Andrea Cipriani

Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis

BACKGROUND Conventional meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants. We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirect comparisons, to assess the effects of 12 new-generation antidepressants on major depression. METHODS We systematically reviewed 117 randomised controlled trials (25 928 participants) from 1991 up to Nov 30, 2007, which compared any of the following antidepressants at therapeutic dose range for the acute treatment of unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The main outcomes were the proportion of patients who responded to or dropped out of the allocated treatment. Analysis was done on an intention-to-treat basis. FINDINGS Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine (odds ratios [OR] 1.39, 1.33, 1.30 and 1.27, respectively), fluoxetine (1.37, 1.32, 1.28, and 1.25, respectively), fluvoxamine (1.41, 1.35, 1.30, and 1.27, respectively), paroxetine (1.35, 1.30, 1.27, and 1.22, respectively), and reboxetine (2.03, 1.95, 1.89, and 1.85, respectively). Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine. INTERPRETATION Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost.

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis

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 Groups 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.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial.

BACKGROUND Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder. METHODS 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332. FINDINGS 59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death). INTERPRETATION For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy. FUNDING Stanley Medical Research Institute; Sanofi-Aventis.

Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis.

Objective To assess whether lithium has a specific preventive effect for suicide and self harm in people with unipolar and bipolar mood disorders. Design Systematic review and meta-analysis. Data sources Medline, Embase, CINAHL, PsycINFO, CENTRAL, web based clinical trial registries, major textbooks, authors of important papers and other experts in the discipline, and websites of pharmaceutical companies that manufacture lithium or the comparator drugs (up to January 2013). Inclusion criteria Randomised controlled trials comparing lithium with placebo or active drugs in long term treatment for mood disorders. Review methods Two reviewers assessed studies for inclusion and risk of bias and extracted data. The main outcomes were the number of people who completed suicide, engaged in deliberate self harm, and died from any cause. Results 48 randomised controlled trials (6674 participants, 15 comparisons) were included. Lithium was more effective than placebo in reducing the number of suicides (odds ratio 0.13, 95% confidence interval 0.03 to 0.66) and deaths from any cause (0.38, 0.15 to 0.95). No clear benefits were observed for lithium compared with placebo in preventing deliberate self harm (0.60, 0.27 to 1.32). In unipolar depression, lithium was associated with a reduced risk of suicide (0.36, 0.13 to 0.98) and also the number of total deaths (0.13, 0.02 to 0.76) compared with placebo. When lithium was compared with each active individual treatment a statistically significant difference was found only with carbamazepine for deliberate self harm. Lithium tended to be generally better than the other active comparators, with small statistical variation between the results. Conclusions Lithium is an effective treatment for reducing the risk of suicide in people with mood disorders. Lithium may exert its antisuicidal effects by reducing relapse of mood disorder, but additional mechanisms should also be considered because there is some evidence that lithium decreases aggression and possibly impulsivity, which might be another mechanism mediating the antisuicidal effect.

Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis

BACKGROUND Conventional meta-analyses have shown inconsistent results for efficacy of pharmacological treatments for acute mania. We did a multiple-treatments meta-analysis, which accounted for both direct and indirect comparisons, to assess the effects of all antimanic drugs. METHODS We systematically reviewed 68 randomised controlled trials (16,073 participants) from Jan 1, 1980, to Nov 25, 2010, which compared any of the following pharmacological drugs at therapeutic dose range for the treatment of acute mania in adults: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. The main outcomes were the mean change on mania rating scales and the number of patients who dropped out of the allocated treatment at 3 weeks. Analysis was done by intention to treat. FINDINGS Haloperidol (standardised mean difference [SMD] -0·56 [95% CI -0·69 to -0·43]), risperidone (-0·50 [-0·63 to -0·38), olanzapine (-0·43 [-0·54 to -0·32], lithium (-0·37 [-0·63 to -0·11]), quetiapine (-0·37 [-0·51 to -0·23]), aripiprazole (-0·37 [-0·51 to -0·23]), carbamazepine (-0·36 [-0·60 to -0·11], asenapine (-0·30 [-0·53 to -0·07]), valproate (-0·20 [-0·37 to -0·04]), and ziprasidone (-0·20 [-0·37 to -0·03]) were significantly more effective than placebo, whereas gabapentin, lamotrigine, and topiramate were not. Haloperidol had the highest number of significant differences and was significantly more effective than lithium (SMD -0·19 [95% CI -0·36 to -0·01]), quetiapine (-0·19 [-0·37 to 0·01]), aripiprazole (-0·19 [-0·36 to -0·02]), carbamazepine (-0·20 [-0·36 to -0·01]), asenapine (-0·26 [-0·52 to 0·01]), valproate (-0·36 [-0·56 to -0·15]), ziprasidone -0·36 [-0·56 to -0·15]), lamotrigine (-0·48 [-0·77 to -0·19]), topiramate (-0·63 [-0·84 to -0·43]), and gabapentin (-0·88 [-1·40 to -0·36]). Risperidone and olanzapine had a very similar profile of comparative efficacy, being more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin. Olanzapine, risperidone, and quetiapine led to significantly fewer discontinuations than did lithium, lamotrigine, placebo, topiramate, and gabapentin. INTERPRETATION Overall, antipsychotic drugs were significantly more effective than mood stabilisers. Risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes. These results should be considered in the development of clinical practice guidelines. FUNDING None.

Conceptual and Technical Challenges in Network Meta-analysis

The increase in treatment options creates an urgent need for comparative effectiveness research. Randomized, controlled trials comparing several treatments are usually not feasible, so other methodological approaches are needed. Meta-analyses provide summary estimates of treatment effects by combining data from many studies. However, an important drawback is that standard meta-analyses can compare only 2 interventions at a time. A new meta-analytic technique, called network meta-analysis (or multiple treatments meta-analysis or mixed-treatment comparison), allows assessment of the relative effectiveness of several interventions, synthesizing evidence across a network of randomized trials. Despite the growing prevalence and influence of network meta-analysis in many fields of medicine, several issues need to be addressed when constructing one to avoid conclusions that are inaccurate, invalid, or not clearly justified. This article explores the scope and limitations of network meta-analysis and offers advice on dealing with heterogeneity, inconsistency, and potential sources of bias in the available evidence to increase awareness among physicians about some of the challenges in interpretation.

Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies

Background: It is unclear whether the use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressant drugs reduce the risk of suicide in people with depression. We explored the association between exposure to SSRIs and risk of suicide completion or attempt. Methods: We conducted a systematic review of observational studies that reported completed or attempted suicide in depressed individuals who were exposed to SSRIs compared with those who were not exposed to antidepressants. We assessed the overall risk of completed or attempted suicide. Results: Eight studies involving more than 200 000 patients with moderate or severe depression were included in the meta-analysis. Although exposure to SSRIs increased the risk of completed or attempted suicide among adolescents (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.51–2.44), the risk was decreased among adults (OR 0.57, 95% CI 0.47–0.70). Among people aged 65 or more years, exposure to SSRIs had a protective effect (OR 0.46, 95% CI 0.27–0.79). Sensitivity analyses did not change these findings. In particular, for studies that used completed suicide as an outcome, exposure to SSRIs was associated with increased risk among adolescents (OR 5.81, 95% CI 1.57–21.51) and decreased risk among adults (OR 0.66, 95% CI 0.52–0.83) and older people (OR 0.53, 95% CI 0.26–1.06). Interpretation: Based on data from observational studies, use of SSRIs may be associated with a reduced risk of suicide in adults with depression. Among adolescents, use of SSRIs may increase suicidality.

Imputing response rates from means and standard deviations in meta-analyses

The principle of intention-to-treat analysis must be strictly applied to both individual randomized controlled trial and meta-analysis but, in doing so, would involve imputation of some missing data. There is little literature on how to perform this in the case of meta-analysis. For dichotomous outcome measures, one possible strategy is to carry out a sensitivity analysis based on the so-called best case/worst case analyses. For continuous outcomes, it may be possible to achieve this if we can dichotomise the continuous outcomes. Here, we empirically examined the appropriateness of converting continuous outcomes (expressed as mean±SD) into dichotomous outcomes (expressed as response rates) in four completed meta-analyses of depression and anxiety, assuming normal distribution of the continuous outcome measures. The agreement between the actually observed versus the imputed raw numbers of responders was indicated by an intraclass correlation coefficient of 0.97 (95% confidence interval 0.95–0.98). The pooled relative risks of the four meta-analyses based on the imputed values were virtually identical to those based on the actually observed values. When individual trials report the means±SDs of their outcome measures but fail to report response rates, it may therefore be possible to impute the response rates based on the means±SDs, and then submit the meta-analysis to worst case/best case analyses. This would allow a more robust and clinically interpretable estimation of the true, underlying treatment effect to be made.

Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis.

Background Depression is a common condition that has been frequently treated with psychotropics. Aims To review systematically the evidence of efficacy and acceptability of antidepressant and benzodiazepine treatments for patients with minor depression. Method A systematic review and meta-analysis of double-blind randomised controlled trials comparing antidepressants or benzodiazepines v. placebo in adults with minor depression. Data were obtained from MEDLINE, CINAHL, EMBASE, PsycInfo, Cochrane Controlled Trials Register and pharmaceutical company websites. Risk of bias was assessed for the generation of the allocation sequence, allocation concealment, masking, incomplete outcome data, and sponsorship bias. Results Six studies met inclusion criteria. Three studies compared paroxetine with placebo; fluoxetine, amitriptyline and isocarboxazid were studied in one study each. No studies compared benzodiazepines with placebo. In terms of failures to respond to treatment (6 studies, 234 patients treated with antidepressants and 234 with placebo) no significant difference between antidepressants and placebo was found (relative risk (RR) 0.94, 95% CI 0.81–1.08). In terms of acceptability, data extracted from two studies (93 patients treated with antidepressants and 93 with placebo) showed no statistically significant difference between antidepressants and placebo (RR = 1.06, 95% CI 0.65–1.73). There was no statistically significant between-study heterogeneity for any of the reported analyses. Conclusions There is evidence showing there is unlikely to be a clinically important advantage for antidepressants over placebo in individuals with minor depression. For benzodiazepines, no evidence is available, and thus it is not possible to determine their potential therapeutic role in this condition.