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ABSTRACT: Objective:To meta-analytically assess the efficacy and tolerability of nonsteroidal anti-inflammatory drugs (NSAIDs) vs placebo in schizophrenia.Method:Searching PubMed, PsycINFO, ISI Web of Science, and the US National Institute of Mental Health clinical trials registry from database inception to December 31, 2012, we conducted a systematic review/meta-analysis of randomized placebo-controlled studies assessing the efficacy of adjunctive NSAIDs. Primary outcome was the change in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes included change in PANSS positive and negative subscores, all-cause discontinuation, and tolerability outcomes. Random effects, pooled, standardized mean changes (Hedges' g) and risk ratios were calculated.Results:Across 8 studies, including 3 unpublished reports (n = 774), the mean effect size for PANSS total score was -0.236 (95% CI: -0.484 to 0.012, P = .063, I(2) = 60.6%), showing only trend-level superiority for NSAIDs over placebo. The mean effect sizes for the PANSS positive and negative scores were -0.189 (95% CI: -0.373 to -0.005, P = .044) and -0.026 (95% CI: -0.169 to 0.117, P = .72), respectively. The relative risk for all-cause discontinuation was 1.13 (95% CI: 0.794 to 1.599, P = .503). Significant superiority of NSAIDs over placebo regarding PANSS total scores was moderated by aspirin treatment (N = 2, P = .017), inpatient status (N = 4, P = .029), first-episode status (N = 2, P = .048), and (in meta-regression analyses) lower PANSS negative subscores (N = 6, P = .026).Interpretation:These results indicate that adjunctive NSAIDs for schizophrenia may not benefit patients treated with first-line antipsychotics judged by PANSS total score change. NSAIDs may have benefits for positive symptoms, but the effect was minimal/small. However, due to a limited database, further controlled studies are needed, especially in first-episode patients.
Schizophrenia Bulletin 05/2013; · 8.80 Impact Factor
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ABSTRACT: Abstract Objective: To report the design and preliminary results of a mirror-image study comparing total psychiatric hospitalization rates pre- and post-switch to aripiprazole once-monthly, an extended release injectable solution. Methods: A multicenter, open-label mirror-image study of patients (18-65 years) with schizophrenia to compare total psychiatric hospitalization rates between retrospective treatment with oral standard-of-care (SOC) antipsychotics and prospective treatment with aripiprazole once-monthly in a naturalistic community setting in North America. Total psychiatric hospitalization rates were assessed between retrospective (Months -4 to -1) and prospective treatment periods (Months 4 to 6) for patients who completed ≥3 months aripiprazole once-monthly. Results: 183 patients entered the prospective phase. After switching to aripiprazole once-monthly, total psychiatric hospitalization rates for the 3-month prospective period were significantly lower (p<0.0001, Exact McNemar's test) compared with the retrospective 3-month period when the same patients received SOC antipsychotics (6.6% [n=8/121] vs. 28.1%; [n=34/121], respectively; rate ratio=0.23). Similarly, total psychiatric hospitalization rates for all patients who entered the prospective treatment phase were significantly lower (p<0.0001, Exact McNemar's test) for the prospective 6 months following switch to aripiprazole once-monthly, compared with the retrospective 6-month SOC period (14.2% [n=26/183] vs. 41.5% [n=76/183], respectively; rate ratio=0.34). Common treatment-emergent adverse events (occurring in ≥5% of patients) were psychotic disorder (7.7%), akathisia (7.2%), and insomnia (7.2%). Discontinuation (all causes) during the prospective phase was 44.8% (n=82/183). Limitations: Mirror-image studies do not include a parallel active control; as each patient serves as their own control, it cannot be determined whether other treatments may have similar effects. Treatment and trial effects may be difficult to separate. Independent factors such as admission patterns, insurance coverage, availability of hospital beds and community support may influence rates of hospitalization. Conclusions: Switching to aripiprazole once-monthly substantially reduced total psychiatric hospitalization rates compared with retrospective rates in the same patients taking oral SOC.
Journal of Medical Economics 05/2013;
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ABSTRACT: The aim of this study was to evaluate the safety and tolerability of aripiprazole once-monthly (ARI-OM) for the maintenance treatment of schizophrenia. This long-term, pivotal study had four phases: oral conversion (phase 1, 4-6 weeks); oral stabilization (phase 2, 4-12 weeks); ARI-OM stabilization with coadministration of oral aripiprazole in the first 2 weeks (phase 3, 12-36 weeks); and a 52-week, randomized [phase 4, ARI-OM vs. placebo (2 : 1)], double-blind, maintenance phase. Safety was assessed across study phases by the time of first onset of adverse events, as were objective measures of extrapyramidal symptoms, fasting metabolic parameters, and body weight. Patient enrollment was phase 1=633; phase 2=710, of whom 210 entered phase 2 directly; phase 3=576; and phase 4=403 (ARI-OM, n=269; placebo, n=134). Adverse events (>5%) in any phase were insomnia, headache, anxiety, akathisia, increase in weight, injection-site pain, and tremor. Headache, somnolence, and nausea had a peak first onset within 4 weeks of treatment initiation. The incidence of extrapyramidal symptoms was similar in all phases. There were no unexpected changes in weight or shifts in fasting metabolic parameters across all study phases. ARI-OM had a safety and tolerability profile comparable with oral aripiprazole in maintenance treatment of schizophrenia.
International clinical psychopharmacology 04/2013; · 3.35 Impact Factor
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ABSTRACT: While combining antipsychotics is common in schizophrenia treatment, the literature on the reasons for antipsychotic polypharmacy (APP) is limited. We aimed to identify prescriber attitudes and rationales for APP in Japan where high APP utilization is reported. Two-hundred and seventeen psychiatrists participated in the survey, which assessed APP attitudes and behaviors. Prescribing APP to 47.7±24.7% (mean±S.D.) of their patients, psychiatrists reported that they were "moderately" concerned about APP. The most APP-justifiable factors were (1="not at all" to 5="extreme") cross titration (4.50±0.67), randomized controlled evidence (3.67±0.83), and treatment of comorbid conditions (3.31±0.83). Conversely, APP-discouraging factors were chronic side effects (4.14±0.64), difficulty determining cause and effect (4.07±0.74), and acute side effects (3.99±0.81). Comparing high to low APP prescribers (>50% vs. ≤50% of patients), no differences emerged regarding APP justification and concerns. In multivariate analyses, high APP use was associated with practice at a psychiatric hospital (OR: 2.70, 95% CI: 1.29-5.67, p=0.009), concern about potential drug-drug interactions (OR: 1.56, 95% CI: 1.04-2.35, p=0.031), and less reliance on case reports of APP showing efficacy (OR: 0.64, 95% CI: 0.44-0.92, p=0.017) (r(2)=0.111, p=0.001). High and low APP prescribers shared a comparable degree of justifications and concerns. Future research should examine the impact of cultural determinants on APP.
Psychiatry research. 04/2013;
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ABSTRACT: OBJECTIVE: To evaluate the relapse prevention efficacy of lurasidone compared with quetiapine XR (QXR) in adults patients with schizophrenia. METHOD: This double-blind study evaluated the relapse prevention efficacy of 12months of flexible-dose treatment with lurasidone (40-160mg/day) compared with QXR (200-800mg/day), in outpatients with an acute exacerbation of chronic schizophrenia who had recently completed a 6-week placebo-controlled trial of treatment with either lurasidone or QXR. The primary endpoint, time-to-relapse, was analyzed using a Cox proportional hazards model in this noninferiority trial. RESULTS: The Kaplan-Meier estimate of the probability of relapse over 12months was 23.7% for subjects receiving lurasidone vs. 33.6% for QXR. The hazard ratio [95% CI] for probability of relapse was 0.728 [0.410, 1.295] (log-rank p=0.280). Since the upper limit of the hazard ratio (1.295) was smaller than the prespecified noninferiority margin (1.93), noninferiority of lurasidone compared with QXR was demonstrated in this study. The probability of hospitalization at 12months was lower for the lurasidone group compared with the QXR group (9.8% vs. 23.1%; log-rank p=0.049). A significantly higher proportion of lurasidone subjects achieved remission at study endpoint compared with the QXR group (61.9% vs. 46.3%; p=0.043). Discontinuation rates due to AEs were similar for lurasidone and QXR (7% vs. 5%). Treatment with lurasidone was not associated with clinically significant changes in weight or metabolic parameters. CONCLUSIONS: Twelve months of treatment with lurasidone met noninferiority criteria, and was associated with higher rates of remission, and reduced risk of hospitalization compared with QXR. No clinically significant effects on weight or metabolic parameters were observed during maintenance treatment with lurasidone.
Biological Psychiatry 04/2013; · 8.28 Impact Factor
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ABSTRACT: Background: The hospital outcome of patients with dementia is significantly worse than that of cognitively intact persons of the same age admitted to medical or surgical units but has not been investigated in psychiatric settings. Aim of study: To determine the medical outcome of patients with dementia admitted for behavioral disturbance to a free-standing psychiatric hospital. Methods: Emergency transfers from the psychiatric setting to a general hospital were used as proxies for medical deteriorations occurring among the 71 patients with dementia (age 78.4 ± 10.4 years; 40.1% males) and 71 age- and gender-matched nondementia control patients. The patients were identified in a cohort of 1000 patients consecutively admitted to a free-standing mental health institution. Logistic regression was used to determine the clinical and laboratory variables independently associated with medical deteriorations. Results: A total of 30 patients with dementia and 25 nondementia patients were transferred to a general hospital after an acute medical deterioration (42.3% vs 35.2%, P = .38). Febrile illnesses and falls with head trauma were the most common reasons for transfers in the dementia group, in which they constituted more than half of medical deteriorations, a proportion significantly higher than in the control group (P = .011). Admission hemoglobin levels were the only independent predictor of medical deterioration in this geriatric sample. Conclusions: Although nearly 50% of patients with dementia admitted for behavioral disturbance to a free-standing psychiatric institution required transfer to a general hospital, their rate of medical deteriorations was similar to age-matched nondementia control patients.
Journal of Geriatric Psychiatry and Neurology 02/2013; · 3.07 Impact Factor
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ABSTRACT: Background:While long-acting injectable antipsychotics (LAIs) are hoped to reduce high relapse rates in schizophrenia, recent randomized controlled trials (RCTs) challenged the benefits of LAIs over oral antipsychotics (OAPs).Methods:Systematic review/meta-analysis of RCTs that lasted ≥6 months comparing LAIs and OAPs. Primary outcome was study-defined relapse at the longest time point; secondary outcomes included relapse at 3, 6, 12, 18, and 24 months, all-cause discontinuation, discontinuation due to adverse events, drug inefficacy (ie, relapse + discontinuation due to inefficacy), hospitalization, and nonadherence.Results:Across 21 RCTs (n = 5176), LAIs were similar to OAPs for relapse prevention at the longest time point (studies = 21, n = 4950, relative risk [RR] = 0.93, 95% confidence interval [CI]: 0.80-1.08, P = .35). The finding was confirmed restricting the analysis to outpatient studies lasting ≥1 year (studies = 12, RR = 0.93, 95% CI:0.71-1.07, P = .31). However, studies using first-generation antipsychotic (FGA)-LAIs (studies = 10, RR = 0.82, 95% CI:0.69-0.97, P = .02) and those published ≤1991 (consisting exclusively of all 8 fluphenazine-LAI studies; RR = 0.79, 95% CI: 0.65-0.96, P = 0.02) were superior to OAPs regarding the primary outcome. Pooled LAIs also did not separate from OAPs regarding any secondary outcomes. Again, studies using FGA-LAIs and those published ≤1991 were associated with LAI superiority over OAPs, eg, hospitalization and drug inefficacy.Conclusions:In RCTs, which are less representative of real-world patients than naturalistic studies, pooled LAIs did not reduce relapse compared with OAPs in schizophrenia patients. The exceptions were FGA-LAIs, mostly consisting of fluphenazine-LAI studies, which were all conducted through 1991. Because this finding is vulnerable to a cohort bias, studies comparing FGA-LAI vs second-generation antipsychotics-LAI and LAI vs OAP RCTs in real-world patients are needed.
Schizophrenia Bulletin 12/2012; · 8.80 Impact Factor
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ABSTRACT: BACKGROUND: Second-generation antipsychotics (SGAs) increase the risk of type 2 diabetes. The mechanism is thought to center on drug-induced weight gain, which starts the dysmetabolic cascade of insulin resistance, increased insulin production and pancreatic beta-cell failure. An independent effect of SGAs on insulin secretion has been suggested in animal models, but has not been demonstrated in clinical samples. OBJECTIVE: To determine the post-challenge insulin secretion in patients treated with SGAs. METHOD: We identified 520 non-diabetic individuals treated with clozapine (N=73), olanzapine (N=190), quetiapine (N=91) or risperidone (N=166) in a consecutive, single-site cohort of 783 adult psychiatric inpatients who underwent a comprehensive metabolic assessment. Insulin secretion was measured as the area under the curve (AUC(insulin)) generated by levels recorded at baseline, 30, 60 and 120min after the intake of 75g of glucose. The independent predictors of insulin secretion were determined with regression analysis in the entire sample and separately in patients with normal glucose tolerance (NGT) and prediabetes. RESULTS: The post-challenge AUC(insulin) was independently predicted by AUC(glucose), waist circumference, triglyceride levels and younger age (p<0.0001); non-smoking status (p=0.0012); and treatment with clozapine (p=0.021). The model explained 33.5% of the variance in insulin secretion (p<0.0001). The clozapine effect was present in the NGT group, but not in prediabetics. CONCLUSIONS: Clozapine, but not olanzapine, quetiapine and risperidone, is an independent predictor of post-challenge insulin secretion in non-diabetics, particularly in those with normal glucose tolerance. The findings suggest that the diabetogenic risk of clozapine may persist even after weight reduction.
Biological Psychiatry 12/2012; · 8.28 Impact Factor
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ABSTRACT: Because early treatment choice is critical in first-episode schizophrenia-spectrum disorders (FES), this meta-analysis compared efficacy and tolerability of individual second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs) in FES. We conducted systematic literature search (until 12 December 2010) and meta-analysis of acute, randomized trials with ⩾1 FGA vs. SGA comparison; patients in their first episode of psychosis and diagnosed with schizophrenia-spectrum disorders; available data for psychopathology change, treatment response, treatment discontinuation, adverse effects, or cognition. Across 13 trials (n = 2509), olanzapine (seven trials) and amisulpride (one trial) outperformed FGAs (haloperidol: 9/13 trials) in 9/13 and 8/13 efficacy outcomes, respectively, risperidone (eight trials) in 4/13, quetiapine (one trial) in 3/13 and clozapine (two trials) and ziprasidone (one trial) in 1/13, each. Compared to FGAs, extrapyramidal symptom (EPS)-related outcomes were less frequent with olanzapine, risperidone and clozapine, but weight gain was greater with clozapine, olanzapine and risperidone. Pooled SGAs were similar to FGAs regarding total psychopathology change, depression, treatment response and metabolic changes. SGAs significantly outperformed FGAs regarding lower treatment discontinuation, irrespective of cause, negative symptoms, global cognition and less EPS and akathisia, while SGAs increased weight more (p < 0.05-0.01). Results were not affected by FGA dose or publication bias, but industry-sponsored studies favoured SGAs more than federally funded studies. To summarize, in FES, olanzapine, amisulpride and, less so, risperidone and quetiapine showed superior efficacy, greater treatment persistence and less EPS than FGAs. However, weight increase with olanzapine, risperidone and clozapine and metabolic changes with olanzapine were greater. Additional FES studies including broader-based SGAs and FGAs are needed.
The International Journal of Neuropsychopharmacology 12/2012; · 4.58 Impact Factor
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Todd Lencz,
Serge Sevy,
Rachel Miller,
Handan Gunduz-Bruce,
Philip R Szeszko, John M Kane,
Julia D Betensky,
Anil K Malhotra,
Joanne McCormack,
Delbert G Robinson,
Robert M Bilder
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ABSTRACT: Nielsen J, Kane JM, Correll CU. Real-world effectiveness of clozapine in patients with bipolar disorder: results from a 2-year mirror-image study. Bipolar Disord 2012: 00: 000-000. © 2012 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd. Objectives: Clozapine remains the drug of choice for treatment-resistant schizophrenia but the evidence for its use in severe bipolar disorder (BD) remains sparse. Methods: A pharmaco-epidemiologic database study was carried out in Denmark, investigating the effectiveness of clozapine in BD patients (without a schizophrenia-spectrum disorder), between 1996 and 2007, using a two-year mirror-image design. Results: A total of 21473 patients with a lifetime diagnosis of International Classification of Diseases-10 (ICD-10) BD were identified, of which only 326 (1.5%) were treated with clozapine and were included in the mirror-image analysis. The mean follow-up time was 544 ± 280 days, the mean clozapine dose was 307.4 mg [95% confidence interval (CI): 287.9-328.2], and 39.3% were male. During clozapine treatment, the mean number of bed-days decreased from 177.8 (95% CI: 149.4-211.6) to 34.6 (95% CI: 24.8-48.2) (p < 0.001). The mean number of admissions was reduced from 3.2 (95% CI: 2.9-3.7) to 2.0 (95% CI: 1.6-2.4) (p < 0.001). Overall, 240 patients (73.6%) had reduced bed-days and 130 (39.9%) were not admitted while treated with clozapine. Moreover, the number of psychotropic co-medications was reduced from 4.5 defined daily doses (DDD) (25-75 percentiles: 2.4-8.2) to 3.9 DDD (25-75 percentiles: 2.4-6.1) (p = 0.045). Somatic hospital visits for intentional self-harm/overdose reduced significantly from 8.3% to 3.1% (p = 0.004). However, non-psychotropic co-medication use for medical conditions did not increase; 0.7 DDD (25-75 percentiles: 0.0-2.9) to 0.8 DDD (25-75 percentiles: 0.1-2.89) (p = 0.3). Conclusions: Clozapine use for BD was associated with a significant and clinically relevant reduction in the number of bed-days, psychiatric admissions, psychotropic co-medications, and hospital contact for self-harm/overdose, without increased medical treatments. Clozapine seems to be an appropriate choice for treatment-resistant BD and should be investigated in randomized controlled trials.
Bipolar Disorders 10/2012; · 5.29 Impact Factor
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ABSTRACT: INTRODUCTION: Antipsychotic polypharmacy (APP), the concomitant use of ≥ 2 antipsychotics, is common in clinical practice. Prior reviews have focused on the efficacy of APP, but no systematic review exists regarding the safety and tolerability of this practice. AREAS COVERED: A systematic review of adverse effects associated with APP was conducted to prepare this review; case series with ≥ 2 patients, chart reviews, naturalistic, database, cohort and randomized studies that reported on the association between APP in general or specific APP combinations and global or specific adverse effect were included. Methodological limitations of available studies are discussed and recommendations for clinicians and future research are provided. EXPERT OPINION: Across mostly small and uncontrolled studies, APP has been associated with increased global side effect burden, rates of Parkinsonian side effects, anticholinergic use, hyperprolactinemia, sexual dysfunction, hypersalivation, sedation/somnolence, cognitive impairment and diabetes. Effects on akathisia and mortality were inconclusive. Although some combinations, particularly aripiprazole augmentation of an agent with greater side effect burden, may reduce weight gain, dyslipidemia, hyperprolactinemia and sexual dysfunction, APP should remain a last-resort treatment option after monotherapy, switching and non-antipsychotic combinations have failed. More data are needed to further inform the individualized risk-benefit evaluation of APP.
Expert Opinion on Drug Safety 05/2012; 11(4):527-42. · 3.02 Impact Factor
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Anil K Malhotra,
Christoph U Correll,
Nabilah I Chowdhury,
Daniel J Müller,
Peter K Gregersen,
Annette T Lee,
Arun K Tiwari, John M Kane,
W Wolfgang Fleischhacker,
Rene S Kahn,
Roel A Ophoff,
Jeffrey A Lieberman,
Herbert Y Meltzer,
Todd Lencz,
James L Kennedy
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ABSTRACT: CONTEXT: Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and nonpsychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk. OBJECTIVE: To identify single-nucleotide polymorphisms associated with antipsychotic drug-induced weight gain. DESIGN: Pharmacogenetic association study. SETTING: The discovery cohort was from a US general psychiatric hospital. Three additional cohorts were from psychiatric hospitals in the United States and Germany and from a European antipsychotic drug trial. PARTICIPANTS: The discovery cohort consisted of 139 pediatric patients undergoing first exposure to SGAs. The 3 additional cohorts consisted of 73, 40, and 92 subjects. Intervention Patients in the discovery cohort were treated with SGAs for 12 weeks. Additional cohorts were treated for 6 and 12 weeks. MAIN OUTCOME MEASURES: We conducted a genome-wide association study assessing weight gain associated with 12 weeks of SGA treatment in patients undergoing first exposure to antipsychotic drugs. We next genotyped 3 independent cohorts of subjects assessed for antipsychotic drug-induced weight gain. RESULTS: Our genome-wide association study yielded 20 single-nucleotide polymorphisms at a single locus exceeding a statistical threshold of P < 10(-5). This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale genome-wide association studies of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight during the 12-week trial. These results were replicated in 3 additional cohorts, with rs489693 demonstrating consistent recessive effects; meta-analysis revealed a genome-wide significant effect (P = 5.59 × 10(-12)). Moreover, we observed consistent effects on related metabolic indices, including triglyceride, leptin, and insulin levels. CONCLUSIONS: These data implicate MC4R in extreme SGA-induced weight gain and related metabolic disturbances. A priori identification of high-risk subjects could lead to alternative treatment strategies in this population.
Archives of general psychiatry 05/2012; · 12.26 Impact Factor
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ABSTRACT: To evaluate the efficacy and tolerability of a once-monthly intramuscular (IM) depot formulation of the dopamine partial agonist aripiprazole as maintenance treatment in adults meeting DSM-IV-TR schizophrenia criteria.
The study was conducted from July 2008 until February 2011. Subjects requiring chronic treatment with an antipsychotic entered a 4- to 12-week oral stabilization phase and received oral aripiprazole (10-30 mg/d). Subjects meeting stability criteria for 4 weeks entered an IM-depot stabilization phase in which they received 400-mg aripiprazole-IM-depot injections every 4 weeks (single decrease to 300 mg permitted) with coadministration of oral aripiprazole tablets in the first 2 weeks. Subjects meeting stability criteria for 12 consecutive weeks were randomly assigned (2:1) to aripiprazole-IM-depot or placebo during a 52-week, double-blind maintenance phase. The primary outcome measure was time to exacerbation of psychotic symptoms/impending relapse (event). Safety and tolerability were also assessed.
710 patients entered oral stabilization, 576 progressed to IM-depot stabilization, and 403 were randomly assigned to double-blind treatment. The study was terminated early because efficacy was demonstrated by the preplanned interim analysis (conducted after 64 events). Time to impending relapse was significantly delayed with aripiprazole-IM-depot treatment compared with placebo in both the interim analysis and the final analysis (P < .0001, log-rank test). The hazard ratio (placebo/aripiprazole-IM-depot) at final analysis was 5.03 (95% CI, 3.15-8.02). The rate of impending relapse was significantly lower with aripiprazole-IM-depot than placebo at endpoint (final analysis, 10.0% [n = 27/269] vs 39.6% [n = 53/134]). Improvements in Clinical Global Impressions-Severity of Illness scale and Positive and Negative Syndrome Scale total scores were maintained with aripiprazole-IM-depot treatment but showed significant worsening with placebo (change from double-blind baseline, P < .0001 for aripiprazole-IM-depot vs placebo). The most common treatment-emergent adverse events (occurring in ≥ 5% of aripiprazole-IM-depot subjects and greater than placebo) were insomnia, tremor, and headache.
Aripiprazole-IM-depot significantly delayed time to impending relapse compared with placebo and appears to be a well-tolerated maintenance treatment option for schizophrenia.
ClinicalTrials.gov identifier: NCT00705783.
The Journal of Clinical Psychiatry 05/2012; 73(5):617-24. · 5.80 Impact Factor
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ABSTRACT: To assess the prevalence and correlates of antipsychotic polypharmacy (APP) across decades and regions.
Electronic PubMed/Google Scholar search for studies reporting on APP, published from 1970 to 05/2009. Median rates and interquartile ranges (IQR) were calculated and compared using non-parametric tests. Demographic and clinical variables were tested as correlates of APP in bivariate and meta-regression analyses.
Across 147 studies (1,418,163 participants, 82.9% diagnosed with schizophrenia [IQR=42-100%]), the median APP rate was 19.6% (IQR=12.9-35.0%). Most common combinations included first-generation antipsychotics (FGAs)+second-generation antipsychotics (SGAs) (42.4%, IQR=0.0-71.4%) followed by FGAs+FGAs (19.6%, IQR=0.0-100%) and SGAs+SGAs (1.8%, IQR=0.0-28%). APP rates were not different between decades (1970-1979:28.8%, IQR=7.5-44%; 1980-1989:17.6%, IQR=10.8-38.2; 1990-1999:22.0%, IQR=11-40; 2000-2009:19.2% IQR=14.4-29.9, p=0.78), but between regions, being higher in Asia and Europe than North America, and in Asia than Oceania (p<0.001). APP increased numerically by 34% in North America from the 1980s 12.7%) to 2000s (17.0%) (p=0.94) and decreased significantly by 65% from 1980 (55.5%) to 2000 (19.2%) in Asia (p=0.03), with non-significant changes in Europe. APP was associated with inpatient status (p<0.001), use of FGAs (p<0.0001) and anticholinergics (<0.001), schizophrenia (p=0.01), less antidepressant use (p=0.02), greater LAIs use (p=0.04), shorter follow-up (p=0.001) and cross-sectional vs. longitudinal study design (p=0.03). In a meta-regression, inpatient status (p<0.0001), FGA use (0.046), and schizophrenia diagnosis (p=0.004) independently predicted APP (N=66, R(2)=0.44, p<0.0001).
APP is common with different rates and time trends by region over the last four decades. APP is associated with greater anticholinergic requirement, shorter observation time, greater illness severity and lower antidepressant use.
Biological Psychiatry 04/2012; 138(1):18-28. · 8.28 Impact Factor
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ABSTRACT: Medical deterioration during admission to free-standing psychiatric hospitals is distressing for patients, interrupts bio-behavioral interventions, and places a substantial burden on health care resources. Emergency transfers to a general hospital are a reasonable marker of significant medical deterioration, but have not been assessed systematically.
To use clinical data available at the time of psychiatric admission to identify risk factors for transfers to a general hospital.
Retrospective review of the hospital course of 1000 adults consecutively admitted for an average of 19.1 ± 21.3 days to a single free-standing psychiatric hospital in 2010.
One hundred forty-four patients (14.4%) were transferred to a general hospital. Transferred and not-transferred groups differed significantly with regard to age, presence of dementia, number of comorbid medical disorder, history of arterial hypertension, blood urea nitrogen (BUN), creatinine, albumin, glucose, calcium, hemoglobin, and hematocrit (P < .001). In a multiple logistic regression analysis, blood urea nitrogen (odds ratio [OR], 63.2), hemoglobin (OR, 35.3), albumin (OR, 7.3) and age (OR, 5.73) were independently associated with transfers. Acute medical deteriorations occurred in 46.2% of patients with azotemia (BUN >24 mg/dL), 32.7% of those with anemia (Hb <12 g/L), 37.5 % of those with hypoalbuminemia (albumin <3.7 g/dL), and 37.4% of patients 65 and older.
Medical deterioration of psychiatric inpatients correlates with higher BUN, lower albumin and hemoglobin, and older age. Baseline azotemia, anemia or hypoalbuminemia should trigger prompt medical evaluation and enhanced monitoring to prevent, identify, and treat somatic disorders.
Comprehensive psychiatry 04/2012; 53(7):968-74. · 2.08 Impact Factor
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The Journal of Clinical Psychiatry 04/2012; 73(4):504-5. · 5.80 Impact Factor
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ABSTRACT: Hyponatremia at time of inpatient admission is associated with increased severity of illness and mortality in patients hospitalized for treatment of medical conditions. This study was conducted to determine the clinical outcome of psychiatric inpatients with admission hyponatremia. The cohort comprised 1000 adults consecutively admitted to a free-standing psychiatric hospital in 2010. Emergency transfer to a general hospital was used as a proxy marker for poor medical outcome. The point prevalence of hyponatremia (sodium level <136mEq/l) at admission was 6.49%. Older age and a diagnosis of arterial hypertension were independent correlates of admission hyponatremia. Medical deteriorations occurred in 26.7% of hyponatremic patients and 13.1% of those with normal sodium levels. Admission hyponatremia is associated with an increased rate of significant medical deteriorations of psychiatric inpatients and should trigger enhanced clinical monitoring to identify and treat somatic disorders.
Psychiatry research. 03/2012; 198(1):24-7.
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ABSTRACT: Relatively small, reproductively isolated populations with reduced genetic diversity may have advantages for genomewide association mapping in disease genetics. The Ashkenazi Jewish population represents a unique population for study based on its recent (< 1,000 year) history of a limited number of founders, population bottlenecks and tradition of marriage within the community. We genotyped more than 1,300 Ashkenazi Jewish healthy volunteers from the Hebrew University Genetic Resource with the Illumina HumanOmni1-Quad platform. Comparison of the genotyping data with that of neighboring European and Asian populations enabled the Ashkenazi Jewish-specific component of the variance to be characterized with respect to disease-relevant alleles and pathways.
Using clustering, principal components, and pairwise genetic distance as converging approaches, we identified an Ashkenazi Jewish-specific genetic signature that differentiated these subjects from both European and Middle Eastern samples. Most notably, gene ontology analysis of the Ashkenazi Jewish genetic signature revealed an enrichment of genes functioning in transepithelial chloride transport, such as CFTR, and in equilibrioception, potentially shedding light on cystic fibrosis, Usher syndrome and other diseases over-represented in the Ashkenazi Jewish population. Results also impact risk profiles for autoimmune and metabolic disorders in this population. Finally, residual intra-Ashkenazi population structure was minimal, primarily determined by class 1 MHC alleles, and not related to host country of origin.
The Ashkenazi Jewish population is of potential utility in disease-mapping studies due to its relative homogeneity and distinct genomic signature. Results suggest that Ashkenazi-associated disease genes may be components of population-specific genomic differences in key functional pathways.
Genome biology 01/2012; 13(1):R2. · 6.63 Impact Factor
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ABSTRACT: A prior 4-week, proof-of-concept study suggested that adjunctive therapy with armodafinil 200mg/day decreases negative symptoms in patients with clinically stable schizophrenia. This study investigated the efficacy and tolerability of adjunctive armodafinil for treatment of negative symptoms in adults with schizophrenia receiving antipsychotic medications.
This parallel-group, 24-week study enrolled adults with schizophrenia who were receiving oral olanzapine, risperidone, or paliperidone for ≥ 6 weeks, and had a Positive and Negative Syndrome Scale (PANSS) negative symptom subscale score of ≥ 15. Patients received one of 3 doses of once-daily armodafinil (150 mg, 200mg, or 250 mg) or placebo. The primary efficacy measure was the change from baseline to final visit in the PANSS negative symptom subscale score. Secondary measures included the PANSS total score, Clinical Global Impression of Severity, Personal and Social Performance Scale, and CNSVitalSigns cognitive battery.
Of 285 randomized patients, 213 received armodafinil and 72 received placebo. The mean (SD) changes in PANSS negative symptom subscale score were -1.9 (3.8) for armodafinil 150 mg (n = 70), -2.3 (3.6) for armodafinil 200mg (n = 69), -2.0 (3.3) for armodafinil 250 mg (n = 71), and -2.2 (4.1) for placebo (n=70) (p ≥ 0.70 for each armodafinil group versus placebo). Secondary measures were generally not different between groups. Armodafinil was generally well tolerated, without worsening positive symptoms.
This study found no benefit of adjunctive armodafinil versus placebo for negative symptoms in patients with schizophrenia receiving treatment with olanzapine, risperidone, or paliperidone. Armodafinil was generally well tolerated in these patients.
Biological Psychiatry 12/2011; 135(1-3):116-22. · 8.28 Impact Factor
