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Abstract: The association between major depressive disorder (MDD) and personality traits has been extensively studied. However, differences in personality traits between patients with melancholic MDD (MEL) and nonmelancholic MDD (NMEL) remain unclear. In this study, we aimed to determine whether neuroticism, which has been associated with MDD, and the five affective temperament subtypes assessed by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A) can be used to distinguish MEL and NMEL. A total of 106 patients with MDD (MEL, n = 52; NMEL, n = 54) and 212 age- and sex-matched healthy controls answered the Eysenck Personality Questionnaire-revised and the short version of TEMPS-A. In hierarchical logistic regression analysis, only depressive temperament scores were identified as a statistically significant feature distinguishing NMEL from MEL. Depressive temperament scores assessed by the short version of TEMPS-A were found to be significantly higher in NMEL patients than in MEL patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: Pharmacological treatments recommended for bipolar depression are inconsistent across guidelines. We compared the efficacy and safety of antipsychotics and mood stabilizers for bipolar depression., Methods: A systemic review and meta-analysis of randomized controlled trials comparing antipsychotics and mood stabilizers for bipolar depression was conducted based on a literature search of major electronic databases., Results: Three studies comparing quetiapine with lithium were identified and analyzed; no other antipsychotic-mood stabilizer combinations were found. The meta-analysis revealed no significant differences between quetiapine and lithium for the following outcomes: (1) remission from depressive episodes (risk ratio [RR]: 1.80, 95% CI: 0.51-6.40, P = 0.36), (2) changes in depressive symptom (standardized mean difference: -0.22, 95% CI: -0.52-0.08, P = 0.15), (3) changes in social function (standardized mean difference: -0.00, 95% CI: -0.19-0.18, P = 0.98), (4) suicide-related events (odds ratio [OR]: 2.35, 95% CI: 0.40-13.65, P = 0.34), (5) severe adverse events (OR: 1.63, 95% CI: 0.51-5.20, P = 0.41), (6) dropouts due to adverse events (RR: 1.19, 95% CI: 0.76-1.87, P = 0.45, 7) dropout for any reasons (RR: 0.95, 95% CI: 0.74-1.22, P = 0.70)., Conclusion: Although this study found no differences in the efficacy and safety of quetiapine and lithium for bipolar depression, a comprehensive comparison of antipsychotics and mood stabilizers was not performed. Further studies are needed to clarify which of these, not just quetiapine and lithium, is more useful for bipolar depression., (© 2022 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: There are few guidelines on the management of depressive episodes in patients with bipolar type II (BDII) and related disorders (other specified bipolar and related disorders [OSBD]). Lurasidone is a potential option for treating depressive episodes in BDII/OSBD. This retrospective chart review study aimed to examine the effectiveness and tolerability of lurasidone for use in patients with bipolar depression., Methods: We reviewed 66 consecutive outpatients with bipolar depression who were prescribed lurasidone between June 2020 and January 2021 and examined 12-week outcomes. Fourteen patients were diagnosed with BDI, and 52 patients were diagnosed with BDII/OSBD (42 BDII and 10 OSBD). Depressive symptoms were evaluated by the Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) at baseline and 2, 4, and 12 weeks. Tolerability was assessed throughout the study period by the incidence of adverse events, such as akathisia, nausea, and manic/hypomanic switch, as well as the lurasidone dropout rate due to adverse events., Results: The total QIDS-SR score at 2 ( P < 0.001), 4 ( P < 0.001), and 12 weeks ( P < 0.001) was significantly lower than that measured at baseline. Remission rate during study period was 29.1%. Of the 66 participants, 47 (71.2%) continued taking lurasidone and 27 (40.9%) and 16 (24.2%) reported adverse events and akathisia, respectively. No significant difference in total QIDS-SR score, dropout rate due to adverse events, rate of adverse events, or rate of akathisia was found between the BDII/OSBD and BDI groups., Implications: Lurasidone is tolerated and could be effective for managing depressive episodes in patients with BDII/OSBD and BDI., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: This systematic review and meta-analysis evaluated whether bright light therapy (BLT) is an effective and safe treatment for manic/depressive symptoms and a preventive measure for recurrent mood episodes in patients with bipolar disorder., Methods: A literature search of major electronic databases was conducted in June 2019, including all published articles up to that date. Two researchers independently selected relevant publications, extracted data, and evaluated methodological quality according to the Cochrane criteria., Results: Six randomized controlled trials (RCT) evaluated the efficacy of BLT for bipolar depression. A meta-analysis found no significant differences between BLT and placebo for the following outcomes: (i) rates of remission from depressive episodes (risk ratio [RR]: 1.81, 95% confidence interval [CI]: 0.43 to 7.64, P = 0.42); (ii) depressive symptom scores (standardized mean difference: -0.25, 95%CI: -0.74 to 0.23, P = 0.30); and (iii) rates of manic switching (RR: 1.00, 95%CI: 0.28 to 3.59, P = 0.26). The sensitivity analysis for studies with low overall indirectness did show a significant antidepressant effect for BLT (RR: 3.09, 95%CI: 1.62 to 5.90, P = 0.006). No RCT investigated the effect of BLT in preventing the recurrence of mood episodes in the euthymic state or in improving manic symptoms in the manic state. No severe adverse events were reported., Conclusion: While a meta-analysis was unable to demonstrate the efficacy of BLT for bipolar depression, a sensitivity analysis did show a significant effect. Further well-designed studies are needed to clarify the effectiveness of BLT, not only for the depressive state but also for other states, in the treatment of bipolar disorder., (© 2020 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

The DSM-5 incorporates a broad concept of mixed states and captured ≥3 nonoverlapping symptoms of the opposite polarity using a "with mixed features" specifier to be applied to manic/hypomanic and major depressive episodes. Pharmacotherapy of mixed states is challenging because of the necessity to treat both manic/hypomanic and depressive symptoms concurrently. High-potency antipsychotics used to treat manic symptoms and antidepressants can potentially deteriorate symptoms of the opposite polarity. This review aimed to provide a synthesis of the current evidence for pharmacotherapy of mixed states with an emphasis on mixed mania/hypomania. A PubMed search was conducted for randomized controlled trials (RCTs) that were at least moderately sized, included a placebo arm, and contained information on acute-phase and maintenance treatments of adult patients with mixed episodes or mania/hypomania with significant depressive symptoms. Most studies were post-hoc subgroup and pooled analyses of the data from RCTs for acute manic and mixed episodes of bipolar I disorder; only two prospectively examined efficacy for mixed mania/hypomania specifically. Aripiprazole, asenapine, carbamazepine, olanzapine, and ziprasidone showed the strongest evidence of efficacy in acute-phase treatment. Quetiapine and divalproex/valproate were also efficacious. Combination therapies with these atypical antipsychotics and mood stabilizers can be considered in severe cases. Olanzapine and quetiapine (alone or in combination with lithium/divalproex) showed the strongest evidence of efficacy in maintenance treatment. Lithium and lamotrigine may be beneficial given their preventive effects on suicide and depressive relapse. Further prospective studies primarily focusing on mixed states are needed.

Background: Difficult-to-treat major depressive disorder (MDD-DT), which involves antidepressant refractoriness or antidepressant-related adverse psychiatric effects, is bipolar in nature; therefore, it may share common temperamental features with bipolar disorder. To examine this hypothesis, affective temperament was compared between MDD-DT, easy-to-treat major depressive disorder (MDD-ET), and bipolar disorder., Methods: Affective temperament was measured in 320 patients (69, 56, and 195 with MDD-ET, MDD-DT, and bipolar disorder, respectively) using the self-rated questionnaire version of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego (TEMPS-A), with between-group differences examined using multiple logistic regression analysis controlling for confounders. Optimal cut-off points for TEMPS-A scores to discriminate between diagnostic groups were determined using receiver-operating characteristic analysis., Results: Of the five temperamental domains, the mode for cyclothymic temperament score was highest, followed by those of bipolar disorder, MDD-DT, and MDD-ET. The cyclothymic temperament score discriminated significantly between bipolar disorder and MDD-DT (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.04-1.20, p=0.0022), MDD-DT and MDD-ET (OR: 1.15, 95% CI: 1.01-1.31, p=0.0334), and bipolar and major depressive disorders (OR: 1.17, 95% CI: 1.07-1.28, p=0.0003). Optimal cut-off points for the cyclothymic temperament scores to discriminate between bipolar disorder and major depressive disorder and MDD-DT and MDD-ET were 9 (sensitivity: 64.6%, specificity: 76.0%) and 6 (66.1%, 62.3%), respectively., Conclusions: MDD-DT has a quantitatively stronger bipolar temperamental feature, cyclothymic temperament, relative to that of MDD-ET. Cut-off points determined in this study could be clinically helpful. Because of our study design, longitudinal changes in temperamental scores during treatment cannot be fully excluded., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Irritability, psychomotor agitation, and distractibility in a major depressive episode (MDE) should not be counted as manic/hypomanic symptoms of DSM-5-defined mixed features; however, this remains controversial. The practical usefulness of this definition in discriminating bipolar disorder (BP) from major depressive disorder (MDD) in patients with depression was compared with that of Benazzi's mixed depression, which includes these symptoms., Methods: The prevalence of both definitions of mixed depression in 217 patients with MDE (57 bipolar II disorder, 35 BP not otherwise specified, and 125 MDD cases), and their operating characteristics regarding BP diagnosis were compared., Results: The prevalence of both Benazzi's mixed depression and DSM-5-defined mixed features was significantly higher in patients with BP than it was in patients with MDD, with the latter being quite low (62.0% vs 12.8% [P < 0.0001], and 7.6% vs 0% [P < 0.0021], respectively). The area under the receiver operating curve for BP diagnosis according to the number of all manic/hypomanic symptoms was numerically larger than that according to the number of manic/hypomanic symptoms excluding the above-mentioned three symptoms (0.798; 95% confidence interval, 0.736-0.859 vs 0.722; 95% confidence interval, 0.654-0.790). The sensitivity/specificity of DSM-5-defined mixed features and Benazzi's mixed depression for BP diagnosis were 5.1%/100% and 55.1%/87.2%, respectively., Conclusions: DSM-5-defined mixed features were too restrictive to discriminate BP from MDD in patients with depression compared with Benazzi's definition. To confirm this finding, studies that include patients with BP-I and using tools to assess manic/hypomanic symptoms during MDE are necessary., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)

Background: Activation syndrome (AS) is a cluster of symptoms listed by the US Food and Drug Administration as possible suicidality precursors during antidepressant treatment. We aimed to clarify whether AS is associated with bipolar II disorder (BP-II) and its related disorder, i.e., bipolar disorder not otherwise specified (BP-NOS), which are often mistreated as major depressive disorder (MDD), as well as bipolar suggestive features in outpatients with depression., Methods: The frequency of AS, bipolar suggestive features, and background variables in consecutive outpatients with a major depressive episode (MDE) due to BP-II/BP-NOS or MDD, who were naturalistically treated with antidepressants, were investigated and analyzed retrospectively., Results: Of 157 evaluable patients (46 BP-II/BP-NOS, 111 MDD), 39 (24.8%) experienced AS. Patients with BP-II/BP-NOS experienced AS significantly more frequently than patients with MDD (52.2% of BP-II/BP-NOS vs. 13.5% of MDD, p<0.01). Univariate analysis revealed that BP-II/BP-NOS diagnosis, cyclothymic temperament, early age at onset of first MDE, psychiatric comorbidities, and depressive mixed state (DMX) were significantly associated with AS development in the entire sample. Multivariate analysis revealed that BP-II/BP-NOS diagnosis and DMX were independent risk factors for AS., Limitations: This is a retrospective and naturalistic study; therefore, patient selection bias could have occurred., Conclusions: Cautious monitoring of AS is needed during antidepressant trials in patients with BP-II/BP-NOS. Clinicians should re-evaluate underlying bipolarity when they confront AS. Antidepressants should be avoided for treating a current DMX beyond the unipolar-bipolar dichotomy. Prospective studies are needed to confirm these results., (© 2013 Elsevier B.V. All rights reserved.)

Background: The study aimed to identify specific predictors of soft bipolarity (bipolar II disorder or bipolar disorder not otherwise specified) in depressed patients and to evaluate the global predictive performance of combinations of these predictors., Methods: Subjects included 199 patients with a major depressive episode (MDE) due to soft bipolarity or major depressive disorder. Independent predictors of soft bipolar diagnosis were extracted from 12 previously proposed bipolar features using multiple logistic regression analyses, and the global performance of the combination of these predictors was evaluated using a receiver operating characteristic (ROC) curve., Results: Recurrent MDEs, family history of bipolar disorders in first-degree relatives, cyclothymic temperament, early age at onset of first MDE, and depressive mixed state were independent predictors of soft bipolarity diagnosis [odds ratio (95% confidence interval): 11.22 (2.19-57.63), 8.82 (1.31-59.15), 7.32 (2.22-24.19), 6.22 (1.58-24.57), and 5.57 (1.91-16.30), respectively]. The area under the ROC curve for the relationship between soft bipolarity diagnosis and the number of these five predictors in each patient was 0.911 (highly accurate). The presence of one or more predictors in each patient resulted in highest sensitivity (92.5%) and good specificity (73.1%), whereas that of two or more predictors resulted in good sensitivity (70.0%) and highest specificity (97.5%) for soft bipolarity diagnosis., Limitations: Structured/semistructured interviews were not used. Tools for temperament assessments were different between institutions., Conclusions: A combination of these predictors was quite helpful for a precise diagnosis of soft bipolarity in patients with depression., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Several studies have been conducted regarding the clinical features of the manic state in elderly patients with bipolar disorder; however, little information is available about bipolar depression in these patients, especially depression related to bipolar II disorder (BP-II) and bipolar disorder not otherwise specified (BP-NOS)., Methods: A chart review study of 87 patients (age > or = 60 years) hospitalized due to a major depressive episode (MDE) was conducted., Results: Thirty-two (36.8%) and 55 (63.2%) patients were diagnosed with bipolar disorder and major depressive disorder (MDD), respectively. BP-II/BP-NOS accounted for 81.3% of bipolar disorder and 29.9% of MDE. Of the 26 BP-II/BP-NOS patients, 73% had been initially diagnosed with MDD (61.0%) or others (12.0%). Compared to MDD patients, BP-II/BP-NOS patients showed a significantly younger age-at-onset of the first MDE (median, 52 vs. 66 years, p=0.000) and significantly more frequent MDEs (median, 3 vs. 1, p=0.000). The depressed mixed state (DMX) was observed in 61.5% of BP-II/BP-NOS patients in contrast to only 16.4% of MDD patients (p=0.000). The multiple logistic regression analysis revealed that younger age at onset of first MDE and DMX were independent markers of bipolarity., Limitations: Certain features were retrospectively specified by a single reviewer., Conclusion: Late-life depression due to BP-II/BP-NOS is generally misdiagnosed, but should never be neglected in elderly inpatients. Some features of the depression suggest bipolarity. In particular, DMX was found to be an independent marker of bipolarity, which supports the mixed nature of this disorder across generations., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background: Depressive mixed state (DMX) has been reported to be one of the most useful clinical markers for bipolar II disorder (BP-II) in the outpatient setting. However, the significance of DMX in emergency psychiatry has not been well studied., Methods: A chart review study of 139 patients who were hospitalized in an emergency psychiatric ward with an initial diagnosis of major depressive disorder (MDD)., Results: In 42 (30.2%) patients, the diagnosis was changed to bipolar disorder after a median observation period of 189 days from hospitalization, and of these, 34 were diagnosed as having BP-II. DMX was observed in 56 (40.3%) patients at the time of hospitalization. Compared with patients who remained in MDD, significantly more patients who later developed bipolar disorder had experienced DMX (59.5% vs. 32.0%, p = 0.0044). In multivariate analysis, DMX was one of the independent predictors of conversion to bipolar disorder (OR 2.45, p = 0.037), and the independent predictors for DMX were chronic depression and atypical features (OR 2.85, p = 0.010; OR 3.67, p = 0.046, respectively). In addition, DMX was significantly more frequently observed at emergency hospitalization than at non-emergency hospitalization (48.6% vs. 29.1%, p = 0.0065)., Limitations: A single reviewer evaluated DMX by chart review., Conclusion: DMX is a useful marker of bipolar disorder (mainly BP-II) in the emergency psychiatric setting and is closely related to emergency hospitalization for mood disorders. To confirm these findings, a prospective study that systematically evaluates DMX is needed.

Masahiro Takeshima,1 Hiroyasu Ishikawa,1 Yoshiaki Umeta,2 Mizuki Kudoh,3 Akise Umakoshi,1 Kazuhisa Yoshizawa,4 Yu Ito,1 Tomoko Hosoya,1 Ko Tsutsui,1 Hidenobu Ohta,1 Kazuo Mishima1 1Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita 010-8543, Japan; 2Department of Psychiatry, Omagari City Hospital, Akita 014-0067, Japan; 3Department of Neuropsychiatry, Nakadori Rehabilitation Hospital, Akita 010-0001, Japan; 4Department of Psychiatry, Akita City Hospital, Akita 010-0933, JapanCorrespondence: Masahiro TakeshimaDepartment of Neuropsychiatry, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita 010-8543, JapanTel +81-18-884-6122Fax +81-18-884-6445Email m.takeshima@med.akita-u.ac.jpPurpose: While depression has been recognized as a risk factor for venous thromboembolism (VTE), the prevalence of VTE in depressed inpatients has never been investigated. The aim of this study was thus to examine VTE prevalence and factors associated with VTE in depressed inpatients.Patients and Methods: We conducted a retrospective cross-sectional study of consecutive depressed inpatients (n = 94) from January 1, 2018, to June 30, 2019, at the psychiatry department of Akita University Hospital. As part of our clinical routine, depressed inpatients were screened for VTE using D-dimer, and patients who screened positive underwent enhanced CT to examine VTE. A variety of data was extracted from medical records, including, amongst others, age, sex, body mass index, diagnoses of psychiatric disorders, total scores on the 17-item Hamilton Depression Rating Scale, duration of current depressive episode, daily dosages of antidepressants and antipsychotics, catatonia, and physical restraint.Results: VTE was detected in 8.5% of depressed inpatients. There were no significant differences between VTE-positive and VTE-negative inpatients regarding any of the considered factors.Conclusion: Our analysis shows a VTE prevalence of 8.5% in depressed inpatients, higher than that of 2.3% reported in a previous study in hospitalized patients with psychiatric disorders including depression. This emphasizes the importance of VTE screening for depressive inpatients.Keywords: antidepressant, bipolar disorder, depression, sudden death, venous thrombosis