Eva M. Sheridan

Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials

OBJECTIVE To compare antipsychotic and mood stabilizer (MS) efficacy and tolerability in youth and adults with bipolar mania. METHODS Medline/PubMed search for studies including: (i) youth (< 18 years) or adults (> or = 18 years); (ii) bipolar I disorder; (iii) double-blind, randomized, placebo-controlled trial (DB-RPCT); (iv) < or = 12 weeks of treatment; and (v) calculable effect sizes (ES) and/or numbers needed to treat/harm (NNT/NNH) +/- 95% confidence intervals (CI). Non-overlapping 95% CIs determined significant group differences. RESULTS We identified nine DB-RPCTs in youth (n = 1,609), 5 evaluating second-generation antipsychotics (SGAs) (n = 1,140) and 4 evaluating MSs (n = 469). We also identified 23 DB-RPCTs in adults (n = 6,501), 14 including SGAs (n = 3,297), 5 using haloperidol as an active comparator (n = 580), and 11 including MSs (n = 2,581). Young Mania Rating Scale scores improved significantly more with SGAs than MSs in youth (ES = 0.65, CI: 0.53-0.78 versus 0.24, CI: 0.06-0.41) and adults (ES = 0.48, CI: 0.41-0.55 versus 0.24, CI: 0.17-0.31). After excluding topiramate studies, SGAs had larger ES than MSs only in youth (ES = 0.65, CI: 0.53-0.78 versus 0.20, CI: 0.02-0.39), but not adults (ES = 0.48, CI: 0.41-0.55 versus 0.46, CI: 0.37-0.55). However, in adults SGAs had significantly larger ES regarding Clinical Global Impressions scores than MSs, even without topiramate (ES = 0.75, CI: 0.68-0.82 versus 0.24, CI: 0.07-0.41). Rates of response, remission, and discontinuation due to any reason compared to placebo were similar between medication and age groups, except for more favorable NNTs for remission with SGAs than MSs in adults after excluding topiramate. SGAs caused more weight gain than MSs in youth (ES = 0.53, CI: 0.41-0.66 versus 0.10, CI: -0.12-0.33), but not in adults (ES = 0.13, CI: 0.05-0.22 versus 0.00, CI: -0.08-0.08). However, results were heterogeneous and not significant in either age group after excluding topiramate. Nevertheless, SGA-related weight gain was significantly greater in youth than adults. In youth, SGA-related somnolence was greater than with MSs (NNH = 4.7, CI: 3.9-6.0 versus 9.5, CI: 6.3-23.5), and more likely than in adults (NNH = 7.1, CI: 6.1-8.8). Conversely, youth experienced less akathisia with SGAs than adults (NNH = 20.4, CI: 14.1-36.5 versus 10.2, CI: 8.1-13.7), likely due to lower doses/slower titration. CONCLUSIONS In treating mania, potentially greater short-term efficacy compared to placebo with SGAs versus MS needs to be balanced against increased adverse events, especially in youth.

Are antipsychotics effective for the treatment of anorexia nervosa? Results from a systematic review and meta-analysis.

OBJECTIVE To assess the utility of antipsychotics for weight gain and improvement of illness-related psychopathology in patients with anorexia nervosa. DATA SOURCES PubMed, the Cochrane Library databases, and PsycINFO citations from the inception of the databases until March 27, 2012, were searched without language restrictions using the following keywords: randomized, random, randomly, and anorexia nervosa. In addition, we hand-searched for additional studies eligible for inclusion in this meta-analysis and contacted authors for unpublished data. STUDY SELECTION Included in this study were randomized placebo- or usual care-controlled trials of antipsychotics in patients with anorexia nervosa. DATA EXTRACTION Two independent evaluators extracted data. The primary outcome of interest was body weight, expressed as the standardized mean difference (SMD) between the 2 groups in baseline to endpoint change of body mass index (BMI), endpoint BMI, or daily weight change. SMD, risk ratio (RR), and number needed to harm (NNH) ± 95% confidence interval (CI) were calculated. RESULTS Across 8 studies (mean duration = 9.6 weeks; range, 7-12 weeks), 221 patients (mean age = 22.5 years, 219 [99.1%] females) with anorexia nervosa were randomly assigned to olanzapine (n = 54), quetiapine (n = 15), risperidone (n = 18), pimozide (n = 8), sulpiride (n = 9), placebo (n = 99), or usual care (n = 18). Both individually (P = .11 to P = .47) and pooled together (SMD = 0.27, 95% CI, -0.01 to 0.56; P = .06, I2 = 0%; 7 studies, n = 195), weight/BMI effects were not significantly different between antipsychotics and placebo/usual care. Moreover, pooled antipsychotics and placebo/usual care did not differ regarding scores on questionnaires related to anorexia nervosa (P = .32, 5 studies, n = 114), body shape (P = .91, 4 studies, n = 100), depressive symptoms (P = .08, 4 studies, n = 103), and anxiety (P = .53, 4 studies, n = 121). Individually, quetiapine (1 study, n = 33) outperformed usual care regarding eating disorder attitudes (P = .01) and anxiety (P = .02). While rates of dropout due to any reason (P = .83, I2 = 0%) and due to adverse events (P = .54, I2 = 5%) were similar in both groups, drowsiness/sedation occurred significantly more often with antipsychotics than placebo/usual care (RR = 3.69, 95% CI, 1.37-9.95; I2 = 67%, P = .01; NNH = 2, P = .001; 5 studies, n = 129), but most other adverse effects were only sparsely reported. CONCLUSIONS Although limited by small samples, this meta-analysis failed to demonstrate antipsychotic efficacy for body weight and related outcomes in females with anorexia nervosa.

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, Tourettes 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.

Neuropsychological Test Performance to Enhance Identification of Subjects at Clinical High Risk for Psychosis and Be Most Promising for Predictive Algorithms for Conversion to Psychosis: A Meta-Analysis.

OBJECTIVE To compare neuropsychological performance in people at clinical high risk for psychosis (CHR), healthy controls (HCs), or subjects with first-episode psychosis (FEP). DATA SOURCES Systematic PubMed/MEDLINE search through January 2014, without language restrictions, using search terms prodrome OR clinical high-risk OR ultra-high risk AND cognition OR individual test names. STUDY SELECTION Studies reporting neuropsychological data in CHR versus a HC or FEP groups or comparing CHR subjects who converted to psychosis (CHR-P) with CHR subjects who did not convert to psychosis (CHR-NP). DATA EXTRACTION Two authors independently extracted and compared neurocognitive test data. RESULTS A meta-analysis was performed on 60 neuropsychological tests from 9 domains in 32 studies with 21 nonoverlapping samples (CHR = 1,684 patients, HC = 986, FEP = 405). Compared to HCs, people with CHR performed significantly worse in 7 of 9 domains (Hedges g effect size [95% confidence limit] = -0.17 [-0.30, -0.04] [attention/vigilance] to -0.42 [-0.64, -0.20] [verbal learning, speed of processing] and -0.43 [-0.68, -0.18] [social cognition]), except reasoning/problem solving and working memory (which separated in longitudinal studies). California Verbal Learning Test (-0.65 [-0.84, -0.46]) and Digit Symbol Test (-0.63 [-0.86, -0.40]) separated groups the most. Compared to FEP subjects, people with CHR performed significantly better in 5 of 6 domains (from 0.29 [0.03, 0.56] [speed of processing] to 0.39 [0.17, 0.62] [attention/vigilance, verbal learning] and -0.40 [0.18, 0.64] [working memory]), except reasoning/problem solving. CHR-P and CHR-NP performed significantly worse than HC (except visual learning, working memory in CHR-NP). Compared to CHR-NP, CHR-P performed significantly worse in 6 of 8 domains (from -0.24 [-0.44, -0.03] [attention/vigilance] to -0.49 [-0.76, -0.22] [verbal learning] and -0.54 [-0.80, -0.27] [visual learning]), without differences in reasoning/problem solving and working memory. Three individual tests (Rey-Osterrieth Complex Figure Test, Verbal Fluency Test/Controlled Oral Word Association Test, and California Verbal Learning Test) discriminated the best between CHR-P and CHR-NP (-0.49 [-0.82, -0.16], -0.45 [-0.86, -0.03], and -0.40 [-0.80, -0.00], respectively). CONCLUSIONS CHR has mild to moderate globally distributed neuropsychological performance deficits that lie between FEP and HCs. Neuropsychological performance deficits are greater in CHR-P than in CHR-NP, but they overlap, reducing their current utility for risk stratification.

Neuromotor Adverse Effects in 342 Youth During 12 Weeks of Naturalistic Treatment With 5 Second-Generation Antipsychotics

OBJECTIVE Second-generation antipsychotic (SGA) effects in youth were monitored to quantify extrapyramidal side effects (EPS) and to identify risk profiles for treatment-emergent EPS. METHOD Data were analyzed for the nonrandomized, prospective Second-generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) inception cohort study. EPS were assessed at baseline and 4, 8, and 12 weeks after naturalistic SGA initiation for schizophrenia, mood, disruptive behavior, and autism spectrum disorders using the Simpson-Angus Scale (SAS), Barnes Akathisia Scale, Abnormal Involuntary Movement Scale (AIMS), and Treatment Emergent Side Effect Scale. Drug-induced parkinsonism was defined by incident mean SAS score >0.33, anticholinergic initiation, or increasing total SAS score ≥2 in patients with baseline EPS. RESULTS In 342 youth aged 13.6 ± 3.5 years (male = 58.2%, antipsychotic-naive = 65.8%), 15.2% developed drug-induced parkinsonism. Raw SGA-grouped drug-induced parkinsonism rates were as follows: quetiapine = 1.5%, olanzapine = 13.8%, risperidone = 16.1%, ziprasidone = 20.0%, and aripiprazole = 27.3%. SGA type, dose, higher age, and lower baseline functioning were jointly associated with drug-induced parkinsonism (R(2) = 0.18; p < .0001). Controlling for these factors, drug-induced parkinsonism rates were significantly lower only for quetiapine and olanzapine. Subjectively reported EPS (5%), EPS-related treatment discontinuation (3.3%), and anticholinergic initiation (3%) were infrequent. Anticholinergic initiation was most frequent with risperidone (10.2%; p = .0004). Treatment-emergent dyskinesia ranged from 4.5% (aripiprazole) to 15.5% (olanzapine). SGA type, younger age, white race/ethnicity, and baseline AIMS were jointly associated with treatment-emergent dyskinesia (R(2) = 0.31; p < .0001). Controlling for these factors, treatment-emergent dyskinesia rates differed among SGA subgroups, with higher rates with olanzapine and ziprasidone. At baseline, psychostimulant use was associated with dyskinesia, and number of psychotropic comedications was associated with subjective EPS. CONCLUSION In youth, SGA-related EPS rates did not generally exceed those reported in adults, with particularly low rates with quetiapine and olanzapine.

Outcome of Youth with Early-Phase Schizophrenia-Spectrum Disorders and Psychosis Not Otherwise Specified Treated with Second-Generation Antipsychotics: 12 Week Results from a Prospective, Naturalistic Cohort Study

OBJECTIVES The purpose of this study was to assess differences in the outcomes of youth with schizophrenia-spectrum disorders (SCZ-S) and psychotic disorder not otherwise specified (PsyNOS) during early antipsychotic treatment. METHODS The study was a prospective, naturalistic, inception cohort study of youth ≤19 years old with SCZ-S (schizophrenia, schizoaffective disorder, schizophreniform disorder) or PsyNOS (PsyNOS, brief psychotic disorder) and ≤24 months of lifetime antipsychotic treatment receiving clinicians choice antipsychotic treatment. Baseline demographic, illness and treatment variables, and effectiveness outcomes were compared at 12 weeks last-observation-carried-forward across SCZ-S and PsyNOS patients, adjusting for significantly different baseline variables. RESULTS Altogether, 130 youth with SCZ-S (n=42) or PsyNOS (n=88), mostly antipsychotic naïve (76.9%), were prescribed risperidone (47.7%), olanzapine (19.2%), aripiprazole (14.6%), quetiapine (11.5%), or ziprasidone (6.9%). Compared with those with PsyNOS, SCZ-S youth were older (16.4±2.1 vs. 14.8±3.2, p=0.0040), and less likely to be Caucasian (19.1% vs. 42.5%, p=0.009). At baseline, SCZ-S patients had significantly higher Clinical Global Impressions-Severity (CGI-S) scores (6.0±0.9 vs. 5.5±0.8, p=0.0018) and lower Childrens Global Assessment Scale (CGAS) scores (29.6±9.2 vs. 36.1±8.9, p=0.0002) and were more likely to be in the severely ill CGAS group (i.e., CGAS≤40). SCZ-S and PsyNOS patients did not differ regarding all-cause discontinuation (40.5 vs. 40.3%. p=0.49), discontinuation because of adverse effects (12.2% vs. 12.4%, p=0.97), or nonadherence (29.3% vs. 30.9%, p=0.88), but somewhat more SCZ-S patients discontinued treatment for inefficacy (19.5% vs. 7.4%, p=0.063). CGI-S and CGAS scores improved significantly in both diagnostic groups (p=0.0001, each). Adjusting for baseline differences, PsyNOS patients experienced significantly better CGI-I improvement (CGI-I) scores (p=0.012) and more frequently reached higher categorical CGAS group status (p=0.021) than SCZ-S patients. CONCLUSIONS Both youth with SCZ-S and those with PsyNOS experienced significant improvements with clinicians choice antipsychotic treatment. However, treatment discontinuation was common within 12 weeks, with greater inefficacy-related discontinuation in the SCZ-S group, whereas CGI-I and CGAS score-based improvements were greater in the PsyNOS group.