Dynamics of depressive states among university students in Japan during the COVID-19 pandemic: an interrupted time series analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic was reported to have increased depression among university students which was associated with impairments in their campus lives. This study examined changes in depressive states among Japanese university students during the COVID-19 pandemic. METHODS: A secondary data analysis from a factorial randomized controlled trial involving smartphone-based cognitive-behavioral therapy was performed. Six cohorts (N = 1626) underwent an 8-week intervention during the spring or autumn of 2019-2021, with a 9-month follow-up. We evaluated participants' depressive states weekly using the Patient Health Questionnaire-9 (PHQ-9) during the intervention, with monthly evaluations thereafter. The follow-up periods included Japan's four states of emergency (SOEs) to control COVID-19. Hypothesizing that SOEs caused a sudden worsening of depressive states, Study 1 compared the cohorts' PHQ-9 scores, and Study 2 employed time series analysis with a mixed-effects model to estimate identified changes in PHQ-9 scores. RESULTS: Although no changes in depressive states were observed in relation to the SOEs, Study 1 identified sudden increases in PHQ-9 scores at the 28-week evaluation point, which corresponded to the beginning of the new academic year for the three autumn cohorts. In contrast, the three spring cohorts did not exhibit similar changes. Study 2 showed that, for all three autumn cohorts (n = 522), the 0.60-point change was significant (95% CI 0.42-0.78; p < .001) at 28 weeks; that is, when their timeline was interrupted. CONCLUSIONS: While the results do not indicate any notable impact of the SOEs, they highlight the influence of the new academic year on university students' mental health during COVID-19. Trial registration UMIN, CTR-000031307. Registered on February 14, 2018.

No benefit from flexible titration above minimum licensed dose in prescribing antidepressants for major depression: systematic review.

BACKGROUND: In fixed-dose antidepressant trials, the lower range of the licensed dose achieves the optimal balance between efficacy and tolerability. Whether flexible upward titration while side-effects permit provides additional benefits is unknown. METHODS: We did a systematic review of placebo-controlled randomized trials that examined selective serotonin reuptake inhibitors (SSRIs), venlafaxine or mirtazapine in the acute treatment of major depression. Our primary outcome was response, defined as 50% or greater reduction in depression severity. Secondary outcomes included drop-outs due to adverse effects and drop-outs for any reason. We conducted random-effects meta-analyses to calculate the ratios of odds ratios (RORs) between trials comparing the flexible dose titrating above the minimum licensed dose against placebo and those comparing the fixed minimum licensed dose against placebo. RESULTS: We included 123 published and unpublished randomized controlled trials (29 420 participants). There was no evidence supporting efficacy of the flexible dosing over the fixed low dose of SSRIs (ROR 0.96, 95% CI: 0.73 to 1.25), venlafaxine (1.24, 0.96 to 1.60) or mirtazapine (0.77, 0.33 to 1.78). No important differences were noted for tolerability or for any subgroup analyses except the superior efficacy of venlafaxine flexible dosing between 75 and 150 mg over the fixed 75 mg (1.30, 1.02 to 1.65). CONCLUSION: There was no evidence to support added value in terms of efficacy, tolerability or acceptability of flexibly titrating up the dosage over the minimum licensed dose of SSRIs or mirtazapine. For venlafaxine, increased efficacy can be expected by flexibly titrating up to 150 mg.

Trajectory of criterion symptoms of major depression under newly started antidepressant treatment: sleep disturbances and anergia linger on while suicidal ideas and psychomotor symptoms disappear early.

OBJECTIVE: In modern psychiatry, depression is diagnosed with the diagnostic criteria; however, the trajectory of each of the criterion symptoms is unknown. This study aims to examine this. METHODS: We made repeated assessments of the nine diagnostic criterion symptoms with the Patient Health Questionnaire-9 (PHQ-9) among 2011 participants of a 25-week pragmatic randomised controlled trial of sertraline and/or mirtazapine for hitherto untreated major depressive episodes. The changes from baseline were estimated with the mixed-effects model with repeated measures. The time to disappearance of each symptom was modeled using the Kaplan-Meier survival analysis. RESULTS: The total score on PHQ-9 was 18.5 (SD = 3.9, n = 2011) at baseline, which decreased to 15.3 (5.2, n = 2011) at week 1, to 11.5 (5.9, n = 1953) at week 3, to 7.8 (6.0, n = 1927) at week 9, and to 6.0 (5.9, n = 1910) at week 25. Suicidal ideas, psychomotor symptoms decreased rapidly, while anergia and sleep disturbance also decreased but only slowly. The survival analyses confirmed the primary analyses. CONCLUSIONS: Upon initiation of antidepressant treatment, patients with newly treated major depressive episodes can expect their suicidal ideas and psychomotor symptoms to disappear first but sleep disturbances and anergia to linger on.

Differences in the placebo response in duloxetine and venlafaxine trials.

OBJECTIVE: Our analysis aimed at comparing the placebo effect sizes from randomized controlled trials (RCTs) of two widely prescribed antidepressants, namely duloxetine and venlafaxine, and at analysing a potential influence of the investigated drugs on the placebo response. METHOD: We conducted a comprehensive systematic review and meta-analysis of placebo-controlled, double-blind RCTs, which examined the efficacy of duloxetine and venlafaxine in the acute treatment of major depressive disorder. RESULTS: We included 71 studies (29 duloxetine trials and 43 venlafaxine trials; one study provided data for the duloxetine and the venlafaxine data set). The placebo effect sizes, defined as pre-postscore change divided by baseline standard deviation, differed significantly between venlafaxine and duloxetine studies (-2.51 vs. -2.09; test for subgroup differences P = 0.028; high heterogeneity). The analysis of effect modifiers and the metaregression analyses confirmed the drug, next to baseline depression severity and publication status, as the most influential independent predictor. CONCLUSION: Our analyses show a significant difference in the placebo response between venlafaxine and duloxetine trials and suggest that the investigated drug has an influence on the placebo response that is not related to baseline severity, changes over the years or other variables we included.

Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis.

OBJECTIVE: The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta-analysis. METHOD: We identified all placebo-controlled, double-blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public-private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed-effects models for repeated measures. RESULTS: We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = -0.04, 95% confidence interval: -0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. CONCLUSION: We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.

Does Internet-based cognitive behavioral therapy (iCBT) prevent major depressive episode for workers? A 12-month follow-up of a randomized controlled trial.

BACKGROUND: In this study we investigated whether an Internet-based computerized cognitive behavioral therapy (iCBT) program can decrease the risk of DSM-IV-TR major depressive episodes (MDE) during a 12-month follow-up of a randomized controlled trial of Japanese workers. METHOD: Participants were recruited from one company and three departments of another company. Those participants who did not experience MDE in the past month were randomly allocated to intervention or control groups (n = 381 for each). A 6-week, six-lesson iCBT program was provided to the intervention group. While the control group only received the usual preventive mental health service for the first 6 months, the control group was given a chance to undertake the iCBT program after a 6-month follow-up. The primary outcome was a new onset of DSM-IV-TR MDE during the 12-month follow-up, as assessed by means of the web version of the WHO Composite International Diagnostic Interview (CIDI), version 3.0 depression section. RESULTS: The intervention group had a significantly lower incidence of MDE at the 12-month follow-up than the control group (Log-rank χ2 = 7.04, p < 0.01). The hazard ratio for the intervention group was 0.22 (95% confidence interval 0.06-0.75), when estimated by the Cox proportional hazard model. CONCLUSIONS: The present study demonstrates that an iCBT program is effective in preventing MDE in the working population. However, it should be noted that MDE was measured by self-report, while the CIDI can measure the episodes more strictly following DSM-IV criteria.

Protocol registration and selective outcome reporting in recent psychiatry trials: new antidepressants and cognitive behavioural therapies.

OBJECTIVE: The selective reporting of favorable outcomes has a serious influence on our evidence base. However, this problem has not yet been systematically investigated in the field of psychiatry. Our study aimed to evaluate registration and outcome reporting in randomized controlled trials (RCTs) of standard treatments for depression: cognitive behavioural therapy (CBT) or new-generation antidepressants (ADs). METHOD: We searched for reports of RCTs examining the efficacy of CBT or AD for depression that were published between 2011 and 2013. We then compared their primary outcomes in the trial registries and those in publications. RESULTS: We identified 170 trials. Among them, 92 trials (54.1%) were registered, 43 trials (25.3%) were properly registered, and only 32 (18.8%) trials were both properly registered and reported (the primary outcomes as recorded in the registries were reported in publications). There was no statistically significant difference in the proportions of properly registered and reported trials for CBT or AD (relative risk: 0.51, 95% CI: 0.25-1.03). High impact factor journals, commercial funding, publication of protocol, and relatively large sample size were significant predictors of proper registration and reporting. CONCLUSION: The prevalence of proper registration and reporting is still very low in depression trials.

Enthusiasm for homework and improvement of psychological distress in subthreshold depression during behavior therapy: secondary analysis of data from a randomized controlled trial.

BACKGROUND: Cognitive behavioral therapy (CBT) usually involves homework, the completion of which is a known predictor of a positive outcome. The aim of the present study was to examine the session-by-session relationships between enthusiasm to complete the homework and the improvement of psychological distress in depressed people through the course of therapy. METHODS: Working people with subthreshold depression were recruited to participate in the telephone CBT (tCBT) program with demonstrated effectiveness. Their enthusiasm for homework was enhanced with motivational interviewing techniques and was measured by asking two questions: "How strongly do you feel you want to do this homework?" and "How confident do you feel you can actually accomplish this homework?" at the end of each session. The outcome was the K6 score, which was administered at the start of each session. The K6 is an index of psychological distress including depression and anxiety. We used structural equation modeling (SEM) to elucidate the relationships between enthusiasm and the K6 scores from session to session. RESULTS: The best fitting model suggested that, throughout the course of behavior therapy (BT), enthusiasm to complete the homework was negatively correlated with the K6 scores for the subsequent session, while the K6 score measured at the beginning of the session did not influence the enthusiasm to complete the homeworks assigned for that session. CONCLUSIONS: Empirical data now support the practitioners of BT when they try to enhance their patient's enthusiasm for homework regardless of the participant's distress, which then would lead to a reduction in distress in the subsequent week. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00885014 . April 20, 2009.

Reliability and validity of the Japanese version of the coping inventory for adults for stressful situations in healthy people.

The present study examined the validity and reliability of the Japanese version of the Coping Inventory for Stressful Situations-2nd Edition™ (CISS; hereafter the CISS-J). The participants were 1,268 healthy Japanese individuals. The factor analyses yielded three major scales (task-, emotion-, and avoidance-oriented coping) corresponding to the original version. In addition, the avoidance-oriented scale of the CISS-J contained two subscales (Distraction and Social diversion), as in the original version. Cronbach's α coefficient was found to be .75-.89 for the three scales and two subscales. Results show that the CISS-J is useful for assessing the coping strategies among this sample of Japanese individuals.

Waiting list may be a nocebo condition in psychotherapy trials: a contribution from network meta-analysis.

OBJECTIVE: Various control conditions have been employed in psychotherapy trials, but there is growing suspicion that they may lead to different effect size estimates. The present study aims to examine the differences among control conditions including waiting list (WL), no treatment (NT) and psychological placebo (PP). METHOD: We comprehensively searched for all randomized controlled trials (RCTs) comparing cognitive-behaviour therapies (CBT) against various control conditions in the acute phase treatment of depression, and applied network meta-analysis (NMA) to combine all direct and indirect comparisons among the treatment and control arms. RESULTS: We identified 49 RCTs (2730 participants) comparing WL, NT, PP and CBT. This network of evidence was consistent, and the effect size estimates for CBT were substantively different depending on the control condition. The odds ratio of response for NT over WL was statistically significant at 2.9 (95% CI: 1.3-5.7). However, the quality of evidence, including publication bias, was less than ideal and none of the preplanned sensitivity analyses limiting to high-quality studies could be conducted, while findings of significant differences did not persist in post hoc sensitivity analyses trying to adjust for publication bias. CONCLUSION: There may be important differences in control conditions currently used in psychotherapy trials.

Comprehensive validation of early diagnostic algorithms for myocardial infarction in the emergency department.

OBJECTIVE: To comprehensively evaluate diagnostic algorithms for myocardial infarction using a high-sensitivity cardiac troponin I (hs-cTnI) assay. PATIENTS AND METHODS: We prospectively enrolled patients with suspected myocardial infarction without ST-segment elevation from nine emergency departments in Japan. The diagnostic algorithms evaluated: (i) based on hs-cTnI alone, such as the European Society of Cardiology (ESC) 0/1-h or 0/2-h and High-STEACS pathways; or (ii) used medical history and physical findings, such as the ADAPT, EDACS, HEART, and GRACE pathways. We evaluated the negative predictive value (NPV), sensitivity as safety measures, and proportion of patients classified as low or high-risk as an efficiency measure for a primary outcome of type 1 myocardial infarction or cardiac death within 30 days. RESULTS: We included 437 patients, and the hs-cTnI was collected at 0 and 1 hours in 407 patients and at 0 and 2 hours in 394. The primary outcome occurred in 8.1% (33/407) and 6.9% (27/394) of patients, respectively. All the algorithms classified low-risk patients without missing those with the primary outcome, except for the GRACE pathway. The hs-cTnI-based algorithms classified more patients as low-risk: the ESC 0/1-h 45.7%; the ESC 0/2-h 50.5%; the High-STEACS pathway 68.5%, than those using history and physical findings (15-30%). The High-STEACS pathway ruled out more patients (20.5%) by hs-cTnI measurement at 0 hours than the ESC 0/1-h and 0/2-h algorithms (7.4%). CONCLUSIONS: The hs-cTnI algorithms, especially the High-STEACS pathway, had excellent safety performance for the early diagnosis of myocardial infarction and offered the greatest improvement in efficiency.

Possible improvement of depression after systematic examination and explanation of live birth rates among women with recurrent miscarriage.

We conducted a prospective study to determine whether systematic examinations and provision of explanation regarding the successful birth rates might improve mood or anxiety disorders among childless women with recurrent miscarriages. A total of 305 first-visit patients with a history of 2-12 miscarriages completed a first questionnaire battery, including: 'K6', a new screening instrument for mood and anxiety disorders, the 'Symptom Checklist-90 Revised' (SCL-90-R) and the 'Emotional Impact' questionnaire. Of these, 170 patients who underwent routine examinations and received an explanation about successful live birth rates responded to the second questionnaire. A total of 15.4% of the patients were estimated to suffer from diagnosable depression or anxiety disorders. Patients with high scores on K6 also showed elevated scores on all the subscales of SCL-90-R, including depression and anxiety. The K6 of patients with translocation was significantly higher than that of patients with antiphospholipid antibodies. The K6 and depression scores in the 2nd questionnaire survey were significantly lower than those in the 1st survey in the 170 patients. Improvement in depression was found in patients who underwent routine examination and received an explanation.

How many well vs. unwell days can you expect over 10 years, once you become depressed?

OBJECTIVE: Prognostic studies of major depression have mainly focused on episode remission and relapse, and only a limited number of studies have examined long-term course of depressive symptomatology at threshold and subthreshold levels. METHOD: The Group for Longitudinal Affective Disorders Study has conducted prospective serial assessments of a cohort of heretofore untreated major depressive episodes for 10 years under naturalistic conditions. RESULTS: Of the 94 patients in the cohort, the follow-up rate was 70% of the 11,280 person-months. Around 77% of the follow-up months were spent in euthymia, 16% in subthreshold depression and 7% in major depression. Duration of the index episode before reaching recovery was the only significant predictor of the ensuing well time. CONCLUSION: On average, patients with major depression starting treatment today may expect to spend three quarters of the next decade in euthymia but the remaining one quarter in subthreshold or threshold depression.

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

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.

Definitions of recovery and outcomes of major depression: results from a 10-year follow-up.

OBJECTIVE: Consensus operational definitions for symptomatic remission and recovery of a major depressive episode have been proposed but only irregularly followed. METHOD: We examined the predictive validity of different definitions of recovery in a multi-center 10-year follow-up study of an inception cohort of untreated unipolar major depressive episodes (n = 95). Time to recovery and time to recurrence after recovery were estimated by Kaplan-Meier survival analyses for alternative definitions requiring 2, 4, 6 or 12 months of remission to declare recovery. RESULTS: The median time to recovery was 3.0, 4.0, 4.0 and 12.0 months respectively. The index episode lasted longer than 24 months in 9.4%, 9.2%, 12.6% and 24.5%. The median time to subthreshold recurrence was 16.0, 32.0, 42.0 and 74.0 months. CONCLUSION: Either 4- or 6-month duration of remission defined a change point before which the episode was continuous and after which the recurrence was reasonably unlikely.

Psychotherapy for depression among incurable cancer patients.

BACKGROUND: The most common psychiatric diagnosis among cancer patients is depression; this diagnosis is even more common among patients with advanced cancer. Psychotherapy is a patient-preferred and promising strategy for treating depression among cancer patients. Several systematic reviews have investigated the effectiveness of psychological treatment for depression among cancer patients. However, the findings are conflicting, and no review has focused on depression among patients with incurable cancer. OBJECTIVES: To investigate the effects of psychotherapy for treating depression among patients with advanced cancer by conducting a systematic review of randomized controlled trials (RCTs). SEARCH STRATEGY: We searched the Cochrane Pain, Palliative and Supportive Care Group Register, The Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL, and PsycINFO databases in September 2005. SELECTION CRITERIA: All relevant RCTs comparing any kind of psychotherapy with conventional treatment for adult patients with advanced cancer were eligible for inclusion. Two independent review authors identified relevant studies. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the original reports using standardized data extraction forms. Two independent review authors also assessed the methodological quality of the selected studies according to the recommendations of a previous systematic review of psychological therapies for cancer patients that utilized ten internal validity indicators. The primary outcome was the standardized mean difference (SMD) of change between the baseline and immediate post-treatment scores. MAIN RESULTS: We identified a total of ten RCTs (total of 780 participants); data from six studies were used for meta-analyses (292 patients in the psychotherapy arm and 225 patients in the control arm). Among these six studies, four studies used supportive psychotherapy, one adopted cognitive behavioural therapy, and one adopted problem-solving therapy. When compared with treatment as usual, psychotherapy was associated with a significant decrease in depression score (SMD = -0.44, 95% confidence interval [CI] = -0.08 to -0.80). None of the studies focused on patients with clinically diagnosed depression. AUTHORS' CONCLUSIONS: Evidence from RCTs of moderate quality suggest that psychotherapy is useful for treating depressive states in advanced cancer patients. However, no evidence supports the effectiveness of psychotherapy for patients with clinically diagnosed depression.

Combined psychotherapy plus antidepressants for panic disorder with or without agoraphobia.

BACKGROUND: Panic disorder can be treated with pharmacotherapy, psychotherapy or in combination, but the relative merits of combined therapy have not been well established. OBJECTIVES: To review evidence concerning short- and long-term advantages and disadvantages of combined psychotherapy plus antidepressant treatment for panic disorder with or without agoraphobia, in comparison with either therapy alone. SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (CCDANCTR-Studies and CCDANCTR-References) were searched on 11/10/2005, together with a complementary search of the Cochrane Central Register of Controlled Trials and MEDLINE, using the keywords antidepressant and panic. A reference search, SciSearch and personal contact with experts were carried out. SELECTION CRITERIA: Two independent review authors identified randomised controlled trials comparing the combined therapy against either of the monotherapies among adult patients with panic disorder with or without agoraphobia. DATA COLLECTION AND ANALYSIS: Two independent review authors extracted data using predefined data formats, including study quality indicators. The primary outcome was relative risk (RR) of "response" i.e. substantial overall improvement from baseline as defined by the original investigators. Secondary outcomes included standardised weighted mean differences in global severity, panic attack frequency, phobic avoidance, general anxiety, depression and social functioning and relative risks of overall dropouts and dropouts due to side effects. MAIN RESULTS: We identified 23 randomised comparisons (representing 21 trials, 1709 patients), 21 of which involved behaviour or cognitive-behaviour therapies. In the acute phase treatment, the combined therapy was superior to antidepressant pharmacotherapy (RR 1.24, 95% confidence interval (CI) 1.02 to 1.52) or psychotherapy (RR 1.17, 95% CI 1.05 to 1.31). The combined therapy produced more dropouts due to side effects than psychotherapy (number needed to harm (NNH) around 26). After the acute phase treatment, as long as the drug was continued, the superiority of the combination over either monotherapy appeared to persist. After termination of the acute phase and continuation treatment, the combined therapy was more effective than pharmacotherapy alone (RR 1.61, 95% CI 1.23 to 2.11) and was as effective as psychotherapy (RR 0.96, 95% CI 0.79 to 1.16). AUTHORS' CONCLUSIONS: Either combined therapy or psychotherapy alone may be chosen as first line treatment for panic disorder with or without agoraphobia, depending on patient preference.