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Background: Psychosocial outcomes from the Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years (PREVENT) study were evaluated.Methods: Adult outpatients with recurrent major depressive disorder (MDD) and response or remission following 6-month continuation treatment with venlafaxine extended release (ER) were randomized to receive venlafaxine ER or placebo for 1 year. Patients without recurrence on venlafaxine ER during year 1 were randomized to venlafaxine ER or placebo for year 2. Psychosocial functioning was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q), Life Enjoyment Scale-Short Version (LES-S), Social Adjustment Scale-Self-Report (SAS-SR) total and individual factors, Short Form Health Survey (SF-36) (vitality, social functioning, and role function-emotional items), and Longitudinal Interval Follow-up Evaluation (LIFE).Results: At year 1 end, better overall psychosocial functioning was seen among patients randomly assigned to venlafaxine ER (n=129) vs placebo (n=129), with significant differences at end point on SF-36 role function-emotional, Q-LES-Q, and SAS-SR total, and work, house work, social/leisure, and extended-family factor scores (p≤0.05). At year 2 end, significant differences favored venlafaxine ER (n=43) vs placebo (n=40) on SF-36 vitality and role function-emotional, Q-LES-Q, LES-S, LIFE, and SAS-SR total, social/leisure, and extended-family factor scores (p≤0.05).Limitations: Patients with chronic MDD or treatment resistance were excluded and long-term specialist care was a financial incentive for treatment compliance. Discontinuation-related adverse events may have compromised the integrity of the treatment blind.Conclusions: For patients with recurrent MDD, 2 years' maintenance therapy with venlafaxine ER may improve psychosocial functioning vs placebo. [ABSTRACT FROM AUTHOR]

Background: Comorbid borderline personality disorder and major depressive disorder is common and often not adequately responsive to standard antidepressant therapies. Ketamine is a potentially life-saving option., Methods: 153 adult patients with MDD were assessed with the Personality Assessment Inventory (PAI) Borderline Subscale. Data was normally distributed with a mean + SD of 38.95 + 11.54. Patients >1 SD above the mean were assigned to the MDD + BF group. All others were assigned to the MDD-BF group. Patients were administered IV ketamine 0.5 mg/kg of ketamine over 40 min. Mood was assessed using the Beck Depression Inventory-II at baseline, 3 and 24 h post-ketamine. Scores between the MDD + BF and MDD-BF group at each time point were compared using t-test or analysis of covariance (ANCOVA) model. The primary outcome was response at 24 h., Results: The LS mean change in BDI at 24 h was -23.8 (15.3) for MDD + BF and -21.0 (13.5) for MDD-BF (F [1151] = 0.043, p = 0.51). The LS mean change in BDI at 3 h was -21.3 (13.2) for MDD + BF and -19.6 (13.2) for MDD-BF (F[1151] = 0.045, p = 0.83). The LS mean change in BDI at 14 days was -23.2 (15.3) for MDD + BF and -15.3 (15.2) for MDD-BF (F[1130] = 4.24, p = 0.04)., Limitations: People in the MDD + BF group were not necessarily diagnosable with borderline personality disorder., Conclusions: These data indicate that IV ketamine is effective in MDD patients with and without elevated borderline features. This can provide clinicians some reassurance about using ketamine in this population., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Patients with bipolar disorder have higher rates of cardiometabolic comorbidities and mortality. Although guidelines emphasize the importance of cardiovascular monitoring, few studies characterized the cardiometabolic risk profile during treatment and their relation to symptomatology and treatment response., Methods: We analyzed data from two similar 24-weeks comparative effectiveness trials, with a combined sample of 770 participants randomized to two different lithium doses, quetiapine (300 mg/day), or standard treatment without lithium. Glucose, lipids and vital signs were measured before and after 24 weeks of treatment. We calculated several cardiovascular risk scores, assessed baseline correlations and compared the four treatment arms via multiple linear regression models., Results: Higher cholesterol and LDL levels were associated with greater depression severity, showing differential correlations to specific symptoms, particularly agitation, low energy and suicidality. Those randomized to quetiapine showed a significant worsening of cardiometabolic markers during the 24-week trial. Neither baseline nor change in lipid levels correlated with differential treatment response., Limitations: Study duration was short from the perspective of cardiometabolic risk markers, and all treatment arms included patients taking adjunct antipsychotics. The trials compared quetiapine to lithium, but not to other medications known to affect similar risk factors., Conclusions: Treatment with 300 mg/day quetiapine for 24 weeks, representing a short and common dose course, resulted in increased cardiometabolic risk markers, emphasizing the importance of monitoring during mood-stabilizing treatment. The symptom-specific associations are in line with previous studies in unipolar depression, suggesting a cardiometabolic-depression link that needs to be further studied in bipolar depression., (Copyright © 2021. Published by Elsevier B.V.)

Background: Up to 15% of patients with major depressive disorder (MDD) attempt suicide and up to 2% complete suicide. This was a post-hoc analysis aimed to evaluate the risk of suicide ideation and behavior associated with adjunctive pimavanserin treatment in adults with MDD., Methods: CLARITY was a randomized, double-blind, placebo-controlled study in patients with MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). For this post-hoc analysis, the primary endpoint was mean change from baseline for HAMD item 3 (suicide). The incidence of suicidal ideation or behavior was also assessed from the Columbia-Suicide Severity Rating Scale (C-SSRS) and reports of adverse events., Results: During Stage 1, LS mean change for HAMD Item 3 was reduced from baseline at each week with pimavanserin with a significant difference between pimavanserin and placebo at Week 3 (p=0.012, effect size: 0.431). At any post-baseline assessment, suicidal ideation on the C-SSRS was reported in 28 (18.1%) of patients with placebo and 9 (17.3%) with pimavanserin during Stage 1 and in 7 (20.7%) with placebo and 4 (13.8%) with pimavanserin during Stage 2. No events of suicidal behavior were observed with either placebo or pimavanserin., Limitations: The post hoc nature, exclusion of patients with any history of suicide from the primary study, and the small number of patients who demonstrated evidence of suicidal ideation., Conclusions: Adjunctive pimavanserin was not associated with an increase in suicidal ideation in patients with MDD. Further study is needed to verify these results., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Shared decision-making (SDM) involves patients and clinicians choosing treatment jointly. SDM in mental health is hampered by lack of well-developed supporting tools. We describe an evidence-based patient decision aid (PDA) to facilitate SDM for treatment-resistant depression (TRD) following US National Quality Forum standards which are based upon the International Patient Decision Aid Standards (IPDAS)., Methods: A web-based PDA was developed by a multidisciplinary steering committee of clinicians, patient advocates, patients and a decision scientist. Development included creating content consistent with decision-making domains that are impacted by patient preference in TRD. Development was guided by literature review, group conference calls/discussions, patient and clinician interviews (N = 8), high and lower literacy focus groups (N = 11) and pilot study (N = 5). The PDA presents risk-benefit information on domains (e.g., effectiveness, mode of administration, side effects, cost) and includes values clarification exercises. Pilot study patients were administered the Decisional Conflict Scale (DCS) and Decision Self-Efficacy Scale (DSES) prior to and following PDA interaction and clinician SDM., Results: During the pilot, prior to PDA interaction, mean (standard deviation) DCS score was 42.2 (14.4) and DSES score was 86.0 (14.6) out of 100. Following PDA interaction and SDM, DCS decreased (improved) to 28.1 (SD 4.1) and DSES increased to 95.5 (6.7). All patients endorsed that the PDA helped them to: recognize pros and cons of options; understand how treatments were administered, possible side-effects, and likelihood of benefit; recognize what was important relative to the decision; organize thoughts and prepare for a discussion with their clinician., Conclusions: This PDA may support SDM in TRD. A future trial to determine impact of the present SMD on decision-making quality is warranted. It also highlights gaps in comparative effectiveness trials that could guide equitable shared decision-making., (Copyright © 2020. Published by Elsevier B.V.)

Background: Bipolar disorder is a heritable disorder, and we aimed to assess the impact of family history of mental disorders in first-degree relatives on the severity and course of bipolar disorder., Methods: The Bipolar CHOICE (lithium versus quetiapine) and LiTMUS (optimized treatment with versus without lithium) comparative effectiveness studies were similar trials among bipolar disorder outpatients studying four different randomized treatment arms for 24 weeks. Patients self-reported on six severe mental disorders among first-degree relatives. We performed ANOVA and linear regression regarding disease severity measures, sociodemographic and cardiometabolic markers and mixed effects linear regression to evaluate treatment response., Results: Among 757 patients, 644 (85.1%) reported at least one first-degree relative with a severe mental disorder (mean=2.8; standard deviation=2.2; range=0-13). Depression (67.1%), alcohol abuse (51.0%) and bipolar disorder (47.0%) were the most frequently reported disorders. Familial psychiatric history correlated with several disease severity measures (hospitalizations, suicide attempts, and earlier onset) and sociodemographic markers (lower education and household income) but not with cardiometabolic markers (e.g. cholesterol or waist circumference) or cardiovascular risk scores, e.g. the Framingham risk score. Patients with familial psychiatric history tended to require more psychopharmacological treatment (p=0.054) but responded similarly (all p>0.1) to all four treatment arms., Conclusions: Our findings indicate that familial psychiatric history is common among outpatients with bipolar disorder and correlates with disease severity and sociodemographic measures. Patients with a greater familial psychiatric load required more intense treatment but achieved similar treatment responses compared to patients without familial psychiatric history., Competing Interests: Declaration of Competing Interest The other authors declare no competing interests., (Copyright © 2020. Published by Elsevier B.V.)

Background: Lithium and quetiapine can cause weight gain, but their comparative longer term anthropometric effects are unknown, as are the potential moderating effects of baseline binge-eating (BE) behavior., Methods: We assessed 6 month changes in body weight, body mass index (BMI) and waist circumference in 482 adults with DSM-IV bipolar disorders who participated in a comparative effectiveness study of lithium and quetiapine with evidence-based adjunctive treatment (Bipolar CHOICE). Anthropometric measurements were obtained at baseline, and at 2, 4, 6, 8, 12, 16, 20, and 24 weeks. BE behavior was defined as affirmative responses to MINI items M1 and M3 at baseline. Data were analyzed using a mixed model repeated measures approach, adjusted for baseline values of dependent measures., Results: On average, body weight and BMI increased over 6 months with lithium and quetiapine. However, those treated with quetiapine experienced greater increases from baseline in body weight (peak change, + 3.6 lbs. vs. + 1.4 lbs.) and BMI (peak change, + 0.6 kg/m 2 vs. + 0.3 kg/m 2 ), starting at 2 weeks (group x time, F 8,3052   = 2.9, p = 0.003 for body weight, F 8,3052   = 3.0, p = 0.002 for BMI). Significant increases in waist circumference were observed only with quetiapine. The relationship between drug treatment and changes in body weight (group x time x binge eating status, F 1,2770   = 2.0, p = 0.002), BMI (F 1,2767   = 2.0, p = 0.002), and waist circumference (women only, F 25,1621   = 2.9, p < 0.0001) were moderated by BE behavior. The largest increases over 24 weeks in body weight and BMI, and waist circumference in women, occurred for quetiapine-treated patients with baseline binge-eating, relative to quetiapine-treated patients without binge eating and lithium-treated patients with or without baseline binge-eating., Limitations: Bipolar CHOICE was not designed to study anthropometric outcomes., Conclusions: Greater changes in body weight, BMI, and waist circumference occurred with quetiapine- versus lithium-based treatment over 6 months of treatment. The effects of study drugs on these anthropometric measures were moderated by BE behavior at baseline., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Not all patients with bipolar depression have suicidal ideation (SI). This study examines some factors that link bipolar depression to SI., Methods: 482 individuals with bipolar I or II were randomized to either lithium or quetiapine plus adjunctive personalized therapy in a 24 week comparative effectiveness trial. Severity of depression and SI were assessed with the Bipolar Inventory of Symptoms Scale (BISS). We examined potential moderators (age, gender, age of illness onset, bipolar type, comorbid anxiety, substance use, past suicide attempts, childhood abuse and treatment arm) and mediators (severity of anxiety, mania, irritability, impairment in functioning (LIFE-RIFT) and satisfaction and enjoyment of life (Q-LES-Q)) of the effect of depression on SI. Statistical analyses were conducted using generalized estimating equations with repeated measures., Results: Bipolar type and past suicide attempts moderated the effect of depression on SI. Life satisfaction mediated the effect of depression and SI. The relationship between anxiety, depression and SI was complex due to the high level of correlation. Treatment with lithium or quetiapine did not moderate the effect of depression on SI., Limitations: Suicide assessment was only done using an item on BISS. Patient population was not specifically chosen for high suicide risk., Discussion: Individuals with Bipolar II experienced more SI with lower levels of depression severity. A history of suicide predisposed patients to higher levels of SI given the same severity of depression. Reduced life satisfaction mediates the effect of depression on SI and may be a target for therapeutic interventions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Complex polypharmacy (CP) is common in bipolar disorder (BD). We assessed the associations between CP, adherence, and side effect burden, and patient traits associated with clinical improvement in relationship to CP., Methods: We conducted a secondary analysis of 482 adult BD participants in the Bipolar CHOICE trial. We examined the associations between CP (use of ≥3 BD medications) and non-adherence (missing >30% of BD medication doses in the last 30 days) and side effect burden (Frequency, Intensity and Burden of Side Effects Rating scale) using multivariate models with patient random effects. We used logistic regression to assess the patient traits associated with remission among those with majority CP use (Clinical Global Impression-Severity for BD score ≤2 for 8+ weeks)., Results: 43% of patients had any CP and 25% had CP for the majority of the study. CP was associated with non-adherence (OR = 2.51, 95% CI [1.81, 3.50]), but not worse side effect burden. Among those with CP, 16% achieved remission; those with non-adherence, comorbid social or generalized anxiety disorder, or BD I vs. II were less likely to achieve remission among those with CP., Limitations: There could be unmeasured confounding between use of CP and side effect burden or adherence. Adherence was measured by self-report, which could be subject to reporting error., Conclusions: BD patients with CP were less likely to adhere to therapy, and those with worse adherence to CP were less likely to clinically respond. Clinicians should assess medication adherence prior to adding another agent to medication regimens., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Approximately 86-89% of patients with BD have a comorbid anxiety disorder associated with poor quality of life and reduced likelihood of recovery from an acute mood episode. The purpose of this study is to assess the prevalence and impact of comorbid anxiety using the Bipolar Inventory of Symptoms Scale (BISS) in patients with BD who participated in a 6-month pragmatic trial., Methods: Participants (N = 482) in the Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (CHOICE) study were adults with BD I or II. Anxiety diagnoses were assessed with the MINI. Global illness severity was assessed using the Clinical Global Impression-Bipolar Version. Mood symptoms and anxiety severity were assessed using the BISS., Results: 61% of the study sample met criteria for a current anxiety disorder. Patients with a higher BISS anxiety score at baseline had a higher overall BD illness severity, depressive severity, and manic episode severity (p < 0.001). A single cutoff value of BISS anxiety had great sensitivity, yet poor specificity for determining a comorbid anxiety diagnosis. There were no significant differences in outcomes for individuals treated for anxiety disorders with anxiolytics compared with those who were not treated with anxiolytics., Limitations: Sample size limitations prevented an analysis of whether the BISS cutoff score of 10 performed differently across varied anxiety disorders., Conclusions: Given its ability to identify patients with co-occurring anxiety, the BISS anxiety subscale shows clinical utility as a screening measure though its application as a clinical assessment measure may not be advisable., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Bipolar patients experience sleep disturbances during and between mood episodes. Yet the impact of sleep on treatment with different medications has not been fully explored. The purpose of this paper is to explore the potential impact of poor sleep at baseline on outcomes in a randomized effectiveness trial of quetiapine and lithium., Methods: The Bipolar CHOICE study was a 6-month, parallel group, multisite randomized controlled trial. Participants with bipolar disorder (N = 482; 59% female and age 18-70 years) received quetiapine or lithium. Patients were allowed to also receive adjunctive personalized treatments, which were guideline-informed, empirically-based medications added to treatment as needed. Medication changes were recorded as necessary clinical adjustments (NCA). Fisher's exact tests, mixed-regression models, and Mann-Whitney U tests were used to assess demographic and clinical characteristics as well as whether sleep disturbance would predict outcomes., Results: 63% of patients had baseline sleep disturbance. Individuals with sleep disturbance had worse bipolar illness severity, greater severity of depression, mania, anxiety, irritability, and psychosis, were less likely to have sustained response (17% vs. 29%; adjusted RR: 0.55, 95% CI: 0.38-0.78, p = 0.0006) and had more NCAs (median 0.71 vs. 0.59, p = 0.03)., Limitations: Our findings were limited by how we defined sleep disturbance, and by how severity of sleep disturbance was assessed with one item with a non-sleep specific measure., Conclusions: Baseline sleep disturbance was associated with more severe bipolar symptoms and worse 6-month outcomes. Further research is warranted on improving sleep in bipolar disorder, especially the role of psychosocial interventions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Gene-environment interaction contributes to the risks of psychiatric disorders. Interactions between FKBP5 gene variants and early-life stress may enhance the risk not only for mood disorder, but also for a number of other behavioral phenotypes. The aim of the present study was to review and conduct a meta-analysis on the results from published studies examining interaction between FKBP5 gene variants and early-life stress and their associations with stress-related disorders such as major depression and PTSD., Methods: A literature search was conducted using PsychINFO and PubMed databases until May 2017. A total of 14 studies with a pooled total of 15109 participants met the inclusion criteria, the results of which were combined and a meta-analysis was performed using the differences in correlations as the effect measure. Based on literature, rs1360780, rs3800373, and rs9470080 SNPs were selected within the FKBP5 gene and systematic review was conducted., Results: Based on the Comprehensive Meta-Analysis software, no publication bias was detected. Sensitivity analysis and credibility of meta-analysis results also indicated that the analyses were stable. The meta-analysis showed that individuals who carry T allele of rs1360780, C-allele of rs3800373 or T-allele of rs9470080 exposed to early-life trauma had higher risks for depression or PTSD., Limitations: The effects of ethnicity, age, sex, and different stress measures were not examined due to limited sample size., Conclusions: These results provide strong evidence of interactions between FKBP5 genotypes and early-life stress, which could pose a significant risk factor for stress-associated disorders such as major depression and PTSD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Suicidal ideation occurs frequently among individuals with bipolar disorder; however, its course and persistence over time remains unclear. We aimed to investigate 6-months trajectories of suicidal ideation among adults with bipolar disorder., Methods: The Bipolar CHOICE study randomized 482 outpatients with bipolar disorder to 6 months of lithium- or quetiapine-based treatment including other psychotropic medications as clinically indicated. Participants were asked at 9 visits about suicidal ideation using the Concise Health Risk Tracking scale. We performed latent Growth Mixture Modelling analysis to empirically identify trajectories of suicidal ideation. Multinomial logistic regression analyses were applied to estimate associations between trajectories and potential predictors., Results: We identified four distinct trajectories. The Moderate-Stable group represented 11.1% and was characterized by constant suicidal ideation. The Moderate-Unstable group included 2.9% with persistent thoughts about suicide with a more fluctuating course. The third (Persistent-low, 20.8%) and fourth group (Persistent-very-low, 65.1%) were characterized by low levels of suicidal ideation. Higher depression scores and previous suicide attempts (non-significant trend) predicted membership of the Moderate-Stable group, whereas randomized treatment did not., Limitations: No specific treatments against suicidal ideation were included and suicidal thoughts may persist for several years., Conclusion: More than one in ten adult outpatients with bipolar disorder had moderately increased suicidal ideation throughout 6 months of pharmacotherapy. The identified predictors may help clinicians to identify those with additional need for treatment against suicidal thoughts and future studies need to investigate whether targeted treatment (pharmacological and non-pharmacological) may improve the course of persistent suicidal ideation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Psychotic bipolar depressive episodes remain remarkably understudied despite being common and having a significant impact on bipolar disorder. The aim of this study is to identify the characteristics of depressed bipolar patients with current psychosis compared to those without psychosis., Methods: We used baseline data of a comparative effectiveness study of lithium and quetiapine for bipolar disorder (the Bipolar CHOICE study) to compare demographic, clinical, and functioning variables between those with and without psychotic symptoms. Of the 482 participants, 303 (62.9%) were eligible for the present study by meeting DSM-IV criteria for an acute bipolar depressive episode. Univariate analyses were conducted first, and then included in a model controlling for symptom severity., Results: The sample was composed mostly of women (60.7%) and the mean age was 39.5±12.1 years. Psychosis was present in 10.6% (n=32) of the depressed patients. Psychotic patients had less education, lower income, and were more frequently single and unemployed. Psychosis was also associated with a more severe depressive episode, higher suicidality, more comorbid conditions and worse functioning. Most group differences disappeared when controlling for depression severity., Limitations: Only outpatients were included and the presence of psychosis in previous episodes was not assessed., Conclusion: Psychosis during bipolar depressive episodes is present even in an outpatient sample. Psychotic, depressed patients have worse illness outcomes, but future research is necessary to confirm if these outcomes are only associated with the severity of the disorder or if some of them are independent of it., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: DSM-5 changed the criteria from DSM-IV for mixed features in mood disorder episodes to include non-overlapping symptoms of depression and hypomania/mania. It is unknown if, by changing these criteria, the same group would qualify for mixed features. We assessed how those meeting DSM-5 criteria for mixed features compare to those meeting DSM-IV criteria., Methods: We analyzed data from 482 adult bipolar patients in Bipolar CHOICE, a randomized comparative effectiveness trial. Bipolar diagnoses were confirmed through the MINI International Neuropsychiatric Interview (MINI). Presence and severity of mood symptoms were collected with the Bipolar Inventory of Symptoms Scale (BISS) and linked to DSM-5 and DSM-IV mixed features criteria. Baseline demographics and clinical variables were compared between mood episode groups using ANOVA for continuous variables and chi-square tests for categorical variables., Results: At baseline, the frequency of DSM-IV mixed episodes diagnoses obtained with the MINI was 17% and with the BISS was 20%. Using DSM-5 criteria, 9% of participants met criteria for hypomania/mania with mixed features and 12% met criteria for a depressive episode with mixed features. Symptom severity was also associated with increased mixed features with a high rate of mixed features in patients with mania/hypomania (63.8%) relative to those with depression (8.0%)., Limitations: Data on mixed features were collected at baseline only and thus do not reflect potential patterns in mixed features within this sample across the study duration., Conclusions: The DSM-5 narrower, non-overlapping definition of mixed episodes resulted in fewer patients who met mixed criteria compared to DSM-IV., (Copyright © 2017. Published by Elsevier B.V.)

Background: Comparative effectiveness research uses multiple tools, but lacks outcome measures to assess large electronic medical records and claims data. Aggregate changes in medications in response to clinical need may serve as a surrogate outcome measure. We developed the Medication Recommendation Tracking Form (MRTF) to record the frequency, types, and reasons for medication adjustments in order to calculate Necessary Clinical Adjustments (NCAs), medication adjustments to reduce symptoms, maximize treatment response, or address problematic side effects., Methods: The MRTF was completed at every visit for 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial., Results: Responders had significantly fewer NCAs compared to non-responders. NCAs predicted subsequent response status such that every additional NCA during the previous visit decreased a patient's odds of response by approximately 30%. Patients with more severe symptoms had a greater number of NCAs at the subsequent visit. Patients with a comorbid anxiety disorder demonstrated a significantly higher rate of NCAs per month than those without a comorbid anxiety disorder. Patients with greater frequency, intensity, and interference of side effects had higher rates of NCAs. Participants with fewer NCAs reported a higher quality of life and decreased functional impairment., Limitations: The MRTF has not been examined in community clinic settings and did not predict response more efficiently than the Clinical Global Impression-Bipolar Version (CGI-BP)., Conclusions: The MRTF is a feasible proxy of clinical outcome, with implications for clinical training and decision-making. Analyses of big data could use changes in medications as a surrogate outcome measure., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Few brief, self-report measures exist that can reliably predict adverse suicidality outcomes in patients with BD. This study utilized the Concise Health Risk Tracking Self-Report (CHRT) to assess suicidality in patients with BD and examined its psychometric performance, clinical correlates, and prospective value in predicting adverse events related to suicidality., Methods: The CHRT was administered at baseline and follow-up to 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial. The Columbia Suicide Severity Rating Scale (CSSRS) was used at baseline to assess lifetime history of suicide attempts and related behaviors. Clinician-rated measures of mood (Bipolar Inventory of Symptoms Scale) and bipolar symptoms (Clinical Global Impressions-Bipolar Version) were conducted at baseline and follow-up., Results: The CHRT showed excellent internal consistency and construct validity and was highly correlated with clinician ratings of depression, anxiety, and overall functioning at baseline and throughout the study. Baseline CHRT scores significantly predicted risk of subsequent suicidality-related Serious Adverse Events (sSAEs), after controlling for mood and comorbidity. Specifically, the hazard of a sSAE increased by 76% for every 10-point increase in baseline CHRT score. Past history of suicide attempts and related behaviors, as assessed by the CSSRS, did not predict subsequent sSAEs., Limitations: The CSSRS was used to assess static risk factors in terms of past suicidal behaviors and may have been a more powerful predictor over longer-term follow-up., Conclusions: The CHRT offers a quick and robust self-report tool for assessing suicidal risk and has important implications for future research and clinical practice., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Little is known about the longer-term effects of adjunctive benzodiazepines on symptom response during treatment in patients with bipolar disorders., Methods: The study sample consisted of 482 patients with bipolar I or II disorder enrolled in a 6-month, randomized, multi-site comparison of lithium- and quetiapine-based treatment. Changes in clinical measures (BISS total and subscales, CGI-BP, and CGI-Efficacy Index) were compared between participants who did and did not receive benzodiazepine treatment at baseline or during follow-up. Selected outcomes were also compared between patients who did and did not initiate benzodiazepines during follow-up using stabilized inverse probability weighted analyses., Results: Significant improvement in all outcome measures occurred within each benzodiazepine exposure group. Benzodiazepine users (at baseline or during follow-up) experienced significantly less improvement in BISS total, BISS irritability, and CGI-BP scores than did benzodiazepine non-users. There were no significant differences in these measures between patients who did and did not initiate benzodiazepines during follow-up in the weighted analyses. There was no significant effect of benzodiazepine use on any outcome measure in patients with comorbid anxiety or substance use disorders., Limitations: This is a secondary analysis of data from a randomized effectiveness trial that was not designed to address differential treatment response according to benzodiazepine use., Conclusions: Adjunctive benzodiazepines may not significantly affect clinical outcome in lithium- or quetiapine-treated patients with bipolar I or II disorder over 6 months, after controlling for potential confounding factors., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Individuals with bipolar disorder lead a sedentary lifestyle associated with worse course of illness and recurrence of symptoms. Identifying potentially modifiable predictors of exercise frequency could lead to interventions with powerful consequences on the course of illness and overall health., Methods: The present study examines baseline reports of exercise frequency of bipolar patients in a multi-site comparative effectiveness study of a second generation antipsychotic (quetiapine) versus a classic mood stabilizer (lithium). Demographics, quality of life, functioning, and mood symptoms were assessed., Results: Approximately 40% of participants reported not exercising regularly (at least once per week). Less frequent weekly exercise was associated with higher BMI, more time depressed, more depressive symptoms, and lower quality of life and functioning. In contrast, more frequent exercise was associated with experiencing more mania in the past year and more current manic symptoms., Limitations: Exercise frequency was measured by self-report and details of the exercise were not collected. Analyses rely on baseline data, allowing only for association analyses. Directionality and predictive validity cannot be determined. Data were collected in the context of a clinical trial and thus, it is possible that the generalizability of the findings could be limited., Conclusion: There appears to be a mood-specific relationship between exercise frequency and polarity such that depression is associated with less exercise and mania with more exercise in individuals with bipolar disorder. This suggests that increasing or decreasing exercise could be a targeted intervention for patients with depressive or mood elevation symptoms, respectively., (© 2013 Elsevier B.V. All rights reserved.)

Background: The clinical effects of antidepressant combinations vs. monotherapy as initial treatment for major depression with melancholic features (MDD-MF) are unknown., Methods: Outpatients with chronic or recurrent major depression (MDD) were randomized to initial treatment with escitalopram+placebo (the MONO condition), bupropion-sustained release+escitalopram, or venlafaxine-extended release+mirtazapine (the COMB conditions) in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial. Secondary data analyses were conducted to compare demographic and clinical characteristics, and contrast clinical responses according to drug treatment, in patients with MDD-MF (n=124) and non-melancholic MDD (n=481)., Results: While numerically lower, remission rates in MDD-MF did not differ significantly from those with non-melancholic MDD either at 12 (33.1% vs. 41.0%, aOR 1.16, p=0.58) or 28 (39.5% vs. 46.8%, aOR=1.02, p=0.93) weeks of treatment. Remission rates did not differ significantly between combination and monotherapy groups in either MDD-MF or non-melancholic MDD patients at either time point. Similar conclusions were reached for response rates, premature study discontinuation, and self-rated depression symptom severity., Limitations: This is a secondary analysis of data from the CO-MED trial, which was not designed to address differential treatment response in melancholic and non-melancholic MDD., Conclusions: We found no evidence of differential remission or response rates to antidepressant combination or monotherapy between melancholic/non-melancholic MDD patients, or according to antidepressant treatment group, after 12 and 28 weeks. Melancholic features may not be a valid predictor of more favorable response to antidepressant combination therapy as initial treatment., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The authors examined the patterns of improvement in cognitive and vegetative symptoms of major depression in individuals treated with cognitive therapy (CT) or pharmacotherapy (PT)., Method: Outpatients diagnosed with major depressive disorder (n=180) were randomized to receive either CT or PT. Cognitive and vegetative symptoms of major depression were measured by the Beck Depression Inventory-II at baseline and regularly throughout 16 weeks of treatment., Results: Multivariate hierarchical linear modeling demonstrated the same patterns of change over time for cognitive and vegetative symptoms within CT and within PT., Limitations: Self-report measures may not be sufficiently specific to capture subtle differences in improvements between vegetative and cognitive symptoms., Conclusions: These results are consistent with Beck's [Beck, A.T., 1984, November. Cognition and theory [Letter to the editor]. Arch. Gen. Psychiatry 41, 1112-1114.] hypothesis that CT and PT have a similar site of action, which when targeted, results in changes in both cognitive and vegetative features.

Background: This study evaluated the clinical and sociodemographic features associated with various degrees of concurrent comorbidity in adult outpatients with nonpsychotic major depressive disorder (MDD)., Methods: Outpatients enrolled in the STAR*D trial completed the Psychiatric Diagnostic Screening Questionnaire (PDSQ). An a priori 90% specificity threshold was set for PDSQ responses to ascertain the presence of 11 different concurrent DSM-IV Axis I disorders., Results: Of 1376 outpatients, 38.2% had no concurrent comorbidities, while 25.6% suffered one, 16.1% suffered two, and 20.2% suffered three or more comorbid conditions. Altogether, 29.3% met threshold for social anxiety disorder, 20.8% for generalized anxiety disorder, 18.8% for posttraumatic stress disorder, 12.4% for bulimia, 11.9% for alcohol abuse/dependence, 13.4% for obsessive-compulsive disorder, 11.1% for panic disorder, 9.4% for agoraphobia, 7.3% for drug abuse/dependence, 3.7% for hypochondriasis, and 2.2% for somatoform disorder. Those with more concurrent Axis I conditions had earlier ages at first onset of MDD, longer histories of MDD, greater depressive symptom severity, more general medical comorbidity (even though they were younger than those with fewer comorbid conditions), poorer physical and mental function, health perceptions, and life satisfaction; and were more likely to be seen in primary care settings., Limitations: Participants had to meet entry criteria for STAR*D. Ascertainment of comorbid conditions was not based on a structured interview., Conclusions: Concurrent Axis I conditions (most often anxiety disorders) are very common with MDD. Greater numbers of concurrent comorbid conditions were associated with increased severity, morbidity, and chronicity of their MDD.

Background: We assessed the therapeutic effects of venlafaxine XR and paroxetine on mood and anxiety symptoms derived from the tripartite model of mood. We hypothesized that the two antidepressants would have largely similar effects on symptoms of negative affect because both agents influence serotonergic systems. However, based on evidence indicating linkages between catecholaminergic activity and the emotional dimension of positive affect, we hypothesized that the catecholaminergic effects of venlafaxine XR would yield particularly pronounced effects on symptoms of positive affect., Methods: Twenty depressed outpatients were randomly assigned to treatment with either venlafaxine XR (225 mg/day) or paroxetine (30 mg/day) during a 12-week treatment trial. Weekly mood ratings were collected using the Mood and Anxiety Symptom Questionnaire [Watson, D., Clark, L.A., Weber, K., Assenheimer, J.S., Strauss, M.E., McCormick, R.A., 1995. Testing a tripartite model: II. Exploring the symptom structure of anxiety and depression in student, adult, and patient samples. J. Abnorm. Psychol. 104 (1), 15-25] [Watson, D., Weber, K., Assenheimer, J.S., Clark, L.A., Strauss, M.E., McCormick, R.A., 1995. Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. J. Abnorm. Psychol. 104 (1), 3-14]., Results: Consistent with predictions, analyses revealed that there were no significant differences between venlafaxine XR and paroxetine on measures of negative affect. However, contrary to predictions, the two medications produced similar changes on measures of positive affect., Limitations: Replication and extension using a larger sample size are mandated., Conclusions: These preliminary results suggest that two antidepressants that appear to have dissimilar mechanisms of action may nevertheless have similar effects on the positive and negative affective components of depression. Alternatively, paroxetine may have a clinically relevant noradrenergic effect at the dose tested.

Background: We assessed the therapeutic effects of bupropion SR and placebo on mood and anxiety symptoms derived from the tripartite model of mood. Based on evidence indicating linkages between dopaminergic activity and the emotional dimension of positive affect/anhedonia, we hypothesized that the dopaminergic effects of bupropion SR would yield particularly pronounced effects on symptoms of anhedonia, relative to anxiety., Methods: Nineteen depressed outpatients were randomly assigned to treatment with either bupropion SR 300 mg/day or placebo during a 6-week initial treatment phase. This was followed by a second open-label phase in which patients previously treated with bupropion SR had their dose increased to 400 mg/day, and the placebo group was initiated on bupropion SR 300 mg/day., Results: Random regression analyses revealed that during the initial double-blind phase, bupropion SR elicited greater declines than placebo on all measures except those that assessed anxiety. By contrast, the weakest placebo effects were evident on anhedonia. Items assessing the low positive affect pole of the anhedonia dimension were more sensitive to earlier/lower dose bupropion SR treatment, whereas items assessing the high positive affect pole were more sensitive to later/higher dose bupropion SR treatment., Limitations: Replication and extension using a larger sample size are mandated., Conclusions: This study suggests that the catecholaminergic effects of bupropion SR tended to produce more robust effects on anhedonia/positive affect than placebo.

Background: The present study was designed to confirm or refute in human fibroblasts the hypothesized cross-talk elicited via neurotransmitter transduction cascades at the level of protein kinase mediated phosphorylation of the nuclear transcription factor CREB., Methods: Human fibroblasts from normal control subjects were subcultured and incubated at confluency after five growth passages with isoproterenol (stimulation of PKA mediated phosphorylation) and/or phorbol 12-myristate 13-acetate (PMA) (stimulation of PKC mediated phosphorylation) followed by the determination of nuclear CREB-P by immunoblotting, enhanced chemiluminescence and quantitation of the autoradiograms by laser densitometry., Results: Using the nuclear transcription factor CREB as a target, both the activation of the cyclic AMP-PKA pathway by isoproterenol and the activation of the PKC pathway by PMA caused phosphorylation of nuclear CREB. This phosphorylation is additive in nature and appears to occur at the same molecular site, serine133 of CREB., Conclusions: The present results in human fibroblasts demonstrate that the hypothesized cross-talk at the level of protein kinase mediated phosphorylation of transcription factors is no longer hypothetical. Since it is the phosphorylation of nuclear CREB that determines its dimerization and transcriptional activation of programs of CRE containing genes, the results suggest that this convergence of the neurotransmitter signals may be the critical mechanism in gene expression following the administration of antidepressant drugs that affect noradrenergic, serotonergic or both transduction cascades. The results may also provide a rationale for the apparent superior clinical efficacy of dual uptake inhibitors.

Background: Previous studies have demonstrated a blunted beta adrenoceptor-linked protein kinase A (PKA) response in the 900xg supernatant fraction of human fibroblasts cultured from patients with major depression., Results: Results of the present studies demonstrate a significant reduction in the B(max) value of [3H]cyclic AMP binding to the regulatory subunit of PKA in the supernatant fraction of fibroblasts from patients with major depression with no change in the K(d) values. The data are consistent with the previous observation that the maximal stimulation of PKA by cyclic AMP is reduced without a change in the EC(50) value. The blunted beta adrenoceptor-mediated PKA response in fibroblasts from patients with major depression is reflected in a significant reduction in the isoproterenol-stimulated phosphorylation of the nuclear transcription factor CREB. Both, the isoproterenol-mediated phosphorylation of nuclear CREB and the activation of the stably transfected luciferase reporter gene, pAD neo2-C12-BGL, were inhibited by the beta(2) adrenoceptor antagonist ICI 118551, thus indicating that the gene activating action of isoproterenol in human fibroblasts is mediated via the beta(2) adrenoceptor cascade. The low EC(50) value of 1 nM isoproterenol for activation of gene expression in stably transfected human fibroblasts appears to be a reflection of the amplification mechanism occurring via the beta adrenoceptor-cyclic AMP-PKA-CREB transduction cascade., Conclusions: The results support the notion that human fibroblasts represent a relevant model for studying processes of signal transduction in patients with affective disorders.