Antipsychotics for primary alcohol dependence: a systematic review and meta-analysis of placebo-controlled trials.

OBJECTIVE: We sought to meta-analytically assess the utility of antipsychotics in patients with primary alcohol dependence. DATA SOURCES: We searched PubMed, Cochrane Library, and PsycINFO without language restrictions from database inception until December 2012, using the following keywords: (randomized, random, OR randomly) AND (placebo) AND (alcohol dependence) AND (neuroleptic OR antipsychotic OR antidopaminergic OR the names of 34 individual antipsychotics). STUDY SELECTION: Included in this study were randomized, placebo-controlled trials of antipsychotics lasting ≥ 2 weeks in patients with primary alcohol dependence and without schizophrenia or bipolar disorder. DATA EXTRACTION: Two independent evaluators extracted data. Standardized mean difference (SMD), risk ratio (RR), and numbers needed to harm (NNH) ± 95% confidence intervals (CIs) were calculated. RESULTS: Across 13 double-blind studies, 1,593 patients were randomly assigned to one of the following: amisulpride (1 study, n = 37), aripiprazole (2 studies, n = 163), flupenthixol decanoate (1 study, n = 142), olanzapine (2 studies, n = 62), quetiapine (4 studies, n = 174), tiapride (3 studies, n = 212), or placebo (13 studies, n = 803). Neither pooled nor individual antipsychotics outperformed placebo regarding relapse prevention (pooled RR = 1.05 [95% CI, 0.95 to 1.16], P = .38, 9 studies, n = 1,405). Antipsychotics were similar to placebo regarding heavy drinking days (P = .15), craving (P = .82), and first alcohol consumption time (P = .94). Placebo outperformed pooled antipsychotics regarding number or percentage of abstinent days/lack of drinking days (SMD = 0.17 [95% CI, 0.01 to 0.33], P = .04, 5 studies, n = 918), without significant group differences after removal of 1 outlying flupenthixol decanoate study (P = .24). Individually, flupenthixol decanoate (1 study, n = 281) was inferior to placebo regarding abstinence/drinking days (P = .004), whereas aripiprazole (1 study, n = 30) was superior regarding heavy drinking days (P < .00001). Antipsychotics caused greater all-cause discontinuation than placebo (RR = 1.24 [95% CI, 1.07 to 1.45], P = .005, NNH = 14), especially aripiprazole (P = .01) and flupenthixol decanoate (P = .001). Discontinuation due to intolerability was similar between antipsychotics and placebo (P = .12), but aripiprazole's risk was higher (P = .003). Drowsiness/sedation (P < .0001, NNH = 9), increased appetite (P = .02, NNH = 14), and dry mouth (P < .0001, NNH = 7) occurred more frequently with pooled antipsychotics. CONCLUSIONS: Except for 1 isolated outcome, the studied antipsychotics did not improve abstinence or reduce drinking or craving in patients with primary alcohol dependence.

Frequency, characteristics and management of adolescent inpatient aggression.

BACKGROUND: Inpatient aggression is a serious challenge in pediatric psychiatry. METHODS: A chart review study in adolescent psychiatric inpatients consecutively admitted over 24 months was conducted, to describe aggressive events requiring an intervention (AERI) and to characterize their management. AERIs were identified based on specific institutional event forms and/or documentation of as-needed (STAT/PRN) medication administration for aggression, both recorded by nursing staff. RESULTS: Among 408 adolescent inpatients (age: 15.2±1.6 years, 43.9% male), 1349 AERIs were recorded, with ≥1 AERI occurring in 28.4% (n=116; AERI+). However, the frequency of AERIs was highly skewed (median 4, range: 1-258). In a logistical regression model, the primary diagnosis at discharge of disruptive behavior disorders and bipolar disorders, history of previous inpatient treatment, length of hospitalization, and absence of a specific precipitant prior to admission were significantly associated with AERIs (R(2)=0.32; p<0.0001). The first line treatment of patients with AERIs (AERI+) was pharmacological in nature (95.6%). Seclusion or restraint (SRU) was used at least once in 59.4% of the AERI+ subgroup (i.e., in 16.9% of all patients; median within-group SRU frequency: 3). Treatment and discharge characteristics indicated a poorer prognosis in the AERI+ (discharge to residential care AERI+: 22.8%, AERI-: 5.6%, p<0.001) and a greater need for psychotropic polypharmacy (median number of psychotropic medications AERI+: 2; AERI-: 1, p<0.001). CONCLUSIONS: Despite high rates of pharmacological interventions, SRU continue to be used in adolescent inpatient care. As both of these approaches lack a clear evidence base, and as adolescents with clinically significant inpatient aggression have increased illness acuity/severity and service needs, structured research into the most appropriate inpatient aggression management is sorely needed.

Early nonresponse determined by the clinical global impressions scale predicts poorer outcomes in youth with schizophrenia spectrum disorders naturalistically treated with second-generation antipsychotics.

OBJECTIVE: The use of early response/nonresponse (ER/ENR) to antipsychotics as a predictor for ultimate response/nonresponse (UR/UNR) may help decrease inefficacious treatment continuation. However, data have been limited to adults, and ER/ENR has only been determined using time-consuming psychopathology rating scales. In the current study, we assessed if early improvement on the Clinical Global Impressions-Improvement (CGI-I) scale predicted UR/UNR in psychiatrically ill youth started on antipsychotic treatment. METHODS: Seventy-nine youth aged 6-19 years, with schizophrenia spectrum disorders, treated naturalistically with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone and evaluated monthly, were divided into ER/ENR groups at week 4, using at least "minimally improved" on the CGI-I scale. Prediction using week 4 ER/ENR status for UR (CGI-I=at least "much improved"), effectiveness and adverse effect outcomes at 8-12 weeks were assessed. RESULTS: At 4 weeks, 45.6% of subjects were ER and 54.4% were ENR without differences regarding baseline demographic, illness, and treatment variables, except for higher age (p=0.034) and maximum risperidone dose (p=0.0043) in ENR. ER/ENR status at 4 weeks predicted UR/UNR at week 12 significantly (p<0.0001): Sensitivity=68.9%, specificity=85.3%, positive predictive value=86.1%, negative predictive value=67.4%. At weeks 4, 8, and 12, ER patients improved significantly more on the CGI-I, CGI-Severity, and Children's Global Assessment of Functioning scales, and more ER patients reached UR compared with ENR patients (83.3% vs. 34.9%, all p<0.0001). ENR patients had more extrapyramidal side effects (EPS) at weeks 4, 8, and 12 (p=0.0019-0.0079). UR was independently associated with ER (odds ratio [OR]=18.09; 95% confidence interval [CI]=4.71-91.68, p<0.0001) and psychosis not otherwise specified (NOS) (OR=4.82 [CI: 1.31-21.41], p=0.017) (r(2)=0.273, p<0.0001). CONCLUSIONS: Older age and EPS were associated with ENR; ENR and schizophrenia were associated with UNR in naturalistically treated youth with schizophrenia spectrum disorders. Early CGI-I-based treatment decisions require further consideration and study.

Efficacy and tolerability of clozapine in Japanese patients with treatment-resistant schizophrenia: results from a 12-week, flexible dose study using raters masked to antipsychotic choice.

Japan approved clozapine for treatment-resistant schizophrenia in June 2009. The aim of this study was to evaluate clozapine's efficacy and tolerability in Japanese patients. A twelve-week, single-arm clinical trial of clozapine in treatment-resistant schizophrenia inpatients, was conducted under real-world conditions using raters masked for type of antipsychotic. Thirty-eight patients were recruited, with 33 (86.8%) completing the trial. At week 12, clozapine was associated with significant improvement in the Positive and Negative Syndrome Scale (PANSS) total (p < 0.0001), PANSS positive (p < 0.0001), negative (p = 0.0055) and general subscale scores (p < 0.0001). Significant improvements occurred in all PANSS scores by week 4, the first post-baseline psychopathology rating. Altogether, 50.0% of patients showed ≥20% reduction in PANSS total score, 20.6% had ≥30% reduction and 14.7% had >40% reduction. Eighteen patients (47.4%) were discharged before week 12. However, all patients experienced ≥1 adverse event. Two of 38 patients (5.2%) dropped out due to moderate leucopenia and one of them developed agranulocytosis after stopping clozapine. However, both patients recovered. Eight adverse events (hypersalivation, fatigue, sedation, constipation, insomnia, nausea/vomiting, chest pain and leucopenia) were observed in 34-79% of patients. These findings suggest that clozapine is beneficial in Japanese treatment-resistant schizophrenia patients. However, attention should be paid to patients' adverse events.

Improving metabolic parameters of antipsychotic child treatment (IMPACT) study: rationale, design, and methods.

BACKGROUND: Youth with serious mental illness may experience improved psychiatric stability with second generation antipsychotic (SGA) medication treatment, but unfortunately may also experience unhealthy weight gain adverse events. Research on weight loss strategies for youth who require ongoing antipsychotic treatment is quite limited. The purpose of this paper is to present the design, methods, and rationale of the Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) study, a federally funded, randomized trial comparing two pharmacologic strategies against a control condition to manage SGA-related weight gain. METHODS: The design and methodology considerations of the IMPACT trial are described and embedded in a description of health risks associated with antipsychotic-related weight gain and the limitations of currently available research. RESULTS: The IMPACT study is a 4-site, six month, randomized, open-label, clinical trial of overweight/obese youth ages 8-19 years with pediatric schizophrenia-spectrum and bipolar-spectrum disorders, psychotic or non-psychotic major depressive disorder, or irritability associated with autistic disorder. Youth who have experienced clinically significant weight gain during antipsychotic treatment in the past 3 years are randomized to either (1) switch antipsychotic plus healthy lifestyle education (HLE); (2) add metformin plus HLE; or (3) HLE with no medication change. The primary aim is to compare weight change (body mass index z-scores) for each pharmacologic intervention with the control condition. Key secondary assessments include percentage body fat, insulin resistance, lipid profile, psychiatric symptom stability (monitored independently by the pharmacotherapist and a blinded evaluator), and all-cause and specific cause discontinuation. This study is ongoing, and the targeted sample size is 132 youth. CONCLUSION: Antipsychotic-related weight gain is an important public health issue for youth requiring ongoing antipsychotic treatment to maintain psychiatric stability. The IMPACT study provides a model for pediatric research on adverse event management using state-of-the art methods. The results of this study will provide needed data on risks and benefits of two pharmacologic interventions that are already being used in pediatric clinical settings but that have not yet been compared directly in randomized trials. TRIAL REGISTRATION: Clinical Trials.gov NCT00806234.

Lack of effect of stimulant combination with second-generation antipsychotics on weight gain, metabolic changes, prolactin levels, and sedation in youth with clinically relevant aggression or oppositionality.

BACKGROUND: Second-generation antipsychotics (SGAs) are associated with weight gain, metabolic abnormalities, sedation/sleep disturbance, and prolactin abnormalities, especially in youths. Although stimulants have opposing dopamine receptor and adverse effects, it is unclear whether stimulant co-treatment counteracts the therapeutic or side effects of antipsychotics. METHODS: This was a naturalistic cohort study including 153 antipsychotic trials in youths aged 4-19 (mean, 11.3 +/- 3.0) years, started on an SGA for clinically significant aggression or oppositionality associated with oppositional defiant disorder, conduct disorder, disruptive behavior disorder not otherwise specified (NOS), impulse control disorder NOS, intermittent explosive disorder, Tourette's disorder, autistic disorder, and pervasive developmental disorder NOS. Patients underwent fasting assessments of body composition, lipids, glucose, insulin, prolactin, sedation, and general efficacy at baseline, weeks 4, 8, and 12, comparing patients co-prescribed stimulants (n = 71) with those not co-prescribed stimulants (n = 82). RESULTS: Patients received risperidone (33.3%), aripiprazole (29.4%), quetiapine (18.4%), olanzapine (11.8%), ziprasidone (5.9%), or clozapine (0.7%). With and without adjustment for differences in baseline variables (sex, prior stimulant use, primary Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition [DSM-IV] disorders, co-morbid attention-deficit/hyperactivity disorder [ADHD], present in 46.3% of youths not receiving stimulants, and some body composition parameters), patients on versus off stimulants did not differ on any of the assessed outcomes (all p values > or = 0.1). CONCLUSIONS: In contrast to guidelines, stimulant use did not precede or accompany antipsychotic use during the current episode of aggression/oppositionality in almost half of those youths who had aggressive/oppositional behavior and a DSM-IV diagnosis of ADHD. At the clinically prescribed doses, stimulant co-treatment of SGAs did not seem to significantly reduce antipsychotic effects on body composition, metabolic parameters, prolactin, sedation, and broad efficacy.