Antipsychotic drug efficacy may have decreased over recent decades. The authors present a meta-analysis of all placebo-controlled trials in patients with acute exacerbations of schizophrenia, and ...they investigate which trial characteristics have changed over the years and which are moderators of drug-placebo efficacy differences.
The search included multiple electronic databases. The outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects. Potential moderators of efficacy were analyzed by meta-regression.
The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time.
Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response. Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response. Drug development may benefit from smaller samples but better-selected patients.
Summary Background Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which ...drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people. Methods We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefined data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023. Findings We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference −0·51, 95% credible interval CrI −0·99 to −0·03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio OR 0·31, 95% CrI 0·13 to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I2 values were 33·21% for efficacy and 0% for tolerability. Interpretation When considering the risk–benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated. Funding National Basic Research Program of China (973 Program).
Summary Background The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy ...based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs. Methods We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. Findings We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73–1·03; amisulpride 0·66, 0·53–0·78; olanzapine 0·59, 0·53–0·65; risperidone 0·56, 0·50–0·63; paliperidone 0·50, 0·39–0·60; zotepine 0·49, 0·31–0·66; haloperidol 0·45, 0·39–0·51; quetiapine 0·44, 0·35–0·52; aripiprazole 0·43, 0·34–0·52; sertindole 0·39, 0·26–0·52; ziprasidone 0·39, 0·30–0·49; chlorpromazine 0·38, 0·23–0·54; asenapine 0·38, 0·25–0·51; lurasidone 0·33, 0·21–0·45; and iloperidone 0·33, 0·22–0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from −0·09 for the best drug (haloperidol) to −0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to −1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to −0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses. Interpretation Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines. Funding None.
Summary Background Because of the debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs, we did a meta-analysis of randomised controlled ...trials to compare the effects of these two types of drugs in patients with schizophrenia. Methods We compared nine second-generation antipsychotic drugs with first-generation drugs for overall efficacy (main outcome), positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and sedation. Findings We included 150 double-blind, mostly short-term, studies, with 21 533 participants. We excluded open studies because they systematically favoured second-generation drugs. Four of these drugs were better than first-generation antipsychotic drugs for overall efficacy, with small to medium effect sizes (amisulpride −0·31 95% CI −0·44 to −0·19, p<0·0001, clozapine −0·52 −0·75 to −0·29, p<0·0001, olanzapine −0·28 −0·38 to −0·18, p<0·0001, and risperidone −0·13 −0·22 to −0·05, p=0·002). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Therefore efficacy on negative symptoms cannot be a core component of atypicality. Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses). Only a few have been shown to induce fewer extrapyramidal side-effects than low-potency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs. The second-generation drugs also differed in their sedating properties. We did not note any consistent effects of moderator variables, such as industry sponsorship, comparator dose, or prophylactic antiparkinsonian medication. Interpretation Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. This meta-analysis provides data for individualised treatment based on efficacy, side-effects, and cost. Funding National Institute of Mental Health.
The authors examined the safety and efficacy of antidepressants added to antipsychotic drugs in the treatment of schizophrenia.
Multiple databases and previous publications were searched through June ...2015 to identify all randomized controlled trials of any add-on antidepressants compared with placebo or no-treatment in schizophrenia. Depressive and negative symptoms (primary outcomes), overall symptoms, positive symptoms, side effects, exacerbation of psychosis, and responder rates were examined. Subgroup, meta-regression, and sensitivity analyses were performed, as well as investigations of publication bias and risk of bias.
Eighty-two randomized controlled trials with a total of 3,608 participants were included. Add-on antidepressants appeared more efficacious than controls for depressive symptoms (standardized mean difference: -0.25, 95% CI=-0.38 to -0.12), negative symptoms (standardized mean difference: -0.30, 95% CI=-0.44 to -0.16), overall symptoms (standardized mean difference: -0.24, 95% CI=-0.39 to -0.09), positive symptoms (standardized mean difference: -0.17, 95% CI=-0.33 to -0.01), quality of life (standardized mean difference: -0.32, 95% CI=-0.57 to -0.06), and responder rate (risk ratio: 1.52, 95% CI=1.29 to 1.78; number-needed-to-treat-to-benefit: 5, 95% CI=4 to 7). The effects on depressive and negative symptoms appeared more pronounced when minimum thresholds of these symptoms were inclusion criteria (standardized mean difference: -0.34, 95% CI=-0.58 to -0.09 and standardized mean difference: -0.58, 95% CI=-0.94 to -0.21, respectively). There were no significant differences between antidepressants and controls in terms of exacerbation of psychosis, premature discontinuation, and the number of participants with at least one adverse event. More patients taking add-on antidepressants suffered from abdominal pain, constipation, dizziness, and dry mouth.
Analysis of primary outcomes (depressive and negative symptoms) suggests small, beneficial effects of adjunctive antidepressants. It would appear that this augmentation can be accomplished with a low risk of exacerbation of psychosis and adverse effects. However, secondary and subgroup analyses should be interpreted cautiously and considered exploratory.
Depression is the single largest contributor to non-fatal health loss worldwide. Second-generation antidepressants are the first-line option for pharmacological management of depression. Optimising ...their use is crucial in reducing the burden of depression; however, debate about their dose dependency and their optimal target dose is ongoing. We have aimed to summarise the currently available best evidence to inform this clinical question.
We did a systematic review and dose-response meta-analysis of double-blind, randomised controlled trials that examined fixed doses of five selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, paroxetine, and sertraline), venlafaxine, or mirtazapine in the acute treatment of adults (aged 18 years or older) with major depression, identified from the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, MEDLINE, PsycINFO, AMED, PSYNDEX, websites of drug licensing agencies and pharmaceutical companies, and trial registries. We imposed no language restrictions, and the search was updated until Jan 8, 2016. Doses of SSRIs were converted to fluoxetine equivalents. Trials of antidepressants for patients with depression and a serious concomitant physical illness were excluded. The main outcomes were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects), and acceptability (dropouts for any reasons), all after a median of 8 weeks of treatment (range 4–12 weeks). We used a random-effects, dose-response meta-analysis model with flexible splines for SSRIs, venlafaxine, and mirtazapine.
28 554 records were identified through our search (24 524 published and 4030 unpublished records). 561 published and 121 unpublished full-text records were assessed for eligibility, and 77 studies were included (19 364 participants; mean age 42·5 years, SD 11·0; 7156 60·9% of 11 749 reported were women). For SSRIs (99 treatment groups), the dose-efficacy curve showed a gradual increase up to doses between 20 mg and 40 mg fluoxetine equivalents, and a flat to decreasing trend through the higher licensed doses up to 80 mg fluoxetine equivalents. Dropouts due to adverse effects increased steeply through the examined range. The relationship between the dose and dropouts for any reason indicated optimal acceptability for the SSRIs in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents. Venlafaxine (16 treatment groups) had an initially increasing dose-efficacy relationship up to around 75–150 mg, followed by a more modest increase, whereas for mirtazapine (11 treatment groups) efficacy increased up to a dose of about 30 mg and then decreased. Both venlafaxine and mirtazapine showed optimal acceptability in the lower range of their licensed dose. These results were robust to several sensitivity analyses.
For the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression.
Japan Society for the Promotion of Science, Swiss National Science Foundation, and National Institute for Health Research.
Summary Background Relapse prevention with antipsychotic drugs compared with placebo in patients with schizophrenia has not been sufficiently addressed by previous systematic reviews. We aimed to ...assess the association between such drugs and various outcomes in patients with schizophrenia to resolve controversial issues. Methods We searched the Cochrane Schizophrenia Group's specialised register for reports published before Nov 11, 2008; and PubMed, Embase, and ClinicalTrials.gov for those before June 8, 2011. We also contacted pharmaceutical companies and searched the reference lists of included studies and previous reviews. Randomised trials of patients with schizophrenia continued on or withdrawn from any antipsychotic drug regimen after stabilisation were eligible. Our primary outcome was relapse between 7 and 12 months. We also examined safety and various functional outcomes. We used the random effects model and verified results for the primary outcome with a fixed effects model. Heterogeneity was investigated with subgroup and meta-regression analyses. Findings We identified 116 suitable reports from 65 trials, with data for 6493 patients. Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27% vs placebo 64%; risk ratio RR 0·40, 95% CI 0·33–0·49; number needed to treat to benefit NNTB 3, 95% CI 2–3). Fewer patients given antipsychotic drugs than placebo were readmitted (10% vs 26%; RR 0·38, 95% CI 0·27–0·55; NNTB 5, 4–9), but less than a third of relapsed patients had to be admitted. Limited evidence suggested better quality of life (standardised mean difference −0·62, 95% CI −1·15 to −0·09) and fewer aggressive acts (2% vs 12%; RR 0·27, 95% CI 0·15–0·52; NNTB 11, 6–100) with antipsychotic drugs than with placebo. Employment data were scarce and too few deaths were reported to allow significant differences to be identified. More patients given antipsychotic drugs than placebo gained weight (10% vs 6%; RR 2·07, 95% CI 2·31–3·25), had movement disorders (16% vs 9%; 1·55, 1·25–1·93), and experienced sedation (13% vs 9%; 1·50, 1·22–1·84). Substantial heterogeneity in size of effect was recorded. In subgroup analyses, number of episodes, whether patients were in remission, abrupt or gradual withdrawal of treatment, length of stability before trial entry, first-generation or second-generation drugs, and allocation concealment method did not significantly affect relapse risk. Depot preparations reduced relapse (RR 0·31, 95% CI 0·21–0·41) more than did oral drugs (0·46, 0·37–0·57; p=0·03); depot haloperidol (RR 0·14, 95% CI 0·04–0·55) and fluphenazine (0·23, 0·14–0·39) had the greatest effects. The effects of antipsychotic drugs were greater in two unblinded trials (0·26, 0·17–0·39) than in most blinded studies (0·42, 0·35–0·51; p= 0·03). In a meta-regression, the difference between drug and placebo decreased with study length. Interpretation Maintenance treatment with antipsychotic drugs benefits patients with schizophrenia. The advantages of these drugs must be weighed against their side-effects. Future studies should focus on outcomes of social participation and clarify the long-term morbidity and mortality of these drugs. Funding German Ministry of Education and Research.
Multivariate pattern recognition approaches have recently facilitated the search for reliable neuroimaging-based biomarkers in psychiatric disorders such as schizophrenia. By taking into account the ...multivariate nature of brain functional and structural changes as well as their distributed localization across the whole brain, they overcome drawbacks of traditional univariate approaches. To evaluate the overall reliability of neuroimaging-based biomarkers, we conducted a comprehensive literature search to identify all studies that used multivariate pattern recognition to identify patterns of brain alterations that differentiate patients with schizophrenia from healthy controls. A bivariate random-effects meta-analytic model was implemented to investigate the sensitivity and specificity across studies as well as to assess the robustness to potentially confounding variables. In the total sample of n=38 studies (1602 patients and 1637 healthy controls), patients were differentiated from controls with a sensitivity of 80.3% (95% CI: 76.7-83.5%) and a specificity of 80.3% (95% CI: 76.9-83.3%). Analysis of neuroimaging modality indicated higher sensitivity (84.46%, 95% CI: 79.9-88.2%) and similar specificity (76.9%, 95% CI: 71.3-81.6%) of rsfMRI studies as compared with structural MRI studies (sensitivity: 76.4%, 95% CI: 71.9-80.4%, specificity of 79.0%, 95% CI: 74.6-82.8%). Moderator analysis identified significant effects of age (p=0.029), imaging modality (p=0.019), and disease stage (p=0.025) on sensitivity as well as of positive-to-negative symptom ratio (p=0.022) and antipsychotic medication (p=0.016) on specificity. Our results underline the utility of multivariate pattern recognition approaches for the identification of reliable neuroimaging-based biomarkers. Despite the clinical heterogeneity of the schizophrenia phenotype, brain functional and structural alterations differentiate schizophrenic patients from healthy controls with 80% sensitivity and specificity.
A significant number of patients with schizophrenia do not respond adequately to an initial antipsychotic trial. As first step within a treatment algorithm for therapy-refractory schizophrenia ...‘pseudoresistance’ should be ruled out (eg, re-evaluation of the diagnosis, comorbidities, compliance and adherence in terms of medication intake, adequate dose and treatment duration, and achievement of sufficient plasma levels). In case of treatment resistance, two strategies that are often used in clinical routine care contain dose increase of the current administered antipsychotic drug (dose escalation, high-dose treatment) and switch to another, new antipsychotic. Although the response rates for both options are generally rather low, we see from the evidence-based perspective a slight advantage of the switching strategy (preferably to an antipsychotic with a different receptor-binding profile) compared to a high-dose treatment. After treatment failures with at least two different antipsychotic drugs, a monotherapy with clozapine is considered to be the treatment option of first choice. At present, pharmacological combination and augmentation strategies cannot be regarded as a generally recommendable evidence-based treatment method. Antipsychotic monotherapy should be preferably sought. In case of combination treatment, it appears more appropriate to combine preferentially two antipsychotics with different receptor-binding profiles. Augmentation of antipsychotics with other agents should be used primarily to treat specific target symptoms.
The concept of dose equivalence is important for many purposes. The classical approach published by Davis in 1974 subsequently dominated textbooks for several decades. It was based on the assumption ...that the mean doses found in flexible-dose trials reflect the average optimum dose which can be used for the calculation of dose equivalence. We are the first to apply the method to second-generation antipsychotics.
We searched for randomized, double-blind, flexible-dose trials in acutely ill patients with schizophrenia that examined 13 oral second-generation antipsychotics, haloperidol, and chlorpromazine (last search June 2014). We calculated the mean doses of each drug weighted by sample size and divided them by the weighted mean olanzapine dose to obtain olanzapine equivalents.
We included 75 studies with 16 555 participants. The doses equivalent to 1 mg/d olanzapine were: amisulpride 38.3 mg/d, aripiprazole 1.4 mg/d, asenapine 0.9 mg/d, chlorpromazine 38.9 mg/d, clozapine 30.6 mg/d, haloperidol 0.7 mg/d, quetiapine 32.3mg/d, risperidone 0.4 mg/d, sertindole 1.1 mg/d, ziprasidone 7.9 mg/d, zotepine 13.2 mg/d. For iloperidone, lurasidone, and paliperidone no data were available.
The classical mean dose method is not reliant on the limited availability of fixed-dose data at the lower end of the effective dose range, which is the major limitation of "minimum effective dose methods" and "dose-response curve methods." In contrast, the mean doses found by the current approach may have in part depended on the dose ranges chosen for the original trials. Ultimate conclusions on dose equivalence of antipsychotics will need to be based on a review of various methods.
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