Theta burst stimulation for depression: a systematic review and network and pairwise meta-analysis.

In clinical practice, theta burst stimulation (TBS) presents as a more efficient and potentially more effective therapeutic modality than conventional repetitive transcranial magnetic stimulation (rTMS), as it allows for the delivery of more stimuli in less time and at similar intensities. To date, accelerated treatment plans according to various continuous (cTBS) and intermittent TBS (iTBS) protocols for depression have been proposed. To investigate which of the TBS protocols provided a favorable risk-benefit balance for individuals with depression, this systematic review and random-effects model network meta-analysis was conducted. The study outcomes included response rate (primary), depression symptom improvement, remission rate, all-cause discontinuation rate, incidence of switch to mania, and incidence of headache/discomfort at treatment site. In this meta-analysis, a total of 23 randomized controlled trials (n = 960, mean age = 41.88 years, with 60.78% females) were included. Approximately 69.57% of the trials included individuals with an exclusive diagnosis of major depressive disorder. The following six TBS protocols (target) were evaluated: cTBS (right-dorsolateral prefrontal cortex [R-DLPFC]), cTBS (R-DLPFC) + iTBS (left-DLPFC [L-DLPFC]), iTBS (L-DLPFC), iTBS (L-DLPFC) + iTBS (R-DLPFC), iTBS (left-dorsomedial prefrontal cortex) + iTBS (right-dorsomedial prefrontal cortex), and iTBS (occipital lobe). Compared to sham, cTBS (R-DLPFC) + iTBS (L-DLPFC), iTBS (L-DLPFC), and iTBS (occipital lobe) had a higher response rate (k = 23); cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) dominated in the depression symptom improvement (k = 23); and iTBS (L-DLPFC) had a higher remission rate (k = 15). No significant differences were found for all-cause discontinuation rate (k = 17), incidence of switch to mania (k = 7), and incidence of headache/discomfort at treatment site (k = 10) between any TBS protocols and sham. Thus, cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) demonstrate favorable risk-benefit balance for the treatment of depression.

Antidepressants for the treatment of adults with major depressive disorder in the maintenance phase: a systematic review and network meta-analysis.

A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to treat adults with major depressive disorder (MDD) in the maintenance phase. This study searched the PubMed, Cochrane Library, and Embase databases and included only double-blind, randomized, placebo-controlled trials with an enrichment design: patients were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or placebo. The outcomes were the 6-month relapse rate (primary outcome, efficacy), all-cause discontinuation (acceptability), discontinuation due to adverse events (tolerability), and the incidence of individual adverse events. The risk ratio with a 95% credible interval was calculated. The meta-analysis comprised 34 studies (n = 9384, mean age = 43.80 years, and %females = 68.10%) on 20 antidepressants (agomelatine, amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, vilazodone, and vortioxetine) and a placebo. In terms of the 6-month relapse rate, amitriptyline, citalopram, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, and vortioxetine outperformed placebo. Compared to placebo, desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had lower all-cause discontinuation; however, sertraline had a higher discontinuation rate due to adverse events. Compared to placebo, venlafaxine was associated with a lower incidence of dizziness, while desvenlafaxine, sertraline, and vortioxetine were associated with a higher incidence of nausea/vomiting. In conclusion, desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had reasonable efficacy, acceptability, and tolerability in the treatment of adults with stable MDD.

GWAS-identified bipolar disorder risk allele in the FADS1/2 gene region links mood episodes and unsaturated fatty acid metabolism in mutant mice.

Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD.

Discontinuation Rate of Lurasidone and Quetiapine Extended Release in Bipolar Depression.

INTRODUCTION: Lurasidone (LUR) was compared with quetiapine extended release (QUE-ER) regarding 1-year discontinuation in patients with bipolar depression (n=317). METHODS: This is a retrospective cohort study. RESULTS: Although the time to all-cause discontinuation was estimated using the Kaplan-Meier survival curve with log-rank tests to compare treatment groups, no difference was found (p=0.317). The Cox proportional hazard model revealed that only the presence of adverse events (AEs) is associated with increased treatment discontinuation (p<0.0001). The most common AEs were akathisia for LUR (17.7%) and somnolence for QUE-ER (34.7%). In other Cox models divided by LUR or QUE-ER, the presence of akathisia or somnolence was associated with increased LUR (p=0.0205) or QUE-ER (p<0.0001) discontinuation, respectively. DISCUSSION: The acceptability of both antipsychotics to bipolar depression in clinical practice may be similar. However, specific AEs for each antipsychotic (LUR: akathisia and QUE-ER: somnolence) were associated with high treatment discontinuation.

Pharmacological treatment for bipolar mania: a systematic review and network meta-analysis of double-blind randomized controlled trials.

A systematic review and random-effects model network meta-analysis was conducted to compare the efficacy, acceptability, tolerability, and safety of pharmacological interventions for adults with acute bipolar mania. We searched PubMed, the Cochrane Library, and Embase databases for eligible studies published before March 14, 2021. Randomized controlled trials (RCTs) of oral medication monotherapy lasting ≥10 days in adults with mania were included, and studies that allowed the use of antipsychotics as a rescue medication during a trial were excluded. The primary outcomes were response to treatment (efficacy) and all-cause discontinuation (acceptability). The secondary outcomes were the improvement of mania symptoms and discontinuation due to inefficacy. Of the 79 eligible RCTs, 72 double-blind RCTs of 23 drugs and a placebo were included in the meta-analysis (mean study duration = 3.96 ± 2.39 weeks, n = 16442, mean age = 39.55 years, with 50.93% males). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed response to treatment (N = 56, n = 14503); aripiprazole, olanzapine, quetiapine, and risperidone had lower all-cause discontinuation; however, topiramate had higher all-cause discontinuation (N = 70, n = 16324). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed the improvement of mania symptoms (N = 61, n = 15466), and aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, valproate, and ziprasidone had lower discontinuation due to inefficacy (N = 50, n = 14284). In conclusions, these antipsychotics, carbamazepine, lithium, tamoxifen, and valproate were effective for acute mania. However, only aripiprazole, olanzapine, quetiapine, and risperidone had better acceptability than the placebo.

Circadian variability of objective sleep measures predicts the relapse of a mood episode in bipolar disorder: findings from the APPLE cohort.

AIM: Sleep disturbance, a core feature of bipolar disorder, is closely associated with mood symptoms. We examined the association between actigraphy sleep parameters and mood episode relapses in patients with bipolar disorder. METHODS: This prospective cohort study analyzed 193 outpatients with bipolar disorder who participated in the Association between the Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study. The participants' sleep was objectively evaluated via actigraphy over seven consecutive days for the baseline assessment and then at the 2-year follow-up appointment for mood episode relapses. The actigraphy sleep parameters were presented using the mean and variability (standard deviation) of each sleep parameter for 7 days. RESULTS: Of the 193 participants, 110 (57%) experienced mood episodes during follow-up. The participants with higher variability in total sleep time had a significantly shorter mean estimated time to mood episode relapses than those with lower variability (12.5 vs. 16.8 months; P < 0.001). The Cox proportional hazards model, when adjusted for potential confounders, demonstrated that variability in total sleep time was significantly associated with an increase in the mood episode relapses (per hour; hazard ratio [HR], 1.407; 95% confidence interval (CI), 1.057-1.873), mainly in the depressive episodes (per hour; HR, 1.477; 95% CI, 1.088-2.006). CONCLUSIONS: Our findings suggest that consistency in sleep time might be useful, as an adjunct therapy, in preventing the recurrence or relapse of mood episodes in bipolar disorder.

Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials.

We searched Embase, PubMed, and CENTRAL from inception until 22 May 2020 to investigate which antipsychotics and/or mood stabilizers are better for patients with bipolar disorder in the maintenance phase. We performed two categorical network meta-analyses. The first included monotherapy studies and studies in which the two drugs used were specified (i.e., aripiprazole, aripiprazole once monthly, aripiprazole+lamotrigine, aripiprazole+valproate, asenapine, carbamazepine, lamotrigine, lamotrigine+valproate, lithium, lithium+oxcarbazepine, lithium+valproate, olanzapine, paliperidone, quetiapine, risperidone long-acting injection, valproate, and placebo). The second included studies on second-generation antipsychotic combination therapies (SGAs) (i.e., aripiprazole, lurasidone, olanzapine, quetiapine, and ziprasidone) with lithium or valproate (LIT/VAL) compared with placebo with LIT/VAL. Outcomes were recurrence/relapse rate of any mood episode (RR-any, primary), depressive episode (RR-dep) and manic/hypomanic/mixed episode (RR-mania), discontinuation, mortality, and individual adverse events. Risk ratios and 95% credible interval were calculated. Forty-one randomized controlled trials were identified (n = 9821; mean study duration, 70.5 ± 36.6 weeks; percent female, 54.1%; mean age, 40.7 years). All active treatments other than carbamazepine, lamotrigine+valproate (no data) and paliperidone outperformed the placebo for RR-any. Aripiprazole+valproate, lamotrigine, lamotrigine+valproate, lithium, olanzapine, and quetiapine outperformed placebo for RR-dep. All active treatments, other than aripiprazole+valproate, carbamazepine, lamotrigine, and lamotrigine+valproate, outperformed placebo for RR-mania. Asenapine, lithium, olanzapine, quetiapine, and valproate outperformed placebo for all-cause discontinuation. All SGAs+LIT/VALs other than olanzapine+LIT/VAL outperformed placebo+LIT/VAL for RR-any. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-dep. Aripiprazole+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-mania. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for all-cause discontinuation. Treatment efficacy, tolerability, and safety profiles differed among treatments.

Effect of nighttime bedroom light exposure on mood episode relapses in bipolar disorder.

OBJECTIVE: A previous cross-sectional study reported that nighttime light is associated with increased occurrence of manic symptoms in bipolar disorder; however, the longitudinal association between nighttime light and subsequent mood episode relapses remains unclear. We determined whether bedroom nighttime light was associated with mood episode relapses in patients with bipolar disorder. METHODS: This prospective cohort study included 172 outpatients with bipolar disorder who participated in an Association between the Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study. A portable photometer was used to measure illuminance in the bedroom from bedtime to rising time during 7 consecutive nights for baseline assessment. Then, the participants were assessed at a 2-year follow-up for mood episode relapses. RESULTS: Of the 172 participants, 157 (91%) completed the 2-year follow-up, and 39 (22%) experienced manic or hypomanic episodes (with or without mixed features), during that time. In the Cox proportional-hazards model, the hazard ratio (HR) for manic/hypomanic episode relapses was significantly higher when the average nighttime illuminance was ≥3 lux (n = 71) than when it was <3 lux (n = 101; HR, 2.54; 95% confidence interval (CI), 1.33-4.84). In the multivariable model adjusted for a propensity score in relation to nighttime light, the relationship remained significant (HR, 2.17; 95% CI, 1.04-4.52). The association between nighttime light and depressive episode relapses was not significantly different. CONCLUSIONS: Keeping the bedroom dark at night may prevent hypomanic and manic episodes.

Comparative Efficacy and Acceptability of 3 Repetitive Transcranial Magnetic Stimulation Devices for Depression: A Meta-Analysis of Randomized, Sham-Controlled Trials.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) has been employed worldwide for therapy-resistant depression. The Food and Drug Administration has approved a number of therapeutic devices for treating major depressive disorder; however, no studies have examined the differences in efficacy and acceptability among commercially available stimulation devices. The aim of our study was to compare the efficacy and acceptability of 3 stimulation devices (NeuroStar, MagPro, and Magstim) for depressive disorders. METHODS: Our study included 31 randomized sham-controlled trials of high-frequency rTMS included in the network meta-analysis by Brunoni. We calculated the risk ratio and 95% confidence intervals, comparing each device with sham for the endpoints of response rate, remission rate, and all-cause discontinuation. We then analyzed the differences among the devices in effect size for those endpoints. RESULTS: After determining the effect sizes for the endpoints, we found no statistically significant subgroup differences in the response rates, all-cause discontinuation, or remission rates among the devices (p = 0.12, p = 0.84, and p = 0.07, respectively). CONCLUSION: Our results suggest similar efficacy and acceptability for the 3 stimulation devices. Future studies need to perform head-to-head comparisons of the efficacy and acceptability of the stimulation devices for treating depression using the same stimulation protocols.

Aripiprazole Once-Monthly Versus Oral Aripiprazole for Schizophrenia in the Maintenance Phase: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: To examine whether aripiprazole once-monthly (AOM) was more beneficial than oral aripiprazole (OARI) in the treatment of adults with schizophrenia during the maintenance phase. METHODS: We performed a systematic review and network meta-analysis of double-blind, randomized controlled trials that included two of the following treatments: AOM, OARI, and placebo. RESULTS: We identified four studies involving 1830 adults. Relapse rates at 26 weeks were lower for both AOM (odds ratio [OR] 0.240, 95% confidence interval [CI] 0.169-0.341) and OARI (OR=0.306, 95%CI=0.217-0.431) than for placebo, although their treatment outcomes did not differ significantly (OR=0.786, 95%CI=0.529-1.168). Rates of all-cause discontinuation were also lower with AOM (OR=0.300, 95% CI=0.227-0.396) and OARI (OR=0.441, 95%CI=0.333-0.582) than with placebo. The rate of all-cause discontinuation was lower with AOM than with OARI (OR=0.681, 95% CI=0.529-0.877)]. Other outcomes did not differ significantly between AOM and OARI. DISCUSSION: Although both AOM and OARI were efficacious in the treatment of schizophrenia during the maintenance phase, AOM was better accepted than OARI.

Shared genetic components between metabolic syndrome and schizophrenia: Genetic correlation using multipopulation data sets.

AIM: The genetic relationship between schizophrenia (SCZ) and other nonpsychiatric disorders remains largely unknown. We examined the shared genetic components between these disorders based on multipopulation data sets. METHODS: We used two data sets for East Asian (EAS) and European (EUR) samples. SCZ data was based on the Psychiatric Genomics Consortium Asia with our own genome-wide association study for EAS and Psychiatric Genomics Consortium for EUR. Nonpsychiatric data (20 binary traits [mainly nonpsychiatric complex disorders] and 34 quantitative traits [mainly laboratory examinations and physical characteristics]) were obtained from Biobank Japan and UK Biobank for EAS and EUR samples, respectively. To evaluate genetic correlation, linkage disequilibrium score regression analysis was utilized with further meta-analysis for each result from EAS and EUR samples to obtain robust evidence. Subsequent mendelian randomization analysis was also included to examine the causal effect. RESULTS: A significant genetic correlation between SCZ and several metabolic syndrome (MetS) traits was detected in the combined samples (meta-analysis between EAS and EUR data) (body mass index [rg  = -0.10, q-value = 1.0 × 10-9 ], high-density-lipoprotein cholesterol [rg  = 0.072, q-value = 2.9 × 10-3 ], blood sugar [rg  = -0.068, q-value = 1.4 × 10-2 ], triglycerides [rg  = -0.052, q-value = 2.4 × 10-2 ], systolic blood pressure [rg  = -0.054, q-value = 3.5 × 10-2 ], and C-reactive protein [rg  = -0.076, q-value = 7.8 × 10-5 ]. However, no causal relationship on SCZ susceptibility was detected for these traits based on the mendelian randomization analysis. CONCLUSION: Our results indicate shared genetic components between SCZ and MetS traits and C-reactive protein. Specifically, we found it interesting that the correlation between MetS traits and SCZ was the opposite of that expected from clinical studies: this genetic study suggests that SCZ susceptibility was associated with reduced MetS. This implied that MetS in patients with SCZ was not associated with genetic components but with environmental factors, including antipsychotics, lifestyle changes, poor diet, lack of exercise, and living conditions.

Discontinuation and remission rates and social functioning in patients with schizophrenia receiving second-generation antipsychotics: 52-week evaluation of JUMPs, a randomized, open-label study.

AIM: Globally, evidence from short-term studies is insufficient for the guidelines to uniformly recommend a particular antipsychotic(s) for the maintenance treatment of schizophrenia. Therefore, long-term comprehensive evaluation of antipsychotics is required from a social rehabilitation perspective, especially for drugs that have not yet been studied. The Japan Useful Medication Program for Schizophrenia (JUMPs) is a large-scale, long-term naturalistic study to present pivotal 52-week data on the continuity of second-generation antipsychotics (SGA: aripiprazole, blonanserin, and paliperidone). METHODS: JUMPs was an open-label, three-arm, randomized, parallel-group, 52-week study. Enrolled patients had schizophrenia, were ≥20 years old, and required antipsychotic treatment or switched from previous therapy. The primary endpoint was treatment discontinuation rate over 52 weeks. Secondary outcomes included remission rate, social functioning, and quality-of-life scores [Personal and Social Performance Scale (PSP) and EuroQol-5 dimensions], and safety. RESULTS: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). The discontinuation rate (P = 0.9771) and remission rates (P > 0.05) over 52 weeks did not differ significantly between the three treatment groups. The discontinuation rates were 68.3%, 68.2%, and 65.5% in the aripiprazole, blonanserin, and paliperidone groups, respectively. Significant improvements (all P < 0.05) from baseline in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favored blonanserin. CONCLUSION: All three SGAs evaluated in this study showed similar treatment discontinuation rates in patients with chronic schizophrenia in Japan.

Polygenic risk score as clinical utility in psychiatry: a clinical viewpoint.

Genome-wide association studies (GWASs) have detected many susceptible variants for common diseases, including psychiatric disorders. However, because of the small effect size of each variant, clinical utility that aims for risk prediction and/or diagnostic assistance based on the individual "variants" is difficult to use. Therefore, to improve the statistical power, polygenic risk score (PRS) has been established and applied in the GWAS as a robust analytic tool. Although PRS has potential predictive ability, because of its current "insufficient" discriminative power at the individual level for clinical use, it remains limited solely in the research area, specifically in the psychiatric field. For a better understanding of the PRS, in this review, we (1) introduce the clinical features of psychiatric disorders, (2) summarize the recent GWAS/PRS findings in the psychiatric disorders, (3) evaluate the problems of PRS, and (4) propose its possible utility to apply PRS into the psychiatric clinical setting.

Determination of novel CYP2D6 haplotype using the targeted sequencing followed by the long-read sequencing and the functional characterization in the Japanese population.

Next-generation sequencing (NGS) has identified variations in cytochrome P450 (CYP) 2D6 associated with drug responses. However, determination of novel haplotypes is difficult because of the short reads generated by NGS. We aimed to identify novel CYP2D6 variants in the Japanese population and predict the CYP2D6 phenotype based on in vitro metabolic studies. Using a targeted NGS panel (PKSeq), 990 Japanese genomes were sequenced, and then novel CYP2D6 haplotypes were determined. Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl-tamoxifen 4-hydroxylation were calculated by in vitro metabolic studies using cDNA-expressed CYP2D6 proteins. After determination of the CYP2D6 diplotypes, phenotypes of the individuals were predicted based on the in vitro metabolic activities. Targeted NGS identified 14 CYP2D6 variants not registered in the Pharmacogene Variation Consortium (PharmVar) database. Ten novel haplotypes were registered as CYP2D6*128 to *137 alleles in the PharmVar database. Based on the Vmax/Km value of each allele, *128, *129, *130, *131, *132, and *133 were predicted to be nonfunctional alleles. According to the results of the present study, six normal metabolizers (NM) and one intermediate (IM) metabolizers were designated as IM and poor metabolizers (PM), respectively. Our findings provide important insights into novel haplotypes and haplotypes of CYP2D6 and the effects on in vitro metabolic activities.

Recurrence rates in stable bipolar disorder patients after drug discontinuation v. drug maintenance: a systematic review and meta-analysis.

BACKGROUND: This random-effects model meta-analysis of double-blind, randomized placebo-controlled trials compared recurrence rates in bipolar disorder (BD) patients between antipsychotic/mood stabilizer discontinuation and maintenance groups. METHODS: We conducted systematic literature search of Embase, PubMed, and CENTRAL databases without language restriction from inception until 22 May 2020. Independent investigators assessed studies and extracted data. We calculated risk ratios (RRs) and numbers needed to benefit or harm (NNTB/NNTH). Primary outcome was the recurrence rate of any mood episode at 6 months. Secondary outcomes were recurrence rates of depressive episodes and manic/hypomanic/mixed episodes and all-cause discontinuation at 6 months. We also investigated these outcomes at 1, 3, 9, 12, 18, and 24 months. RESULTS: We identified 22 studies (n = 5462) receiving aripiprazole, asenapine, divalproex, long-acting injectable (LAI)-aripiprazole, LAI-risperidone, lamotrigine, lithium, olanzapine, paliperidone, or quetiapine. Mean study duration was 64.50 ± 69.35 weeks. The maintenance group demonstrated lower recurrence rates of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes as well as reduced all-cause discontinuation at every observational point. The RRs (95% confidence interval, NNTB/NNTH) of recurrence rate at 6 months were 0.61 (0.54-0.70, 5) for any mood episode, 0.72 (0.60-0.87, 13) for depressive episodes, and 0.45 (0.36-0.57, 6) for manic/hypomanic/mixed episodes. The RR for all-cause discontinuation at 6 months was 0.71 (0.61-0.82, 6). CONCLUSIONS: Maintaining drug treatment during clinically stable BD prevented recurrence for up to 24 months. Discontinuation of medications for ⩾1 month significantly increased recurrence risk. However, 47.3% of patients who discontinued drugs for 6 months did not experience recurrence.

Effects of a conventional mood stabilizer alone or in combination with second-generation antipsychotics on recurrence rate and discontinuation rate in bipolar I disorder in the maintenance phase: A systematic review and meta-analysis of randomized, placebo-controlled trials.

OBJECTIVES: A systematic review and meta-analysis of double-blind, randomized placebo-controlled trials were conducted to examine how soon an increase in recurrence risk could be observed among bipolar I disorder (BDI) patients who were clinically stable with the combination therapy of mood stabilizers with second-generation antipsychotics (SGA+MS) treatment following second-generation antipsychotics discontinuation (i.e., MS alone) compared with SGA+MS maintenance. METHODS: Embase, PubMed, and CENTRAL databases were used for systematic literature searches until May/22/2020. The primary outcome was the recurrence rate of any mood episode at 6 months. The secondary outcomes were the recurrence rates of manic/hypomanic/mixed and depressive episodes and all-cause discontinuation at 6 months. The recurrence rates at 1, 2, 3, 9, and 12 months were also investigated. RESULTS: Eight studies (mean study duration = 58.25 ± 33.63 weeks) were identified (SGA+MS group [n = 1,456: 3 aripiprazole+MS studies, 1 lurasidone+MS study, 1 olanzapine+MS study, 2 quetiapine+MS studies, 1 ziprasidone+MS study] and placebo+MS group [n = 1,476]). Pooled SGA+MS exhibited lower recurrence rates of any mood episode, manic/hypomanic/mixed episodes, and depressive episodes as well as reduced all-cause discontinuation at every observational point. The risk ratios (95% confidence interval) of the recurrence rate at 6 months were 0.51 (0.39-0.86) for any mood episode, 0.42 (0.30-0.59) for manic/hypomanic/mixed episodes, and 0.39 (0.28-0.54) for depressive episodes. The RR for all-cause discontinuation was 0.67 (0.50-0.89). Both aripiprazole+MS and quetiapine+MS outperformed placebo+MS in the recurrence of any mood, manic/hypomanic/mixed, and depressive episodes at 6 months. CONCLUSIONS: SGA+MS prevented recurrence for up to 12 months for BDI compared with placebo+MS.

Preventive effect of morning light exposure on relapse into depressive episode in bipolar disorder.

OBJECTIVE: Light therapy has been suggested to have a curative effect on bipolar depression; however, preventive effects of light exposure on depressive episodes remain unclear. This study evaluated whether daytime light exposure in real-life situations was associated with a preventive effect on relapse into depressive episodes in patients with bipolar disorder. METHODS: This prospective, naturalistic, observational study was conducted in Japan between August 2017 and June 2020. Outpatients with bipolar disorder were objectively evaluated for daytime light exposure over 7 consecutive days using an actigraph that could measure ambient light at baseline assessment and then assessed at 12-month follow-up for relapse into mood episodes. RESULTS: Of 202 participants, 198 (98%) completed follow-up at 12 months and 78 (38%) experienced relapse into depressive episodes during follow-up. In a Cox proportional hazards model adjusting for potential confounders, a longer time above 1000 lux at daytime was significantly associated with decrease in relapse into depressive episodes (per log min; hazard ratio, 0.66; 95% confidence interval, 0.50-0.91). In addition, a higher average illuminance and longer time above 1000 lux in the morning exhibited a significant decrease in relapse into depressive episodes (per log lux and per log min; hazard ratio, 0.65 and 0.61; 95% confidence interval, 0.49-0.86 and 0.47-0.78, respectively). The association between daytime light exposure and relapse into manic/hypomanic/mixed episodes was not significantly different. CONCLUSION: A significant association was observed between increased daytime light exposure, mainly in the morning, and decreased relapse into depressive episodes.

Effect of evening light exposure on sleep in bipolar disorder: A longitudinal analysis for repeated measures in the APPLE cohort.

OBJECTIVE: Sleep disturbance, a core feature of bipolar disorder, is associated with residual mood symptoms, mood episode recurrence and suicide ideation. We investigated the effect of evening light exposure on sleep in patients with bipolar disorder. METHODS: In this longitudinal analysis, we measured the sleep parameters of 207 outpatients with bipolar disorder using actigraphy at their homes for seven consecutive nights. We measured the white-light illuminance and the irradiance of each wavelength during the 4 hours before each participant's bedtime. We used mixed-effect linear regression analysis for repeated measures to evaluate the effect of evening light exposure on subsequent sleep parameters. RESULTS: The median white-light illuminance was 25.8 lux (interquartile range, 12.9-50.1 lux). In a multivariable model adjusted for potential confounders, we found higher white-light illuminance to be significantly associated with lower sleep efficiency (per log lux: 95% confidence interval = [-1.328, -0.133]; p = 0.017), prolonged sleep-onset latency (95% confidence interval = [0.006, 0.172]; p = 0.035) and longer wake after sleep onset (95% confidence interval = [1.104, 4.459]; p = 0.001). This effect size was larger in the younger age group (aged < 44 years) stratified by median age. Higher irradiance of the blue wavelength range was significantly associated with longer wake after sleep onset, a result similar to those for the green and red wavelength ranges. CONCLUSION: We observed significant associations between evening light exposure and subsequent sleep in patients with bipolar disorder. The effects of various light wavelengths on sleep in bipolar disorder require further investigation.

Recurrence of Mania or Depression Among Adult Bipolar Patients Who Continued Using Lithium: A Single-group Summary Meta-analysis of Randomized Trials.

BACKGROUND: The exact recurrence rate of bipolar disorder in patients receiving lithium maintenance phase treatment and the modifiers associated with recurrence are still unknown. METHODS: We searched Embase, PubMed, and CENTRAL from inception until April 28, 2020. Outcomes included recurrence rate of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes; all-cause discontinuation rate; and discontinuation rate due to adverse events. A random-effects model, single-group summary meta-analysis was conducted. A meta-regression analysis to examine whether the modifiers (total number of patients, %female, mean age, duration of study, duration of preliminary phase, publication year, bipolar disorder type, mood status at recruitment, presence of a placebo arm, sponsorship, enrichment design, number of treatment arms, and risk of bias for blinding or randomization) were associated with the event rate of the outcomes was also performed. RESULTS: We identified 21 randomized trials (n = 1,415; mean study duration, 78.40 ± 32.10 weeks; %female, 54.85%; mean age, 43.47 ± 4.88 years). The event rates (95% confidence interval [CI]) were as follows: recurrence of any mood episode, 39.8% (32.8%, 47.1%); depressive episodes, 25.6% (18.8%, 34.0%); manic/hypomanic/mixed episodes, 18.5% (13.7%, 24.7%); all-cause discontinuation rate, 67.0% (57.2%, 75.5%); and discontinuation rate due to adverse events, 8.7% (5.1%, 14.7%). After adjusting for multiple testing, our meta-regression analysis showed association only between the all-cause discontinuation rate and presence of a placebo arm. CONCLUSIONS: The recurrence rate of depressive episodes seemed to be higher than the recurrence rate of manic/hypomanic/mixed episodes. The all-cause discontinuation rate was high. However, the studies included in our meta-analysis were of short duration.

A double-blind, randomized, placebo-controlled trial of adjunctive blue-blocking glasses for the treatment of sleep and circadian rhythm in patients with bipolar disorder.

OBJECTIVES: Recent studies have suggested that evening blue light exposure is associated with sleep and circadian rhythm abnormalities. This study examined the effect of blue-blocking (BB) glasses on sleep and circadian rhythm in patients with bipolar disorder (BD). METHODS: We used a randomized, placebo-controlled, double-blinded design. Outpatients with BD and also with insomnia were randomly assigned to wear either orange glasses (BB) or clear ones (placebo) and were instructed to use these from 20:00 hours until bedtime for 2 weeks. The primary outcome metric was the difference in change from baseline to after intervention in sleep quality, as measured by the visual analog scale (VAS). RESULTS: Forty-three patients were included in this study (BB group, 21; placebo group, 22). The change in sleep quality as per the VAS metric was not significantly different between the two groups (95% confidence interval [CI], -3.34 to 24.72; P = .13). However, the Morningness-Eveningness Questionnaire score had shifted to an advanced rhythm in the BB group and to a delayed rhythm in the placebo group, and the difference in these changes was statistically significant (95% CI, 1.69-7.45; P = .003). The change in the actigraphy sleep parameters and mood symptoms was not significantly different between the two groups. CONCLUSION: Although concurrent medications may have influenced, our results suggest that BB glasses may be useful as an adjunctive treatment for circadian rhythm issues in patients with BD.