Ichiro M Omori

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.

Psychotherapy for depression among children and adolescents: a systematic review.

Objective:  To examine the clinical benefit, the harm and the cost‐effectiveness of psychotherapies in comparison with no treatment, waiting‐list controls, attention‐placebos, and treatment as usual in depressed youths.

Safety Reporting and Adverse-Event Profile of Mirtazapine Described in Randomized Controlled Trials in Comparison with Other Classes of Antidepressants in the Acute-Phase Treatment of Adults with Depression Systematic Review and Meta-Analysis

Background: Mirtazapine has a unique mechanism of antidepressant action, and thus is thought to have a different profile of adverse events from that of other antidepressants.Objective: To present a methodologically rigorous systematic review of the adverse event profile of mirtazapine and point to possible problems with safety reporting in randomized controlled trials (RCTs) of the acute-phase treatment of major depression in adults with mirtazapine in comparison with other types of antidepressant.Methods: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register was electronically searched using the following search terms: ‘depress*rs’, ‘dysthymi*’, ‘adjustment disorder*’, ‘mood disorder*’, ‘affective disorder’, ‘affective symptoms’ and ‘mirtazapine’. Pharmaceutical companies and experts in this field were contacted, and the reference lists of the relevant RCTs were checked, for additional data. No language restriction was imposed. Two authors independently assessed the quality of trials for inclusion in the review. Disagreements were resolved by consensus. Two authors independently extracted data on adverse events. Disagreements were resolved by consensus. The adequacy of safety reporting was assessed by one author.Regarding the adequacy of safety reporting, the qualitative and quantitative parameters of safety reporting were determined. Regression analyses were conducted to assess characteristics of trials influencing safety reporting.The primary and secondary outcomes in the systematic review of the adverse events associated with mirtazapine were defined as the proportion of patients having each of 43 adverse events listed in the modified version of the WHO Adverse Reaction Terminology, and the proportion of patients experiencing at least one adverse event, respectively. Meta-analyses were conducted for these outcomes.Results: Twenty-five RCTs involving 4842 patients were identified as meeting our inclusion criteria. With regard to safety reporting, only two trials and no trials were rated as ‘adequate’ in terms of the reporting of clinical adverse events and laboratory-determined toxicity, respectively. The proportion of text in the results sections of the study reports devoted to safety reporting was a mean of 22%. No associations were observed between the adequacy of safety reporting and any characteristics of the trials; however, sample size over 100 participants in total and over 50 subjects in a study arm, double blindness and sponsorship by the company marketing mirtazapine were significantly associated with a greater number of reported adverse events in mirtazapine recipients.In terms of individual adverse events, mirtazapine was significantly less likely to cause hypertension or tachycardia (risk ratio [RR] 0.51) and tremor (RR 0.43) than tricyclic antidepressants (TCAs). In comparison with selective serotonin uptake inhibitors (SSRIs), mirtazapine was significantly more likely to cause weight gain or increased appetite (RR 3.68), increased salivation (RR 3.66), somnolence (RR 1.62) and fatigue (RR 1.45), but less likely to cause flatulence (RR 0.26), sweating (RR 0.28), sexual dysfunction (RR 0.34), tremor (RR 0.37), nausea or vomiting (RR 0.40), sleep disturbance (RR 0.55) and diarrhoea (RR 0.61). In comparison with the serotonin-noradrenaline (norepinephrine) reuptake inhibitor (SNRI) venlafaxine, mirtazapine was significantly more likely to cause fatigue (RR 2.02), but less likely to cause sleep disturbance (RR 0.03), sweating (RR 0.03) and constipation (RR 0.25). Relative to trazodone, mirtazapine was significantly more likely to cause weight gain or increased appetite (RR 4.00). Approximately 70% of patients treated with mirtazapine experienced at least one adverse event, with no significant difference in comparison with other antidepressants.Conclusions: The study confirmed the paucity of adequate safety reporting in trials comparing mirtazapine with other types of antidepressant in the acute-phase treatment of depression in adults. Based on the available evidence, mirtazapine appears to have a unique adverse-event profile. Using these findings, clinicians can inform their patients, not only of the simple frequency of adverse events with mirtazapine, but also of the relative difference in the frequency of adverse events in comparison with that of other antidepressants, to aid pragmatic clinical decisions.

Changes after behavior therapy among responsive and nonresponsive patients with obsessive-compulsive disorder

Neuroimaging studies have suggested that behavior therapy (BT) might change abnormal activity in the frontal-subcortical circuits of the brain in patients with obsessive-compulsive disorder (OCD). However, the results of these studies have been rather inconsistent. The aim of the present study was to use statistical parametric mapping (SPM) analysis to explore the effects of successful BT on regional cerebral blood flow (rCBF) in patients with OCD. Forty-five OCD patients who were treatment-resistant to a single serotonin reuptake inhibitor (SRI) trial were examined. Single photon emission computed tomography (SPECT) using 99mTc-ECD was performed before and after the completion of 12 weeks of BT. Although no significant differences in pre-treatment rCBF were observed between responders and nonresponders to BT, the post-treatment rCBF values in the left medial prefrontal cortex (Brodmann area 10) and bilateral middle frontal gyri (Brodmann area 10) were significantly lower in the responders than in the nonresponders. Furthermore, the baseline rCBF in the bilateral orbitofrontal cortex (OFC) was significantly correlated with the change in the Y-BOCS score among the responders. Our results support the hypothesis that while the OFC may be associated with the BT response, BT may result in changes in rCBF in the medial and middle frontal cortex.

Distinct neuropsychological profiles of three major symptom dimensions in obsessive-compulsive disorder.

Recent neuroimaging studies have suggested that different symptom dimensions are mediated by partially distinct neural systems in obsessive-compulsive disorder (OCD). However, the correlations between neuropsychological profiles and symptom dimensions in OCD are unknown. The aim of this study was to examine the extent to which OCD symptom dimensions were associated with episodic memory and attention and executive functions. The symptom dimensions of 63 patients with OCD were assessed using both the Padua Inventory and the Y-BOCS symptom checklist. Then, we administered the Logical Memory (LM) subset of the Wechsler Memory Scale-Revised (WMR-R) test and evaluated inhibition (Stroop test, Trail Making test) and cognitive flexibility (Digit Symbol test, Letter Fluency, and Category Fluency). While associations were observed between scores on the contamination/cleaning dimension and better performances on the LM and Trail Making tests, associations were also observed between scores on the aggressive/checking dimension and poorer performances on the Trail Making test. In addition, we found that scores on the symmetry/ordering dimension were associated with poorer performances on the LM and Trail Making tests. Our results support the hypothesis that different symptoms may represent distinct and partially overlapping neurocognitive networks in OCD patients.

Efficacy and Tolerability of Milnacipran in the Treatment of Major Depression in Comparison with Other Antidepressants : A Systematic Review and Meta-Analysis

AbstractBackground: Milnacipran, a dual serotonin-noradrenaline reuptake inhibitor, is one of the newer antidepressants that clinicians use for the routine care of patients with major depression. We undertook a systematic review and meta-analysis of randomized controlled trials that compared the efficacy and tolerability of milnacipran with other antidepressants. Objective: To assess the efficacy and tolerability of milnacipran in comparison with TCAs, SSRIs and other drugs in the acute phase of treatment for major depression. Methods: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials registers, journals, conference proceedings, trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished randomized controlled trials that compared the efficacy and adverse events of milnacipran versus any other antidepressant. The search was conducted in December 2006 and updated in May 2007. No language restrictions were applied. All relevant authors were contacted to supplement any incomplete reporting in the original papers.Randomized controlled trials comparing milnacipran with any other active antidepressants as monotherapy in the acute phase of treatment for major depression were selected. Participants were aged ≥18 years, of both sexes and with a primary diagnosis of unipolar major depression. Studies were excluded when the participants had specific psychiatric and medical co-morbidities. Two independent reviewers assessed the quality of trials for inclusion, and subsequently extracted data. Disagreements were resolved by consensus. Meta-analyses were conducted for efficacy and tolerability outcomes. Sixteen randomized controlled trials (n = 2277) were included in the meta-analyses. Results: No differences were found in achieving clinical improvement, remission or overall tolerability when comparing milnacipran with other antidepressants. However, compared with the TCAs, fewer patients taking milnacipran were early treatment withdrawals due to adverse events (number needed to harm (NNH) = 15; 95% CI 10, 48). Significantly more patients taking TCAs experienced adverse events compared with milnacipran (NNH = 4; 95% CI 3, 7). Conclusions: The overall effectiveness and tolerability of milnacipran versus other antidepressants does not seem to differ in the acute phase of treatment for major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of premature withdrawal due to adverse events and the rates of patients experiencing adverse events. Milnacipran may benefit some patient populations who experience adverse effects from other antidepressants in the acute phase of treatment for major depression.

Can pill placebo augment cognitive-behavior therapy for panic disorder?

BackgroundIn a number of drug and psychotherapy comparative trials, psychotherapy-placebo combination has been assumed to represent psychotherapy. Whether psychotherapy plus pill placebo is the same as psychotherapy alone is an empirical question which however has to date never been examined systematically.MethodsWe conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) that directly compared cognitive-behavior therapy (CBT) alone against CBT plus pill placebo in the treatment of panic disorder.ResultsExtensive literature search was able to identify three relevant RCTs. At the end of the acute phase treatment, patients who received CBT plus placebo had 26% (95%CI: 2 to 55%) increased chances of responding than those who received CBT alone. At follow-up the difference was no longer statistically significant (22%, 95%CI: -10% to 64%).ConclusionThe act of taking a pill placebo may enhance the placebo effect already contained in the effective psychotherapeutic intervention during the acute phase treatment. Theoretically this is an argument against the recently claimed null hypothesis of placebo effect in general and clinically it may point to some further room for enhancing the psychotherapeutic approach for panic disorder.

Efficacy, tolerability and side-effect profile of fluvoxamine for major depression: meta-analysis.

Abstract Fluvoxamine, one of the oldest selective serotonin reuptaking inhibitors, is commonly prescribed to patients with major depression. Several studies have reviewed the efficacy and tolerability of fluvoxamine for the treatment of major depression. However, these reviews are outdated, have not been systematic and/or suffered from several methodological weaknesses. We conducted a systematic review to synthesize the best available evidence on the efficacy of fluvoxamine for adult patients suffering from major depression in comparison with other active antidepressive agents. Relevant randomized controlled trials were identified through a comprehensive search. The primary outcome was a relative risk of response, and the secondary outcome was a relative risk of remission. Tolerability and side-effect profile were also examined. Fifty-three trials were included. There were no large differences between fluvoxamine and any other antidepressants in terms of efficacy and tolerability. There is evidence of differing side effect profiles, especially when comparing gastrointestinal side effects between fluvoxamine and tricyclics. Clinicians should focus on practically or clinically relevant differences including those in side-effect profiles.

Sulpiride Augmentation for Schizophrenia

Jijun Wang, Ichiro M. Omori, Mark Fenton, and Bernardo Soares Department of EEG Source Imaging, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wan Ping NanRoad,Shanghai200030,Shanghai,China; CochraneSchizophreniaGroup,UniversityofNottingham,Nottingham,UK;Databaseof Uncertainties about the Effects of Treatments (DUETs), James Lind Initiative, Oxford, UK; Brazilian Cochrane Centre, Universidade Federal de Sao Paulo, Sao Paulo, Brazil

Making the best use of available evidence: the case of new generation antidepressants A response to: Are all antidepressants equal?

In this issue of Evidence-Based Mental Health , Gartlehner and Gaynes1 comment (see page 98) on our recently published systematic review2 that investigated the comparative efficacy and acceptability of 12 new generation antidepressants (see page 107) . In their view, methodological shortcomings limit the validity of our results and the conclusions reached. In this commentary, our aim is to explain the rationale for doing this systematic review, outline its main findings and address the points raised by Gartlehner and Gaynes.1 Scientific debate can illuminate and clarify complex analyses and we are, therefore, delighted to respond to their critique. While we consider that some of the issues raised are substantive and merit reasoned response, we also believe that some of their criticisms seem rather overstated. We understand that Gartlehner and Gaynes too have published an analysis comparing antidepressants and we note that this is now the third occasion on which they have published similar criticisms of our work.3 ,4 In most countries, demonstration of a difference against placebo, and not against an active comparator, makes a new drug eligible for registration. The European Medicines Agency, for example, is willing to evaluate new antidepressants in the absence of comparison with active existing treatments.5 In situations where no (or a few) active treatments are available, this may not be important. In the field of antidepressants, however, where many potentially effective agents are already available, this process has serious implications. The approval of a new antidepressant as effective and safe in comparison solely with placebo allows the marketing of new drugs that may, in fact, be potentially more effective, similarly effective or even less effective than others currently in use. Many antidepressants have never been directly compared with each other. The picture is further complicated by …