Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis.

A significant clinical issue encountered after a successful acute major depressive disorder (MDD) treatment is the relapse of depressive symptoms. Although continuing maintenance therapy with antidepressants is generally recommended, there is no established protocol on whether or not it is necessary to prescribe the antidepressant used to achieve remission. In this meta-analysis, the risk of relapse and treatment failure when either continuing with the same drug used to achieved remission or switching to a placebo was assessed in several clinically significant subgroups. The pooled odds ratio (OR) (±95% confidence intervals (CI)) was calculated using a random effects model. Across 40 studies (n = 8890), the relapse rate was significantly lower in the antidepressant group than the placebo group by about 20% (OR = 0.38, CI: 0.33-0.43, p < 0.00001; 20.9% vs 39.7%). The difference in the relapse rate between the antidepressant and placebo groups was greater for tricyclics (25.3%; OR = 0.30, CI: 0.17-0.50, p < 0.00001), SSRIs (21.8%; OR = 0.33, CI: 0.28-0.38, p < 0.00001), and other newer agents (16.0%; OR = 0.44, CI: 0.36-0.54, p < 0.00001) in that order, while the effect size of acceptability was greater for SSRIs than for other antidepressants. A flexible dose schedule (OR = 0.30, CI: 0.23-0.48, p < 0.00001) had a greater effect size than a fixed dose (OR = 0.41, CI: 0.36-0.48, p < 0.00001) in comparison to placebo. Even in studies assigned after continuous treatment for more than 6 months after remission, the continued use of antidepressants had a lower relapse rate than the use of a placebo (OR = 0.40, CI: 0.29-0.55, p < 0.00001; 20.2% vs 37.2%). The difference in relapse rate was similar from a maintenance period of 6 months (OR = 0.41, CI: 0.35-0.48, p < 0.00001; 19.6% vs 37.6%) to over 1 year (OR = 0.35, CI: 0.29-0.41, p < 0.00001; 19.9% vs 39.8%). The all-cause dropout of antidepressant and placebo groups was 43% and 58%, respectively, (OR = 0.47, CI: 0.40-0.55, p < 0.00001). The tolerability rate was ~4% for both groups. The rate of relapse (OR = 0.32, CI: 0.18-0.64, p = 0.0010, 41.0% vs 66.7%) and all-cause dropout among adolescents was higher than in adults. To prevent relapse and treatment failure, maintenance therapy, and careful attention for at least 6 months after remission is recommended. SSRIs are well-balanced agents, and flexible dose adjustments are more effective for relapse prevention.

Effect of lithium on circadian rhythm in bipolar disorder: A systematic review and meta-analysis.

OBJECTIVES: Circadian rhythm disruption is commonly reported in patients with bipolar disorder. Lithium has been suggested to have effects on the circadian clock, the biological basis of the circadian rhythm. The objective of the current review was to review systematically the existing studies on the effect of lithium on circadian rhythm in patients with bipolar disorder. METHODS: We systematically searched the scientific literature up to September 2020 for experimental or observational studies which measured circadian rhythm in bipolar patients taking lithium (in comparison with placebo or other active treatments) and carried out a meta-analysis. Circadian rest-activity was our primary outcome, but we also collected data about sleep quality and chronotype (Morningness-Eveningness). The protocol was registered in PROSPERO (CRD42018109790). RESULTS: Four observational studies (n = 668) and one experimental study (n = 29) were included. Results from the meta-analysis suggest a potential association between lithium and shifts towards morningness (standardized mean difference [SMD]: 0.42, 95% confidence interval [CI]: -0.05 to 0.90). One cohort study with 21 days of follow-up found that patients treated with lithium had significantly larger amplitude (0.68, 0.01 to 1.36) when compared to anticonvulsants. CONCLUSION: This review highlights the insufficient evidence to inform us about the effect of lithium on circadian rhythm. However, we found that chronotype can be a potential target for further exploration of biomarkers or biosignatures of lithium treatment in patients with bipolar disorder. Further studies with prospective and longitudinal study design, adopting actigraphy to monitor daily circadian rest-activity changes are needed.

Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.

BACKGROUND: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. METHODS: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. FINDINGS: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. INTERPRETATION: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. FUNDING: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

Optimising first- and second-line treatment strategies for untreated major depressive disorder - the SUN☺D study: a pragmatic, multi-centre, assessor-blinded randomised controlled trial.

BACKGROUND: For patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline strategies remain unestablished. METHODS: This multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixed-model repeated-measures analysis adjusted for key baseline covariates. RESULTS: Between December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9 score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), - 0.58 to 1.07, P = 0.55). Other outcomes proved similar in the two groups. In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine (n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points (0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage of remission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects. CONCLUSIONS: In patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs 50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 by switching sertraline to mirtazapine or by adding mirtazapine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01109693 . Registered on 23 April 2010.

Miscellaneous treatments for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. This review, one in a series examining the treatment of TD, covers miscellaneous treatments not covered elsewhere. OBJECTIVES: To determine whether drugs, hormone-, dietary-, or herb-supplements not covered in other Cochrane reviews on TD treatments, surgical interventions, electroconvulsive therapy, and mind-body therapies were effective and safe for people with antipsychotic-induced TD. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including trial registers (16 July 2015 and 26 April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We included reports if they were randomised controlled trials (RCTs) dealing with people with antipsychotic-induced TD and schizophrenia or other chronic mental illnesses who remained on their antipsychotic medication and had been randomly allocated to the interventions listed above versus placebo, no intervention, or any other intervention. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We included 31 RCTs of 24 interventions with 1278 participants; 22 of these trials were newly included in this 2017 update. Five trials are awaiting classification and seven trials are ongoing. All participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. Studies were primarily of short (three to six6 weeks) duration with small samples size (10 to 157 participants), and most (61%) were published more than 20 years ago. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment, generation of the sequence, and blinding.Nineteen of the 31 included studies reported on the primary outcome 'No clinically important improvement in TD symptoms'. Two studies found moderate-quality evidence of a benefit of the intervention compared with placebo: valbenazine (RR 0.63, 95% CI 0.46 to 0.86, 1 RCT, n = 92) and extract of Ginkgo biloba (RR 0.88, 95% CI 0.81 to 0.96, 1 RCT, n = 157), respectively. However, due to small sample sizes we cannot be certain of these effects.We consider the results for the remaining interventions to be inconclusive: Low- to very low-quality evidence of a benefit was found for buspirone (RR 0.53, 95% CI 0.33 to 0.84, 1 RCT, n = 42), dihydrogenated ergot alkaloids (RR 0.45, 95% CI 0.21 to 0.97, 1 RCT, n = 28), hypnosis or relaxation, (RR 0.45, 95% CI 0.21 to 0.94, 1 study, n = 15), pemoline (RR 0.48, 95% CI 0.29 to 0.77, 1 RCT, n = 46), promethazine (RR 0.24, 95% CI 0.11 to 0.55, 1 RCT, n = 34), insulin (RR 0.52, 95% CI 0.29 to 0.96, 1 RCT, n = 20), branched chain amino acids (RR 0.79, 95% CI 0.63 to 1.00, 1 RCT, n = 52), and isocarboxazid (RR 0.24, 95% CI 0.08 to 0.71, 1 RCT, n = 20). There was low- to very low-certainty evidence of no difference between intervention and placebo or no treatment for the following interventions: melatonin (RR 0.89, 95% CI 0.71 to 1.12, 2 RCTs, n = 32), lithium (RR 1.59, 95% CI 0.79 to 3.23, 1 RCT, n = 11), ritanserin (RR 1.00, 95% CI 0.70 to 1.43, 1 RCT, n = 10), selegiline (RR 1.37, 95% CI 0.96 to 1.94, 1 RCT, n = 33), oestrogen (RR 1.18, 95% CI 0.76 to 1.83, 1 RCT, n = 12), and gamma-linolenic acid (RR 1.00, 95% CI 0.69 to 1.45, 1 RCT, n = 16).None of the included studies reported on the other primary outcome, 'no clinically significant extrapyramidal adverse effects'. AUTHORS' CONCLUSIONS: This review has found that the use of valbenazine or extract of Ginkgo biloba may be effective in relieving the symptoms of tardive dyskinesia. However, since only one RCT has investigated each one of these compounds, we are awaiting results from ongoing trials to confirm these results. Results for the remaining interventions covered in this review must be considered inconclusive and these compounds probably should only be used within the context of a well-designed evaluative study.

Effect of Recruitment Methods on Response Rate in a Web-Based Study for Primary Care Physicians: Factorial Randomized Controlled Trial.

BACKGROUND: Low participation rates are one of the most serious disadvantages of Web-based studies. It is necessary to develop effective strategies to improve participation rates to obtain sufficient data. OBJECTIVE: The objective of this trial was to investigate the effect of emphasizing the incentive in the subject line of the invitation email and the day of the week of sending the invitation email on the participation rate in a Web-based trial. METHODS: We conducted a 2×2 factorial design randomized controlled trial. We contacted 2000 primary care physicians from members of the Japan Primary Care Association in January 2017 and randomly allocated them to 1 of 4 combinations of 2 subject lines (presence or absence of an emphasis on a lottery for an Amazon gift card worth 3000 yen or approximately US $30) and 2 delivery days (sending the invitation email on Tuesday or Friday). The primary outcome was the response rate defined as the number of participants answering the first page of the questionnaire divided by the number of invitation emails delivered. All outcomes were collected between January 17, 2017, and February 8, 2017. RESULTS: We analyzed data from 1943 out of 2000 participants after excluding those whose email addresses were invalid. The overall response rate was 6.3% (123/1943). There was no significant difference in the response rates between the 2 groups regarding incentive in the subject line: the risk ratio was 1.12 (95% CI 0.80 to 1.58) and the risk difference was 0.7% (95% CI -1.5% to 2.9%). Similarly, there was no significant difference in the response rates between the 2 groups regarding sending the email on Tuesday or Friday: the risk ratio was 0.98 (95% CI 0.70 to 1.38) and the risk difference was -0.1% (95% CI -2.3% to 2.1%). CONCLUSIONS: Neither emphasizing the incentive in the subject line of the invitation email nor varying the day of the week the invitation email was sent led to a meaningful increase in response rates in a Web-based trial with primary care physicians. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000025317; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000029121 (Archived by WebCite at http://www.webcitation. org/6wOo1jl9t).

Behavioural therapies versus other psychological therapies for depression.

BACKGROUND: Behavioural therapies represent one of several categories of psychological therapies that are currently used in the treatment of depression. However, the effectiveness and acceptability of behavioural therapies for depression compared with other psychological therapies remain unclear. OBJECTIVES: 1. To examine the effects of all BT approaches compared with all other psychological therapy approaches for acute depression.2. To examine the effects of different BT approaches (behavioural therapy, behavioural activation, social skills training and relaxation training) compared with all other psychological therapy approaches for acute depression.3. To examine the effects of all BT approaches compared with different psychological therapy approaches (CBT, third wave CBT, psychodynamic, humanistic and integrative psychological therapies) for acute depression. SEARCH METHODS: We searched the Cochrane Depression Anxiety and Neurosis Group Trials Specialised Register (CCDANCTR, 31/07/2013), which includes relevant randomised controlled trials from The Cochrane Library (all years), EMBASE, (1974-), MEDLINE (1950-) and PsycINFO (1967-). We also searched CINAHL (May 2010) and PSYNDEX (June 2010) and reference lists of the included studies and relevant reviews for additional published and unpublished studies. SELECTION CRITERIA: Randomised controlled trials that compared behavioural therapies with other psychological therapies for acute depression in adults. DATA COLLECTION AND ANALYSIS: Two or more review authors independently identified studies, assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Twenty-five trials involving 955 participants compared behavioural therapies with one or more of five other major categories of psychological therapies (cognitive-behavioural, third wave cognitive-behavioural, psychodynamic, humanistic and integrative therapies). Most studies had a small sample size and were assessed as being at unclear or high risk of bias. Compared with all other psychological therapies together, behavioural therapies showed no significant difference in response rate (18 studies, 690 participants, risk ratio (RR) 0.97, 95% confidence interval (CI) 0.86 to 1.09) or in acceptability (15 studies, 495 participants, RR of total dropout rate 1.02, 95% CI 0.65 to 1.61). Similarly, in comparison with each of the other classes of psychological therapies, low-quality evidence showed better response to cognitive-behavioural therapies than to behavioural therapies (15 studies, 544 participants, RR 0.93, 95% CI 0.83 to 1.05) and low-quality evidence of better response to behavioural therapies over psychodynamic therapies (2 studies, 110 participants, RR 1.24, 95% CI 0.84 to 1.82).When compared with integrative therapies and humanistic therapies, only one study was included in each comparison, and the analysis showed no significant difference between behavioural therapies and integrative or humanistic therapies. AUTHORS' CONCLUSIONS: We found low- to moderate-quality evidence that behavioural therapies and other psychological therapies are equally effective. The current evidence base that evaluates the relative benefits and harms of behavioural therapies is very weak. This limits our confidence in both the size of the effect and its precision for our key outcomes related to response and withdrawal. Studies recruiting larger samples with improved reporting of design and fidelity to treatment would improve the quality of evidence in this review.

'Third wave' cognitive and behavioural therapies versus treatment as usual for depression.

BACKGROUND: So-called 'third wave' cognitive and behavioural therapies represent a new generation of psychological therapies that are increasingly being used in the treatment of psychological problems. However, the effectiveness and acceptability of third-wave cognitive and behavioural therapy (CBT) approaches as treatment for acute depression remain unclear. OBJECTIVES: 1. To examine the effects of all third wave CBT approaches compared with treatment as usual/waiting list/attention placebo/psychological placebo control conditions for acute depression.2. To examine the effects of different third wave CBT approaches (ACT, compassionate mind training, functional analytic psychotherapy, dialectical behaviour therapy, MBCT, extended behavioural activation and metacognitive therapy) compared with treatment as usual/waiting list/attention placebo/psychological placebo control conditions for acute depression.3. To examine the effects of all third wave CBT approaches compared with different types of comparators (treatment as usual, no treatment, waiting list, attention placebo, psychological placebo) for acute depression. SEARCH METHODS: We searched the Cochrane Depression Anxiety and Neurosis Group Trials Specialised Register (CCDANCTR to 01/01/12), which includes relevant randomised controlled trials from The Cochrane Library (all years), EMBASE, (1974-), MEDLINE (1950-) and PsycINFO (1967-). We also searched CINAHL (May 2010) and PSYNDEX (June 2010) and reference lists of the included studies and relevant reviews for additional published and unpublished studies. An updated search of CCDANCTR restricted to search terms relevant to third wave CBT therapies was conducted in March 2013 (CCDANCTR to 01/02/13). SELECTION CRITERIA: Randomised controlled trials that compared third wave CBT therapies with control conditions for acute depression in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently identified studies, assessed trial quality and extracted data. Study authors were contacted for additional information when required. We rated the quality of evidence using GRADE methods. MAIN RESULTS: Four small studies (224 participants) were included in the review. Little information was provided about the process of allocating participants to groups. None of the studies used independent outcome assessors, and evidence suggested researcher allegiance towards the active treatments. The four studies examined a diversity of third wave CBT approaches (extended behavioural activation, acceptance and commitment therapy and competitive memory training) and control conditions. None of the studies conducted follow-up assessments. The results showed a significant difference in clinical response rates in favour of third wave CBT when compared with treatment as usual (TAU) conditions (three studies, 170 participants, risk ratio (RR) 0.51, 95% confidence interval (CI) 0.27 to 0.95; very low quality). No significant difference in treatment acceptability based on dropout rates was found between third wave CBT approaches and TAU (four studies, 224 participants, RR 1.01, 95% CI 0.08 to 12.30; very low quality). Both analyses showed substantial statistical heterogeneity. AUTHORS' CONCLUSIONS: Very low quality evidence suggests that third wave CBT approaches appear to be more effective than treatment as usual in the treatment of acute depression. The very small number of available studies and the diverse types of interventions and control comparators, together with methodological limitations, limit the ability to draw any conclusions on their effect in the short term or over a longer term. The increasing popularity of third wave CBT approaches in clinical practice underscores the importance of completing further studies of third wave CBT approaches in the treatment of acute depression, on a short- and long-term basis, to provide evidence of their effectiveness to policy-makers, clinicians and users of services.

Availability of virtual-assisted lung mapping affects procedure selection for early-stage lung cancer: a web-based cross-sectional study.

OBJECTIVES: The availability of new techniques may affect surgeons' procedure selection and thereby affect clinical outcomes. This study aimed to evaluate the effect of the availability of virtual-assisted lung mapping (VAL-MAP) on the selection of lung resection methods. METHODS: Members of the Japanese Association for Chest Surgeons were invited to participate in a web-based survey. Participants were divided into those who had never used VAL-MAP (group 0), those who had used only VAL-MAP 1.0 (multiple dye marks on the pleural surface; group 1) and those who had used VAL-MAP 2.0 (multiple dye marks and intrabronchial microcoils for three-dimensional mapping; group 2). Participants were shown chest computed tomography images of 6 ground-glass opacity nodules and asked to choose surgical procedures to resect the nodules with sufficient resection margins greater than the lesion diameter or 2 cm. RESULTS: There were 197 surgeons in group 0, 49 in group 1 and 26 in group 2. All groups showed a similar trend of avoiding wedge resection for deeply located nodules. However, group 1 showed a trend of disagreeing with the selection of wedge resection compared with group 0 as measured by a Likert scale (1-5) by -0.21 points (95% confidence interval, -0.41 to -0.008 points, P = 0.042). This tendency disappeared in group 2. CONCLUSIONS: The availability of VAL-MAP 1.0 led to the selection of segmentectomy, while the availability of VAL-MAP 2.0 led to aggressive deep wedge resection.

Assessment of blinding in randomized controlled trials of antidepressants for depressive disorders 2000-2020: A systematic review and meta-analysis.

Background: In double-blind randomized controlled trials (RCTs) of antidepressants, blinding can be broken due to the apparent side effects, and unsuccessful blinding can lead to overestimation of effect sizes. New generation antidepressants with less severe side effects may be less susceptible to broken blinding. However, successfulness of blinding in new generation antidepressant trials and its influence on trial effect size estimates remain unclear. Methods: Extending a previous systematic review assessing blinding successfulness in psychiatric trials (2000-2010), we searched PubMed/Medline for double-blinded antidepressant RCTs (2010-2020) for trials assessing blinding success. Our primary outcome was the degree of blinding successfulness, measured as kappa statistics between guesses and true allocations. We used random-effects meta-analysis to synthesize studies. We used meta-regression and Pearson's r to examine the relationship between blinding success and effect sizes. This study is registered with PROSPERO (CRD42021249973). Findings: Among 154 eligible studies, 11 (7·1%) contained information on blinding assessment between 2010 and 2020. Five studies were added from the previous review, and altogether nine of the 16 studies provided usable data. Agreement in individual studies ranged from κ=-0·14 to 0·38. The summary agreement between guesses and the truth was 0·21 (95% CI: 0·14 to 0·28) among patients and 0·17 (95% CI: 0·05 to 0·30) among assessors. Blinding success was not associated with effect size (patients: r = 0·37, p = 0·32; assessors: r = 0·28; p = 0·72). Meta-regression also failed to find a significant relationship between blinding success and depression effect sizes (ß=0·06, p = 0·09). Interpretation: Less than 10% of the antidepressant RCTs reported blinding assessment. The results in new generation antidepressant trials indicated that patients and assessors were unlikely to be able to judge treatment allocation. There was little evidence that the extent of unblinding biased the effect size estimates of new generation antidepressants. Funding: None.

Initial treatment choices to achieve sustained response in major depression: a systematic review and network meta-analysis.

Major depression is often a relapsing disorder. It is therefore important to start its treatment with therapies that maximize the chance of not only getting the patients well but also keeping them well. We examined the associations between initial treatments and sustained response by conducting a network meta-analysis of randomized controlled trials (RCTs) in which adult patients with major depression were randomized to acute treatment with a psychotherapy (PSY), a protocolized antidepressant pharmacotherapy (PHA), their combination (COM), standard treatment in primary or secondary care (STD), or pill placebo, and were then followed up through a maintenance phase. By design, acute phase treatment could be continued into the maintenance phase, switched to another treatment or followed by discretionary treatment. We included 81 RCTs, with 13,722 participants. Sustained response was defined as responding to the acute treatment and subsequently having no depressive relapse through the maintenance phase (mean duration: 42.2±16.2 weeks, range 24-104 weeks). We extracted the data reported at the time point closest to 12 months. COM resulted in more sustained response than PHA, both when these treatments were continued into the maintenance phase (OR=2.52, 95% CI: 1.66-3.85) and when they were followed by discretionary treatment (OR=1.80, 95% CI: 1.21-2.67). The same applied to COM in comparison with STD (OR=2.90, 95% CI: 1.68-5.01 when COM was continued into the maintenance phase; OR=1.97, 95% CI: 1.51-2.58 when COM was followed by discretionary treatment). PSY also kept the patients well more often than PHA, both when these treatments were continued into the maintenance phase (OR=1.53, 95% CI: 1.00-2.35) and when they were followed by discretionary treatment (OR=1.66, 95% CI: 1.13-2.44). The same applied to PSY compared with STD (OR=1.76, 95% CI: 0.97-3.21 when PSY was continued into the maintenance phase; OR=1.83, 95% CI: 1.20-2.78 when PSY was followed by discretionary treatment). Given the average sustained response rate of 29% on STD, the advantages of PSY or COM over PHA or STD translated into risk differences ranging from 12 to 16 percentage points. We conclude that PSY and COM have more enduring effects than PHA. Clinical guidelines on the initial treatment choice for depression may need to be updated accordingly.

Physician characteristics associated with proper assessment of overstated conclusions in research abstracts: A secondary analysis of a randomized controlled trial.

OBJECTIVES: Little is known about the physician characteristics associated with appraisal skills of research evidence, especially the assessment of the validity of study methodology. This study aims to explore physician characteristics associated with proper assessment of overstated conclusions in research abstracts. DESIGN: A secondary analysis of a randomized controlled trial. SETTING AND PARTICIPANTS: We recruited 567 volunteers from the Japan Primary Care Association. METHODS: Participants were randomly assigned to read the abstract of a research paper, with or without an overstatement, and to rate its validity. Our primary outcome was proper assessment of the validity of its conclusions. We investigated the association of physician characteristics and proper assessment using logistic regression models and evaluated the interaction between the associated characteristics and overstatement. RESULTS: We found significant associations between proper assessment and post-graduate year (odds ratio [OR] = 0.67, 95% confidence interval [CI] 0.49 to 0.91, for every 10-year increase) and research experience as a primary investigator (PI; OR = 2.97, 95% CI 1.65 to 5.34). Post-graduate year and PI had significant interaction with overstatement (P = 0.015 and < 0.001, respectively). Among participants who read abstracts without an overstatement, post-graduate year was not associated with proper assessment (OR = 1.04, 95% CI 0.82 to 1.33), and PI experience was associated with lower scores of the validity (OR = 0.58, 95% CI 0.35 to 0.96). CONCLUSION: Physicians who have been in practice longer should be trained in distinguishing overstatements in abstract conclusions. Physicians with research experience might be informed that they tend to rate the validity of research lower regardless of the presence or absence of overstatements. TRIAL REGISTRATION: UMIN000026269.

Exploratory analyses of effect modifiers in the antidepressant treatment of major depression: Individual-participant data meta-analysis of 2803 participants in seven placebo-controlled randomized trials.

BACKGROUND: It is clinically important to know who are likely to respond more or less to antidepressants. However, meaningful effect modifiers (variables associated with differential response depending on the treatment) are yet to be identified. METHODS: We conducted individual participant data (IPD) meta-analysis and meta-regression to explore effect modifiers in placebo-controlled antidepressant trials conducted so far in Japan. RESULTS: We obtained access to IPD from seven placebo-controlled trials comparing bupropion, duloxetine, escitalopram, mirtazapine, paroxetine or venlafaxine with placebo in the acute phase treatment of major depression (total n = 2803). The higher the guilt subscale score of the baseline Hamilton Rating Scale for Depression (HRSD), the greater the difference in reduction in depression severity between the antidepressants and placebo at week 6, while the older the current age or the age at onset, the smaller the difference. At week 8, the guilt subscale score of HRSD and presence of suicidal ideation at baseline predicted greater, and the anhedonia subscale and insomnia subscale scores of HRSD and early response at week 2 predicted smaller, difference in reduction. LIMITATIONS: Different studies measured different sets of baseline variables and we were able to analyze only a limited set of candidate variables for effect modification. CONCLUSION: Age, age at onset, several HRSD subscales including guilt, anhedonia and insomnia, presence of suicidal ideation at baseline and early response are potential effect modifiers for response to antidepressants in the acute phase antidepressant treatment of major depression. Future trials need to measure these and additional variables in concerted efforts to enable matching of treatments with individual characteristics in depression.

Development and validation of a prediction model for the probability of responding to placebo in antidepressant trials: a pooled analysis of individual patient data.

BACKGROUND: Identifying potential placebo responders among apparent drug responders is critical to dissect drug-specific and nonspecific effects in depression. OBJECTIVE: This project aimed to develop and test a prediction model for the probability of responding to placebo in antidepressant trials. Such a model will allow us to estimate the probability of placebo response among drug responders in antidepressants trials. METHODS: We identified all placebo-controlled, double-blind randomised controlled trials (RCTs) of second generation antidepressants for major depressive disorder conducted in Japan and requested their individual patient data (IPD) to pharmaceutical companies. We obtained IPD (n=1493) from four phase II/III RCTs comparing mirtazapine, escitalopram, duloxetine, paroxetine and placebo. Out of 1493 participants in the four clinical trials, 440 participants allocated to placebo were included in the analyses. Our primary outcome was response, defined as 50% or greater reduction on Hamilton Rating Scale for Depression at study endpoint. We used multivariable logistic regression to develop a prediction model. All available candidate of predictor variables were tested through a backward variable selection and covariates were selected for the prediction model. The performance of the model was assessed by using Hosmer-Lemeshow test for calibration and the area under the ROC curve for discrimination. FINDINGS: Placebo response rates differed between 31% and 59% (grand average: 43%) among four trials. Four variables were selected from all candidate variables and included in the final model: age at onset, age at baseline, bodily symptoms, and study-level difference. The final model performed satisfactorily in terms of calibration (Hosmer-Lemeshow p=0.92) and discrimination (the area under the ROC curve (AUC): 0.70). CONCLUSIONS: Our model is expected to help researchers discriminate individuals who are more likely to respond to placebo from those who are less likely so. CLINICAL IMPLICATIONS: A larger sample and more precise individual participant information should be collected for better performance. Examination of external validity in independent datasets is warranted. TRIAL REGISTRATION NUMBER: CRD42017055912.

Comparative efficacy and acceptability of antidepressants in the long-term treatment of major depression: protocol for a systematic review and networkmeta-analysis.

INTRODUCTION: Pharmacotherapy plays an important role in the treatment of major depression. At the initiation of antidepressant treatment, both improvement of symptoms in the short term and relapse prevention in the long term should be taken into account. However, there is insufficient evidence regarding the efficacy and the acceptability of continuation/maintenance treatments and the relative efficacy/acceptability of antidepressants. OBJECTIVE: We will conduct a pairwise meta-analysis and a network meta-analysis (NMA) to examine the relative efficacy, tolerability and acceptability of antidepressants in the long-term treatment of major depression. METHODS AND ANALYSIS: We will include double-blind randomised controlled trials comparing any of the following antidepressants, which we included in our previous NMA of the acute treatment for major depression, with placebo or with another active drug for long-term treatment of major depression: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. Our primary outcomes will be sustained response and all-cause dropouts. We will include four types of designs that are used to investigate long-term treatment. We will conduct two main analyses. First, we will conduct a pairwise meta-analysis comparing all antidepressants versus placebo to investigate whether continuing antidepressants after achieving a positive response in the acute-phase treatment is beneficial and/or safe. Second, we will conduct an NMA to examine the comparative efficacy and acceptability of the drugs. We will use a novel approach that will combine the results of acute-phase treatment NMA with long-term treatment studies to include all related designs in the NMA. We will ensure the validity of combining different designs and our new approach by checking the distribution of important effect modifiers and consistency of network. ETHICS AND DISSEMINATION: This study did not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42018114561; Pre-results.

Comparative Efficacy and Acceptability of 21 Antidepressant Drugs for the Acute Treatment of Adults With Major Depressive Disorder: A Systematic Review and Network Meta-Analysis.

(Reprinted with permission from Lancet 2018; 391:1357-66).

Overstatements in abstract conclusions claiming effectiveness of interventions in psychiatry: A meta-epidemiological investigation.

OBJECTIVE: Abstracts of scientific reports are sometimes criticized for exaggerating significant results when compared to the corresponding full texts. Such abstracts can mislead the readers. We aimed to conduct a systematic review of overstatements in abstract conclusions in psychiatry trials. METHODS: We searched for randomized controlled trials published in 2014 that explicitly claimed effectiveness of any intervention for mental disorders in their abstract conclusion, using the Cochrane Register of Controlled Trials. Claims of effectiveness in abstract conclusion were categorized into three types: superiority (stating superiority of intervention to control), limited superiority (intervention has limited superiority), and equal efficactiveness (claiming equal effectiveness of intervention with standard treatment control), and full text results into three types: significant (all primary outcomes were statistically significant in favor of the intervention), mixed (primary outcomes included both significant and non-significant results), or all results non-significant. By comparing these classifications, we assessed whether each abstract was overstated. Our primary outcome was the proportion of overstated abstract conclusions. RESULTS: We identified and included 60 relevant trials. 20 out of 60 studies (33.3%) showed overstatements. Nine reports reported only significant results although none of their primary outcomes were significant. Large sample size (>300) and publication in high impact factor (IF>10) journals were associated with low occurrence of overstatements. CONCLUSIONS: We found that one in three psychiatry studies claiming effectiveness in their abstract conclusion, either superior to control or equal to standard treatment, for any mental disorders were overstated in comparison with the full text results. Readers of the psychiatry literature are advised to scrutinize the full text results regardless of the claims in the abstract. TRIAL REGISTRATION: University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000018668).

Influence of overstated abstract conclusions on clinicians: a web-based randomised controlled trial.

OBJECTIVES: To investigate whether overstatements in abstract conclusions influence primary care physicians' evaluations when they read reports of randomised controlled trials (RCTs) DESIGN: RCT setting: This study was a parallel-group randomised controlled survey, conducted online while masking the study hypothesis. PARTICIPANTS: Volunteers were recruited from members of the Japan Primary Care Association in January 2017. We sent email invitations to 7040 primary care physicians. Among the 787 individuals who accessed the website, 622 were eligible and automatically randomised into 'without overstatement' (n=307) and 'with overstatement' (n=315) groups. INTERVENTIONS: We selected five abstracts from published RCTs with at least one non-significant primary outcome and overstatement in the abstract conclusion. To construct a version without overstatement, we rewrote the conclusion sections. The methods and results sections were standardised to provide the necessary information of primary outcome information when it was missing in the original abstract. Participants were randomly assigned to read an abstract either with or without overstatements and asked to evaluate the benefit of the intervention. OUTCOME MEASURES: The primary outcome was the participants' evaluation of the benefit of the intervention discussed in the abstract, on a scale from 0 to 10. A secondary outcome was the validity of the conclusion. RESULTS: There was no significant difference between the groups with respect to their evaluation of the benefit of the intervention (mean difference: 0.07, 95% CI -0.28 to 0.42, p=0.69). Participants in the 'without' group considered the study conclusion to be more valid than those in the 'with' group (mean difference: 0.97, 95% CI 0.59 to 1.36, P<0.001). CONCLUSION: The overstatements in abstract conclusions did not significantly influence the primary care physicians' evaluations of the intervention effect when necessary information about the primary outcomes was distinctly reported. TRIAL REGISTRATION NUMBER: UMIN000025317; Pre-results.

Overstatements in abstract conclusions claiming effectiveness of interventions in psychiatry: a study protocol for a meta-epidemiological investigation.

INTRODUCTION: Abstracts are the major and often the most important source of information for readers of the medical literature. However, there is mounting criticism that abstracts often exaggerate the positive findings and emphasise the beneficial effects of intervention beyond the actual findings mentioned in the corresponding full texts. In order to examine the magnitude of this problem, we will introduce a systematic approach to detect overstated abstracts and to quantify the extent of their prevalence in published randomised controlled trials (RCTs) in the field of psychiatry. METHODS AND ANALYSIS: We will source RCTs published in 2014 from the Cochrane Register of Controlled Trials (CENTRAL) that claim effectiveness of any intervention for mental disorders. The abstract conclusions will be categorised into three types: superior (only stating significant superiority of intervention to control), limited (suggesting that intervention has limited superiority to control) and equal (claiming equal effectiveness of intervention as control). The full texts will also be classified as one of the following based on the primary outcome results: significant (all primary outcomes were statistically significant in favour of the intervention), mixed (primary outcomes included both significant and non-significant results) or all non-significant results. By comparing the abstract conclusion classification and that of the corresponding full text, we will assess whether each study exhibited overstatements in its abstract conclusion. ETHICS AND DISSEMINATION: This trial requires no ethical approval. We will publish our findings in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000018668; Pre-results.