Atsuo Nakagawa

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.

Pharmacological Strategies to Counteract Antipsychotic-Induced Weight Gain and Metabolic Adverse Effects in Schizophrenia: A Systematic Review and Meta-analysis

BACKGROUND Antipsychotic-induced metabolic adversities are often difficult to manage. Using concomitant medications to counteract these adversities may be a rational option. OBJECTIVE To systematically determine the effectiveness of medications to counteract antipsychotic-induced metabolic adversities in patients with schizophrenia. DATA SOURCES Published articles until November 2013 were searched using 5 electronic databases. Clinical trial registries were searched for unpublished trials. STUDY SELECTION Double-blind randomized placebo-controlled trials focusing on patients with schizophrenia were included if they evaluated the effects of concomitant medications on antipsychotic-induced metabolic adversities as a primary outcome. DATA EXTRACTION Variables relating to participants, interventions, comparisons, outcomes, and study design were extracted. The primary outcome was change in body weight. Secondary outcomes included clinically relevant weight change, fasting glucose, hemoglobin A1c, fasting insulin, insulin resistance, cholesterol, and triglycerides. DATA SYNTHESIS Forty trials representing 19 unique interventions were included in this meta-analysis. Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to -3.17 kg (95% CI: -4.44 to -1.90 kg) compared to placebo. Pooled effects for topiramate, sibutramine, aripiprazole, and reboxetine were also different from placebo. Furthermore, metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids. CONCLUSION When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia.

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.

Pathway to psychiatric care in Japan: A multicenter observational study.

BackgroundThis study examines pathways to psychiatric care in Japan using the same method as the collaborative study carried out in 1991 under the auspices of the World Health Organization.MethodsThirteen psychiatric facilities in Japan were involved. Of the 228 patients who contacted psychiatric facilities with any psychiatric illness, eighty four visiting psychiatric facilities for the first time were enrolled. Pathways to psychiatric care, delays from the onset of illness to treatment prior to reaching psychiatrists were surveyed.ResultsThirty three patients (39.4%) directly accessed mental health professionals, 32 patients (38.1%) reached them via general hospital, and 13 patients (15.5%) via private practitioners. The patients who consulted mental health professionals as their first carers took a longer time before consulting psychiatrists than the patients who consulted non-mental health professionals as their first carers. The patients who presented somatic symptoms as their main problem experienced longer delay from the onset of illness to psychiatric care than the patients who complained about depressive or anxiety symptoms. Prior to the visit to mental health professionals, patients were rarely informed about their diagnosis and did not receive appropriate treatments from their physicians. Private practitioners were more likely to prescribe psychotropics than physicians in general hospitals, but were less likely to inform their patients of their diagnosis.ConclusionThis first pathway to psychiatric care study in Japan demonstrated that referral pathway in Japan heavily relies on medical resources. The study indicates possible fields and gives indications, underlining the importance of improving skills and knowledge that will facilitate the recognition of psychiatric disorders presenting with somatic and depressive symptoms in the general health care system and by private practitioners.

Comorbid anxiety in bipolar disorder: does it have an independent effect on suicidality?

OBJECTIVE Comorbid anxiety disorder is reported to increase suicidality in bipolar disorder. However, studies of the impact of anxiety disorders on suicidal behavior in mood disorders have shown mixed results. The presence of personality disorders, often comorbid with anxiety and bipolar disorders, may explain these inconsistencies. This study examined the impact of comorbid Cluster B personality disorder and anxiety disorder on suicidality in bipolar disorder. METHODS A total of 116 depressed bipolar patients with and without lifetime anxiety disorder were compared. Multiple regression analysis tested the association of comorbid anxiety disorder with past suicide attempts and severity of suicidal ideation, adjusting for the effect of Cluster B personality disorder. The specific effect of panic disorder was also explored. RESULTS Bipolar patients with and without anxiety disorders did not differ in the rate of past suicide attempt. Suicidal ideation was less severe in those with anxiety disorders. In multiple regression analysis, anxiety disorder was not associated with past suicide attempts or with the severity of suicidal ideation, whereas Cluster B personality disorder was associated with both. The results were comparable when comorbid panic disorder was examined. CONCLUSIONS Comorbid Cluster B personality disorder appears to exert a stronger influence on suicidality than comorbid anxiety disorder in persons with bipolar disorder. Assessment of suicide risk in patients with bipolar disorder should include evaluation and treatment of Cluster B psychopathology.

A community intervention trial of multimodal suicide prevention program in Japan: A Novel multimodal Community Intervention program to prevent suicide and suicide attempt in Japan, NOCOMIT-J

BackgroundTo respond to the rapid surge in the incidence of suicide in Japan, which appears to be an ongoing trend, the Japanese Multimodal Intervention Trials for Suicide Prevention (J-MISP) have launched a multimodal community-based suicide prevention program, NOCOMIT-J. The primary aim of this study is to examine whether NOCOMIT-J is effective in reducing suicidal behavior in the community.Methods/DesignThis study is a community intervention trial involving seven intervention regions with accompanying control regions, all with populations of statistically sufficient size. The program focuses on building social support networks in the public health system for suicide prevention and mental health promotion, intending to reinforce human relationships in the community. The intervention program components includes a primary prevention measures of awareness campaign for the public and key personnel, secondary prevention measures for screening of, and assisting, high-risk individuals, after-care for individuals bereaved by suicide, and other measures. The intervention started in July 2006, and will continue for 3.5 years. Participants are Japanese and foreign residents living in the intervention and control regions (a total of population of 2,120,000 individuals).DiscussionThe present study is designed to evaluate the effectiveness of the community-based suicide prevention program in the seven participating areas.Trial registrationUMIN Clinical Trials Registry (UMIN-CTR) UMIN000000460.

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.

Effectiveness of a Multimodal Community Intervention Program to Prevent Suicide and Suicide Attempts: A Quasi-Experimental Study

Background Multilevel and multimodal interventions have been suggested for suicide prevention. However, few studies have reported the outcomes of such interventions for suicidal behaviours. Methods We examined the effectiveness of a community-based multimodal intervention for suicide prevention in rural areas with high suicide rates, compared with a parallel prevention-as-usual control group, covering a total of 631,133 persons. The effectiveness was also examined in highly populated areas near metropolitan cities (1,319,972 persons). The intervention started in July 2006, and continued for 3.5 years. The primary outcome was the incidence of composite outcome, consisting of completed suicides and suicide attempts requiring admission to an emergency ward for critical care. We compared the rate ratios (RRs) of the outcomes adjusted by sex, age group, region, period and interaction terms. Analyses were performed on an intention-to-treat basis and stratified by sex and age groups. Findings In the rural areas, the overall median adherence of the intervention was significantly higher. The RR of the composite outcome in the intervention group decreased 7% compared with that of the control group. Subgroup analyses demonstrated heterogeneous effects among subpopulations: the RR of the composite outcome in the intervention group was significantly lower in males (RR = 0.77, 95% CI 0.59–0.998, p = 0.0485) and the RR of suicide attempts was significantly lower in males (RR = 0.39, 95% CI 0.22–0.68, p = 0.001) and the elderly (RR = 0.35, 95% CI 0.17–0.71, p = 0.004). The intervention had no effect on the RR of the composite outcome in the highly populated areas. Interpretation Our findings suggest that this community-based multimodal intervention for suicide prevention could be implemented in rural areas, but not in highly populated areas. The effectiveness of the intervention was shown for males and for the elderly in rural areas. Trial Registration ClinicalTrials.gov NCT00737165 UMIN Clinical Trials Registry UMIN000000460

Current status of research on cognitive therapy/cognitive behavior therapy in Japan

Cognitive therapy/cognitive behavior therapy was introduced into the field of psychiatry in the late 1980s in Japan, and the Japanese Association for Cognitive Therapy (JACT), founded in 2004, now has more than 1500 members. Along with such progress, awareness of the effectiveness of cognitive therapy/cognitive behavioral therapy has spread, not only among professionals and academics but also to the public. The Study Group of the Procedures and Effectiveness of Psychotherapy, funded by the Ministry of Health, Labor and Welfare, has conducted a series of studies on the effectiveness of cognitive therapy/cognitive behavior therapy since 2006 and shown that it is feasible for Japanese patients. As a result, in April 2010 cognitive therapy/cognitive behavior therapy for mood disorders was added to the national health insurance scheme in Japan. This marked a milestone in Japans psychiatric care, where pharmacotherapy has historically been more common. In this article the authors review research on cognitive therapy/cognitive behavior therapy in Japan.

Cognitive behavioral therapy for depression among adults in Japanese clinical settings: a single-group study

BackgroundEmpirical support for cognitive behavioral therapy (CBT) for treating Japanese patients with major depression is lacking, therefore, a feasibility study of CBT for depression in Japanese clinical settings is urgently required.FindingsA culturally adapted, 16-week manualized individual CBT program for Japanese patients with major depressive disorder was developed. A total of 27 patients with major depression were enrolled in a single-group study with the purpose of testing the feasibility of the program. Twenty six patients (96%) completed the study. The mean total score on the Beck Depression Inventory-II (BDI-II) for all patients (Intention-to-treat sample) improved from 32.6 to 11.7, with a mean change of 20.8 (95% confidence interval: 17.0 to 24.8). Within-group effect size at the endpoint assessment was 2.64 (Cohens d). Twenty-one patients (77.7%) showed treatment response and 17 patients (63.0%) achieved remission at the end of the program. Significant improvement was observed in measurement of subjective and objective depression severity (assessed by BDI-II, Quick Inventory of Depressive Symptomatology-Self Rated, and Hamilton Depression Rating Scale), dysfunctional attitude (assessed by Dysfunctional Attitude Scale), global functioning (assessed by Global Assessment of Functioning of DSM-IV) and subjective well-being (assessed by WHO Subjective Well-being Inventory) (all p values < 0.001).ConclusionsOur manualized treatment comprised of a 16-week individual CBT program for major depression appears feasible and may achieve favorable treatment outcomes among Japanese patients with major depression. Further research involving a larger sample in a randomized, controlled trial design is warranted.Trial registrationUMIN-CTR UMIN000002542.