacy and safety of adjunctive aripiprazole to standard ADT in patients with major depressive disorder (DSM-IV-TR criteria) who had a prior inadequate response to 1-3 ADTs (CN138-139 [September 2004-December 2006], CN138-163 [June 2004-April 2006], and CN138-165 [March 2005-April 2008]). Response levels were defined as percent decreases from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score after 6 weeks of treatment, with a ≤ 25% decrease for minimal, > 25 to < 50% decrease for partial, ≥ 50% to < 75% decrease for moderate, and ≥ 75% decrease for a robust response to treatment. RESULTS: More patients receiving adjunctive aripiprazole exhibited a partial (23.9% vs 17.9%, P = .017), moderate (23.1% vs 15.0%, P < .001), and robust response (14.3% vs 7.4%, P < .001) compared with adjunctive placebo. Adjunctive aripiprazole treatment compared with adjunctive placebo treatment was associated with a significantly greater proportion of patients achieving an early response (week 2, ≥ 50% reduction in MADRS total score, n = 110/539 vs n = 47/525, P < .001, number needed to treat = 9) and an endpoint response (relative risk = 1.7, 95% CI = 1.4-2.0, P < .001, number needed to treat = 7). A univariate logistic regression analysis revealed that an early response was a significant predictor of endpoint remission (P < .001). CONCLUSIONS: Aripiprazole augmentation was associated with a significantly greater proportion of patients achieving a partial, moderate, or robust response to treatment compared with ADT alone. Patients showing an early response (week 2) to augmentation maintained their response through endpoint, suggesting that clinicians may make clinically meaningful decisions early during treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00095823, NCT00095758, and NCT00105196.

A double-blind randomized trial of mood stabilizer augmentation using lamotrigine and valproate for patients with schizophrenia who are stabilized and partially responsive.

OBJECTIVE: To compare the efficacy of mood stabilizer augmentation of an antipsychotic for patients with schizophrenia who are both stabilized and partially responsive. METHOD: Adult patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for schizophrenia or schizoaffective disorder were enrolled in a 12-week, double-blind randomized trial. Patients were stabilized on an antipsychotic, and dose remained constant. Patients were randomly assigned to 1 of 3 adjunctive treatments: (1) with lamotrigine, (2) with divalproex sodium, or (3) with placebo. Efficacy assessments included the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, a Demoralization Scale, and the Clinical Global Impression severity and improvement scores. The Lehman quality of life improvement scale was used to assess quality of life and social functioning. Ratings were done at each study visit, including the last visit when they had been tapered off the adjunctive treatment. RESULTS: There were no differences in global outcomes, symptoms, quality of life, or demoralization among the 3 groups. Short-term adverse effects were minimal. CONCLUSIONS: Augmenting antipsychotics with the mood stabilizers of lamotrigine or divalproex sodium for most partially responsive patients with chronic schizophrenia did not seem to be a useful treatment strategy for improving the residual symptoms. The small sample size limits firm conclusions.

Divalproex ER combined with olanzapine or risperidone for treatment of acute exacerbations of schizophrenia.

The objective of this study was to evaluate the efficacy and safety of divalproex sodium extended release (divalproex ER) vs placebo in combination with olanzapine or risperidone for the treatment of acute exacerbations of schizophrenia. In this 12-week, randomized, double-blind, parallel-group, multi-center trial, a total of 402 patients were randomized and treated; 103 received olanzapine/placebo, 99 received olanzapine/divalproex ER, 101 received risperidone/placebo, and 99 received risperidone/divalproex ER. Divalproex ER was initiated on day 1 at 20 mg/kg per day q AM and was titrated to clinical effect on days 3, 7, and 10, not to exceed a maximum dosage of 35 mg/kg per day. Olanzapine and risperidone were initiated at 5 and 2 mg/day q PM, respectively, increased to 10 and 4 mg/day on day 3, and increased to fixed target doses of 15 and 6 mg/day on day 6. No significant treatment difference was demonstrated between the combination therapy and antipsychotic monotherapy groups on the primary efficacy variable of the mean change from baseline to day 14 last observation carried forward on the Positive and Negative Syndrome Scale (PANSS) total score, although antipsychotic monotherapy did demonstrate superiority to combination therapy on the PANSS Negative subscale at several time points. Combination therapy also failed to show an advantage over antipsychotic monotherapy at day 84 on the PANSS total score. Most adverse events observed in the study were mild to moderate in severity, and the overall number of adverse events did not differ significantly between the combination therapy groups and their corresponding antipsychotic monotherapy group.

Efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia: results from a randomized, double-blind, placebo-controlled, multicenter, dose-finding study.

RATIONALE: Bifeprunox is a partial dopamine agonist with a unique receptor-binding profile and potential antipsychotic properties. OBJECTIVES: The current study evaluated the efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia. MATERIALS AND METHODS: In this 6-week, double-blind, placebo-controlled study, 589 patients were randomly assigned to once-daily treatment with bifeprunox 5, 10, or 20 mg, placebo, or risperidone 6 mg. Efficacy was assessed by changes in symptom rating scales [Positive and Negative Syndrome Scale (PANSS) total and subscale scores; PANSS-derived BPRS scores; Clinical Global Impression--Severity (CGI--S) and Clinical Global Impression--Improvement (CGI--I) scores]. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms (EPS), laboratory values, electrocardiograms, prolactin levels, and weight. RESULTS: Compared with placebo, bifeprunox 20 mg produced a statistically significantly greater reduction from baseline to last assessment in the primary efficacy variable (PANSS total score; effect size = -0.339), as well as most secondary efficacy measures. No statistically significant differences in efficacy were seen with lower doses of bifeprunox. The most common treatment-emergent adverse events (TEAEs) noted with bifeprunox were gastrointestinal; no clear dose-related trend in the incidence of any TEAE was observed in the bifeprunox groups. Compared to placebo, treatment with bifeprunox led to small but statistically significant decreases in weight and prolactin levels. EPS were comparable between bifeprunox and placebo. The active reference in this study, risperidone 6 mg, showed statistically significant differences from placebo for the primary efficacy parameter (effect size = -0.628) and all secondary efficacy parameters. CONCLUSIONS: These data suggest that 20 mg of bifeprunox may be efficacious in improving symptoms in patients with an acute exacerbation of schizophrenia. Bifeprunox appeared to be safe and well tolerated by patients in this 6-week study.

Comparison of metabolic syndrome incidence among schizophrenia patients treated with aripiprazole versus olanzapine or placebo.

BACKGROUND: Metabolic syndrome is a strong determinant of new-onset diabetes and coronary heart disease in general populations. Given the higher prevalence of metabolic syndrome among mentally ill patients, the syndrome poses a greater health risk to this population. Atypical antipsychotic treatment may exacerbate this condition. We compared both the rate and incidence of metabolic syndrome among schizophrenia patients (DSM-IV criteria) treated with the atypical antipsychotics aripiprazole or olanzapine or placebo from 4 double-blind, randomized, controlled clinical trials. METHOD: Metabolic syndrome was defined according to the Third Adult Treatment Panel (ATP III) Guidelines as the presence on follow-up of 3 of the following abnormalities: waist circumference > 102 cm if male and > 88 cm if female, high density lipoprotein (HDL) < 40 mg/dL if male and < 50 mg/dL if female, diastolic blood pressure >or= 85 mm Hg or systolic blood pressure >or= 130 mm Hg, fasting triglycerides >or= 150 mg/dL, fasting plasma glucose >or= 110 mg/dL. Both the rate of metabolic syndrome and the person-time incidence were computed from the on-treatment follow-up. RESULTS: In the placebo-controlled trials, the rate of metabolic syndrome was 25.8% among 155 placebo patients and 19.9% for 267 aripiprazole patients (p = .466 by stratified log rank). The incidence of metabolic syndrome was 14.3% for 91 placebo patients versus 5.3% for 151 aripiprazole patients (p < .001). In the active comparator trials, patients treated with olanzapine (N = 373) versus aripiprazole (N = 380) exhibited rates of 41.6% and 27.9%, respectively (p = .0002). Incidence rates were 27.4% for 212 olanzapine patients versus 15.7% for 198 aripiprazole patients (p = .0055). CONCLUSION: Both the rate and incidence of clinically relevant metabolic syndrome differ according to the choice of antipsychotic agent. The association between metabolic syndrome and treatment warrants careful consideration in the choice of antipsychotic agents.

Implications of the CATIE trial on treatment: extrapyramidal symptoms.

Development of extrapyramidal symptoms (EPS), particularly tardive dyskinesia (TD), has long been a troubling side effect for patients taking antipsychotics. Atypical antipsychotics have been hailed as an improvement over conventional antipsychotics, offering similar efficacy with more favorable EPS profiles. In the recent Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, which compared the conventional antipsychotic perphenazine with atypical antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone in patients with schizophrenia, no significant differences in time to treatment discontinuation due to intolerability were observed between treatment groups. However, perphenazine was associated with a higher rate of patients experiencing EPS as well as a significantly higher rate of discontinuation due to EPS, despite the fact that patients with TD at baseline were excluded from the perphenazine group. Unfortunately, due to short treatment duration, the CATIE study did not have the assay sensitivity to detect differences in TD risk among any of the drugs. Thus, the atypical antipsychotics remain the first line of treatment for most patients, with specific drug selection based on benefit-risk profiles that best fit the individual patient's needs. Frequent monitoring, while noting a patient's subjective experience, remains the best strategy for choosing therapy to maximize symptom relief and minimize the impact of EPS and other side effects over the long- term. This article explores the reported results of the CATIE trial regarding EPS and emphasizes the differentiation of the atypicals from perphenazine on EPS and how these results should be incorporated into daily practice for the clinician.

Schizophrenia and increased risks of cardiovascular disease.

OBJECTIVE: The aim of the study is to review the absolute and relative impacts of the major causes for premature mortality among patients with schizophrenia. DATA SOURCES: We reviewed published articles on causes of mortality in the general population as well as among patients with schizophrenia. STUDY SELECTION: We selected articles which published total and cause-specific mortality rates. DATA EXTRACTION: We reviewed the causes of mortality and their risk factors. DATA SYNTHESIS: The average life expectancy of the general population is 76 years (72 years in men, 80 years in women), whereas the corresponding figure is 61 years (57 years in men, 65 years in women) among patients with schizophrenia. Thus, patients with schizophrenia have approximately a 20% reduced life expectancy compared with the general population. Although patients with schizophrenia are 10 to 20 times more likely than the general population to commit suicide, more than two thirds of patients with schizophrenia, compared with approximately one-half in the general population, die of coronary heart disease (CHD). The chief risk factors for this excess risk of death are cigarette smoking, obesity leading to dyslipidemia, insulin resistance and diabetes, and hypertension. CONCLUSIONS: The chief cause of excess premature mortality among patients with schizophrenia is CHD, caused mainly by their adverse risk factor profile. Because patients with schizophrenia have less access to medical care, consume less medical care, and are less compliant with their regimens, the choice of antipsychotic drug regimens that do not further adversely affect their risk factor for CHD is a major clinical and public health challenge among patients with schizophrenia.

Metabolic issues and cardiovascular disease in patients with psychiatric disorders.

Individuals with psychiatric disorders tend to have excessive morbidity. They typically have high rates of respiratory illnesses, infectious diseases, substance abuse (including smoking), obesity, diabetes mellitus, and cardiovascular disease (CVD). Persons with schizophrenia and affective disorders also have a high prevalence of risk factors for CVD, such as diabetes and obesity, which are on the order of 1.5 to 2.0 times higher than in the general population; this translates into increased mortality rates due to CVD. The use of certain psychotropics results in metabolic sequelae, such as obesity, dyslipidemia, glucose dysregulation, and the metabolic syndrome. These sequelae exacerbate the already elevated risk of CVD and diabetes in this group of people. Therefore, the use of psychotropic agents that result in, for example, excessive weight gain not only add another complication for physicians managing a patient with schizophrenia but also may have serious prognostic and cost implications with respect to treatment-related diabetes and coronary disease incidence. The recent American Diabetes Association (ADA) Consensus Panel concluded that some agents are associated with greater diabetes risk than others. The current review describes the prevalence of the metabolic syndrome in people with affective disorders and schizophrenic populations, its prognostic relevance, and its exacerbation among patients treated with particular psychotropic agents, including certain atypical antipsychotics, selective serotonin reuptake inhibitors, and mood stabilizers. The costs associated with the treatment of the metabolic syndrome, diabetes, and coronary heart disease in populations with schizophrenia are also described.

Dyslipidemia and atypical antipsychotic drugs.

Dyslipidemia is an increasing problem in most industrialized societies and is a risk factor for coronary heart disease (CHD). Imbalances in individual lipid components, including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and serum triglycerides, have each been shown to contribute to this increased risk. Certain psychiatric patient populations, such as those afflicted with schizophrenia, are of particular concern. Psychiatric patients with schizophrenia are naturally at increased risk for dyslipidemia and obesity, in part due to poor diet and sedentary lifestyle, but these conditions can be exacerbated by some antipsychotic medications. Clozapine and olanzapine, for example, appear to be associated with hyperlipidemia, which may be associated with changes in body weight. Other, newer antipsychotic agents may exhibit less liability for weight gain and the development of dyslipidemia. This review is intended to briefly highlight the association between dyslipidemia and cardiovascular disease, the changes in serum lipids associated with some antipsychotic agents, and how these changes in serum lipids affect the monitoring of schizophrenia patients.

Physical health monitoring of patients with schizophrenia.

OBJECTIVE: Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings. METHOD: A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached. RESULTS: Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations. CONCLUSIONS: The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.

Pathophysiology of antipsychotic drug-induced movement disorders.

Explaining the underlying mechanisms of antipsychotic drug-induced movement disorders remains a substantial challenge. The association of atypical antipsychotic agents with fewer drug-induced movement disorders than conventional agents has engendered several pathophysiologic hypotheses: (1) the hypothesis that, unlike conventional antipsychotic agents, atypical antipsychotics have greater activity in blocking serotonin-2A (5-HT(2A)) receptors than dopamine-2 (D(2)) receptors, which mitigates extrapyramidal symptoms; (2) the hypothesis that atypical antipsychotics block D(2) receptors only long enough to cause an antipsychotic action, but not as long as conventional agents; (3) the hypothesis that, in tardive dyskinesia, the nigrostriatal dopamine receptor system might develop increased sensitivity to dopamine as a result of treatment with conventional antipsychotic drugs, but this may not occur with atypical antipsychotics; and (4) the hypothesis that there might be a genetic association in tardive dystonia relating to the dopamine D(3) allele. A number of factors contribute to the difficult task of gaining insight into the pathophysiologic processes of antipsychotic agents and why these agents may lead to drug-induced movement disorders.

Adjunctive divalproex and hostility among patients with schizophrenia receiving olanzapine or risperidone.

OBJECTIVE: This study compared the specific antihostility effects of atypical antipsychotic monotherapy (olanzapine or risperidone) with that of combination treatment with divalproex sodium among patients with schizophrenia experiencing an acute psychotic episode. METHODS: A total of 249 inpatients with schizophrenia were randomly assigned to receive olanzapine plus placebo, olanzapine plus divalproex, risperidone plus placebo, or risperidone plus divalproex in a double-blind, 28-day multicenter trial. The target daily dose was 15 milligrams for olanzapine, 6 milligrams for risperidone, and up to 30 milligrams per kilogram (minimum, 15 milligrams per kilogram) for divalproex. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the PANSS items reflecting positive symptoms of schizophrenia (delusions, suspiciousness/persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinatory behavior). RESULTS: Combination treatment with risperidone or olanzapine plus divalproex was associated with different scores on the hostility item of the PANSS compared with antipsychotic monotherapy. Combination therapy had a significantly greater antihostility effect at days 3 and 7 than monotherapy. This result was not seen beyond the first week of treatment, but there was a trend toward a difference in effect for the entire treatment period. The effect on hostility appears to be statistically independent of antipsychotic effect on other PANSS items reflecting delusional thinking, a formal thought disorder, or hallucinations. CONCLUSIONS: Divalproex sodium may be useful as an adjunctive agent in specifically reducing hostility in the first week of treatment with risperidone or olanzapine among patients with schizophrenia experiencing an acute psychotic episode.

Effect of a novel potential atypical antipsychotic drug, Y-931, in producing dystonia in cebus monkeys.

The effect of Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine maleate), a novel potential atypical antipsychotic candidate, in producing dystonia in Cebus monkeys was investigated. Y-931 induced relatively weak dystonia in several observation periods at doses greater than 0.1 mg/kg, i.m. Although Y-931 significantly increased total dystonia scores (the sum of 15 to 360 min after injection) at doses greater than 0.5 mg/kg, i.m., the scores did not exceed 20, up to a dose of 1.0 mg/kg, i.m. and lacked a dose-response relationship. The present result suggests that Y-931 is predicted to have a low risk of extrapyramidal side effects.

Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study.

RATIONALE: Switching patients from one antipsychotic to another can lead to tolerability problems or transient symptom exacerbations. It is important to compare switching strategies to determine which methods produce the best possible patient outcomes. OBJECTIVE: To investigate the efficacy, safety and tolerability of three dosing strategies for switching chronic, stable patients with schizophrenia from current oral antipsychotic monotherapy to once-daily oral aripiprazole monotherapy. METHOD: Patients in this 8-week, open-label, outpatient study were randomized to: 1). immediate initiation of 30 mg/day aripiprazole with simultaneous immediate discontinuation of current antipsychotic; 2). immediate initiation of 30 mg/day aripiprazole while tapering off current antipsychotic over 2 weeks; or 3). up-titrating aripiprazole to 30 mg/day over 2 weeks, while simultaneously tapering off current antipsychotic. Efficacy assessments included PANSS, CGI-S, and CGI-I scores. Safety assessments included: adverse events (AEs) recording, evaluation of extrapyramidal symptoms (EPS), vital signs, ECG, and clinical laboratory tests. RESULTS: Efficacy with aripiprazole was maintained during the study with numerical improvements compared with baseline in all three groups. The overall incidence of AEs was broadly comparable across all groups, and AEs were generally mild to moderate in severity and time-limited. Discontinuations due to AEs were comparable across the groups. No deterioration in EPS occurred in any group. The reduction in body weight and plasma prolactin levels following switch to aripiprazole were comparable across the three groups. CONCLUSION: Any of the three strategies evaluated can be used safely for switching patients to aripiprazole from antipsychotic monotherapy. Furthermore, patients' symptoms may continue to improve after switching to aripiprazole.

Long-term treatment goals: enhancing healthy outcomes.

The long-term management of schizophrenia with a goal of functional rehabilitation remains an enormous challenge to clinicians despite improvements in drug therapy, psychosocial treatments, and family and community interventions. The goals of long-term therapy are to preserve the gains made during acute treatment, prevent symptom exacerbation, enhance psychosocial functioning, and improve quality of life. Schizophrenia is an illness that disrupts broad areas of mental function, including thought, cognition, affect, and motor performance. The new antipsychotics should aid physicians in meeting higher treatment goals for persons with schizophrenia. These agents combine high efficacy with improved tolerability, mainly through a low liability for extrapyramidal symptoms and probably improve cognitive affect. Recent studies have demonstrated efficacy of these new antipsychotics in improving psychopathology and symptoms and in preventing relapse during long-term use. These drugs are likely to provide physicians with an increasingly viable option in the long-term treatment and rehabilitation of patients with schizophrenia.

Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia.

This double-blind, randomized, multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia. Patients (n = 249) who met DSM-IV criteria for schizophrenia were randomly assigned to receive olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone for 28 days. Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day. Olanzapine and risperidone, were, respectively, initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day. Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups, with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale (PANSS) total score, derived Brief Psychiatric Rating Scale (BPRSd) total score, as well as PANSS and BPRSd subscales. These findings were confirmed in post hoc repeated-measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total (p = 0.020) and PANSS positive scale scores (p = 0.002). Both combination therapy and antipsychotic monotherapy were well tolerated. Treatment with divalproex in combination with an atypical antipsychotic agent resulted in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia. Further evaluation is warranted to confirm these findings.