Major depressive disorder (MDD) is a common condition with a lifetime prevalence of 15% to 18%, which leads to considerable suffering and disability. Some antipsychotics have been reported to induce ...remission in major depression, when added to an antidepressant.
To evaluate the effects of second-generation antipsychotic (SGA) drugs (alone or augmentation) compared with placebo or antidepressants for people with MDD or dysthymia.
The Cochrane Depression, Anxiety and Neurosis Group's controlled trial registers (CCDANCTR-Studies and CCDANCTR-References) were searched up to 21 July 2010. The author team ran complementary searches on clinicaltrials.gov and contacted key authors and drug companies.
We included all randomised, double-blind trials comparing oral SGA treatment (alone or augmentation) with other forms of pharmaceutical treatment or placebo in people with MDD or dysthymia.
We extracted data independently. For dichotomous data we calculated the odds ratio (OR) and 95% confidence interval (CI) on an intention-to-treat basis, and for continuous data the mean difference (MD), based on a random-effects model. We presented each comparison separately; we did not perform a pooled data analysis.
We included 28 trials with 8487 participants on five SGAs: amisulpride, aripiprazole, olanzapine, quetiapine and risperidone.Three studies (1092 participants) provided data on aripiprazole augmentation in MDD. All efficacy data (response n = 1092, three RCTs, OR 0.48; 95% CI 0.37 to 0.63), (MADRS n = 1077, three RCTs, MD -3.04; 95% CI -4.09 to -2) indicated a benefit for aripiprazole but more side effects (weight gain, EPS) .Seven trials (1754 participants) reported data on olanzapine. Compared to placebo fewer people discontinued treatment due to inefficacy; compared to antidepressants there were no efficacy differences, olanzapine augmentation showed symptom reduction (MADRS n = 808, five RCTs, MD -2.84; 95% CI -5.48 to -0.20), but also more weight or prolactin increase.Quetiapine data are based on seven trials (3414 participants). Compared to placebo, quetiapine monotherapy (response n = 1342, three RCTs, OR 0.52; 95% CI 0.41 to 0.66) and quetiapine augmentation (response n = 937, two RCTs, OR 0.68; 95% CI 0.52 to 0.90) showed symptom reduction, but quetiapine induced more sedation.Four trials (637 participants) presented data on risperidone augmentation, response data were better for risperidone (n = 371, two RCTs, OR 0.57; 95% CI 0.36 to 0.89) but augmentation showed more prolactin increase and weight gain.Five studies (1313 participants) presented data on amisulpride treatment for dysthymia. There were some beneficial effects compared to placebo or antidepressants but tolerability was worse.
Quetiapine was more effective than placebo treatment. Aripiprazole and quetiapine and partly also olanzapine and risperidone augmentation showed beneficial effects compared to placebo. Some evidence indicated beneficial effects of low-dose amisulpride for dysthymic people. Most SGAs showed worse tolerability.
Despite the widespread use of the Brief Psychiatric Rating Scale (BPRS), the clinical meaning of its total score and cut-off values used to define treatment response are unclear.
To link the BPRS to ...Clinical Global Impression (CGI) ratings.
Equipercentile linking of BPRS and CGI ratings from seven drug trials in acutely ill patients with schizophrenia (n=1979).
'Mildly ill' according to the CGI approximately corresponded to a BPRS total score of 31, 'moderately ill'to a BPRS score of 41 and'markedly ill'to a BPRS score of 53.'Minimally improved'according to the CGI score was associated with percentage BPRS reductions of 24, 27 and 30% at weeks 1, 2 and 4, respectively. The corresponding numbers for a CGI rating of 'much improved' were 44, 53 and 58%.
The results provide a clearer understanding of how to interpret BPRS total and percentage reduction scores in clinical trials with patients acutely ill with schizophrenia who are experiencing positive symptoms.
Previous studies have shown that placebo response rates in antidepressant trials have been increasing since the 1970s. However, these studies have been based on outdated or limited datasets and have ...used inappropriate statistical methods. We did a systematic review of placebo-controlled randomised controlled trials of antidepressants to examine associations between placebo-response rates and study and patient characteristics.
In this systematic review, we searched for published and unpublished double-blind randomised placebo-controlled trials of first-generation and second-generation antidepressants for acute treatment of major depression in adults (update: Jan 8, 2016). The log-transformed proportions of placebo response, defined as 50% or greater reduction in depression severity score from baseline, were meta-analytically synthesised for each year. We then looked for a structural break point in the secular changes in these characteristics through the years and examined the influence of the study year and other trial and patient characteristics on the response rates through meta-regression.
We identified 252 placebo-controlled trials (26 324 patients on placebo) done between 1978 and 2015. There was a structural break in 1991, and since then, the average placebo response rates in antidepressant trials have remained constant in the range between 35% and 40% (relative risk RR 1·00, 95% CI 0·97-1·03, p=0·99, for every 5-year increase). The length of the study and the number of study centres were significant factors (RR 1·03, 95% CI 1·01-1·05 for 1 more week in trial length; 1·32, 1·11-1·57 for multicentre vs single-centre trials).
Contrary to the widely held belief, the average placebo response rates in antidepressant trials have been stable for more than 25 years. This new evidence should have an effect on the interpretation of the scientific literature and the future of psychopharmacology, both from a clinical and methodological point of view.
Japan Society for Promotion of Science, Great Britain Sasakawa Foundation.
Abstract Applying various psychopharmacological combination and augmentation strategies in schizophrenia is common clinical practice. This meta-analysis evaluated the efficacy of benzodiazepines ...added to antipsychotics. The Cochrane Schizophrenia Group trial register (until February 2011) and PubMed/Medline (until July 2012) were searched for randomized controlled trials (RCTs) with a minimum duration of one week that compared benzodiazepine augmentation of antipsychotics with a control group receiving antipsychotic monotherapy in schizophrenia and schizophrenia-like psychoses. Study selection and data extraction were conducted independently by at least two authors. The primary outcome was response to treatment. Secondary outcomes were positive and negative schizophrenic symptoms, anxiety symptoms, and dropouts due to any reason, inefficacy of treatment, and adverse events. Pooled risk ratios (RRs) with the 95% confidence intervals (CIs) were calculated using a random-effects model, with number-needed-to-treat/harm (NNT/H) calculations where appropriate. Overall, 16 relevant RCTs with 1045 participants were identified. Benzodiazepine augmentation was not associated with statistically significantly more responders ( N =6; n =511; RR 0.97, 95% CI 0.77–1.22). Adjunctive benzodiazepines were well accepted and tolerated according to dropout-rates and adverse effects apart from dizziness ( N =3; n =190; RR 2.58, 95% CI 1.08–6.15) and somnolence ( N =2; n =118; RR 3.30, 95% CI 1.04–10.40). There is no evidence for antipsychotic efficacy of additional benzodiazepine medication in schizophrenia. Therefore, benzodiazepines should be considered primarily for desired ultra short-term sedation of acutely agitated patients but not for augmentation of antipsychotics in the medium- and long-term pharmacotherapy of schizophrenia and related disorders.
Although several polymorphisms in olanzapine-metabolizing enzymes have been identified, the clear role and benefit for pharmacotherapy remain uncertain. The aim of the study was to investigate the ...potential influence of polymorphisms in the CYP1A2 gene (*1D,*1F), in the UGT1A4 gene (*3), and in the POR gene (rs2302429) on olanzapine serum concentrations and the clinical outcome.
Ninety-eight white inpatients who received olanzapine as part of their treatment for at least 4 weeks were included in the retrospective investigation. Moreover, a sample of 209 inpatients receiving olanzapine or clozapine was built to investigate the influence of the relevant polymorphisms CYP1A2*1F, *1D, and CYP1A2 inducers on the clinical outcome.
Carriers of the delT-allele (*1D) developed significantly higher dose-corrected olanzapine serum concentrations (analysis of covariance; P < 0.001, delT + delTdelT: 3.1, TT: 1.6 ng·mL·mg, adjusted model including the confounding factors age, sex, baseline weight, CYP1A2*1F genotype, and concomitant CYP1A2 inducers). Moreover, the CYP1A2*1F (AA) genotype also revealed a significant impact on olanzapine serum concentrations according to the analysis of covariance model (P = 0.028; CC + CA: 2.05, AA: 1.44 ng·mL·mg). The other polymorphisms studied revealed no significant influence. Regarding response and adverse effects, a higher increase of weight could be observed in schizophrenic Paranoid Depressive Scale (responder: +5.7 vs nonresponder: +1.8 kg; P = 0.007) and Clinical Global Impression responders (4.6 vs 1.8 kg; P = 0.017). No direct correlation between olanzapine serum concentrations and response or weight gain could be detected. Patients with at least 2 factors promoting higher serum concentrations (no CYP1A2 inducer, *1D deltT-allele, or *1F C-allele) showed a better response according to the Paranoid Depressive Scale (P = 0.002) and a significant correlation with the Clinical Global Impression Scale-2 after 4 weeks (n = 193, r = -0.177; P = 0.005).
We, for the first time, identified a significant influence of polymorphisms in CYP1A2 in combination with CYP1A2 inducer status on the clinical outcome. Therefore, genotyping for CYP1A2*1D and *1F may be a useful tool for dose optimization and identification of high-risk patients. Further and larger studies are needed before genotype-based dosage recommendations can help patients treated with CYP1A2 metabolized drugs.
IntroductionMany antidepressants are indicated for the treatment of major depression. Two network meta-analyses have provided the most comprehensive assessments to date, accounting for both direct ...and indirect comparisons; however, these reported conflicting interpretation of results. Here, we present a protocol for a systematic review and network meta-analysis aimed at updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression.Methods and analysisWe will include all randomised controlled trials reported as double-blind and comparing one active drug with another or with placebo in the acute phase treatment of major depression in adults. We are interested in comparing the following active agents: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The main outcomes will be the proportion of patients who responded to or dropped out of the allocated treatment. Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least two independent reviewers. We will conduct a random effects network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. To rank the various treatments for each outcome, we will use the surface under the cumulative ranking curve and the mean ranks. We will employ local as well as global methods to evaluate consistency. We will fit our model in a Bayesian framework using OpenBUGS, and produce results and various checks in Stata and R. We will also assess the quality of evidence contributing to network estimates of the main outcomes with the GRADE framework.Ethics and disseminationThis review does not require ethical approval.PROSPERO registration numberCRD42012002291.
Compliance with antipsychotic medication is a major issue in schizophrenia treatment, and noncompliance with antipsychotic treatment is closely related to relapse and rehospitalization. An enhanced ...involvement of patients with schizophrenia in treatment decisions ("shared decision making") is expected to improve long-term compliance and reduce rehospitalizations. The aim of the present analysis was to study whether shared decision making (SDM) in antipsychotic drug choice would influence long-term outcome.
From February 2003 to January 2004, psychiatric state hospital inpatients with a diagnosis of schizophrenia (ICD-10; N = 107) were recruited for the trial using a cluster-randomized controlled design. An SDM program on antipsychotic drug choice consisting of a decision aid and a planning talk between patient and physician was compared with routine care with respect to long-term compliance and rehospitalizations (6-month and 18-month follow-up).
On the whole, we found high rates of noncompliance and rehospitalization. There were no differences between intervention and control groups in the univariate analyses. However, when controlling for confounding factors in a multivariate analysis, there was a positive trend (p = .08) that patients in the SDM intervention had fewer rehospitalizations. Additionally, a higher desire of the patient for autonomy and better knowledge at discharge were associated with higher hospitalization rates.
The intervention studied showed a positive trend but no clear beneficial effect on long-term outcomes. A more thorough implementation of SDM (e.g., iterative administration of decision aid) might yield larger effects. Those patients with higher participation preferences are at higher risk for poor treatment outcomes and therefore require special attention. Strategies to match these patients' needs might improve compliance and long-term outcomes.
Cognitive impairment in schizophrenia represents one of the main obstacles to clinical and functional recovery. This expert group paper brings together experts in schizophrenia treatment to discuss ...scientific progress in the domain of cognitive impairment to address cognitive impairments and their consequences in the most effective way. We report on the onset and course of cognitive deficits, linking them to the alterations in brain function and structure in schizophrenia and discussing their role in predicting the transition to psychosis in people at risk. We then address the assessment tools with reference to functioning and social cognition, examining the role of subjective measures and addressing new methods for measuring functional outcomes including technology based approaches. Finally, we briefly review treatment options for cognitive deficits, focusing on cognitive remediation programs, highlighting their effects on brain activity and conclude with the potential benefit of individualized integrated interventions combing cognitive remediation with other approaches.
To understand what given scores of the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS) mean from a clinical point of view is important for the translation ...of research results into practice. We therefore (a) compared the absolute change of the BPRS/PANSS with the Clinical Global Impressions Ratings (CGI) -improvement score and the change of the CGI severity score, (b) analyzed whether the severity of illness at baseline had an impact on the latter association, and (c) attempted to replicate previous BPRS findings using a completely different data set based upon the PANSS-derived BPRS. The method used was equipercentile linking of BPRS and CGI ratings from 14 drug trials in acutely ill patients with schizophrenia (n=5970). An absolute reduction of the BPRS/PANSS by approximately 10/15 points corresponded to a CGI change of 'minimally improved' and to a change of the CGI severity score by one severity step. However, the latter associations depended on the severity of symptoms at baseline. Less severely ill patients required less BPRS/PANSS total score reduction to achieve the same CGI-improvement score than more severely ill patients. This effect of initial severity was attenuated using percentage rather than absolute BPRS/PANSS reduction scores. The linking analysis between the absolute BPRS/PANSS reduction and the CGI may have an implication for the interpretation of efficacy differences found in clinical trials, and for sample size estimations. Clinicians seem to base CGI ratings on relative change rather than on absolute change of symptoms.
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