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Sex is seldom considered as a potential moderator of the impact of bipolar disorder (BD) on cardiovascular disease (CVD) risk. We aimed to characterize the sex-specific association of CVD and BD using data from the UK Biobank.In a cross-sectional analysis, we compared the odds ratio between women and men with BD for seven CVD diagnoses (coronary artery disease, myocardial infarction, angina, atrial fibrillation, heart failure, stroke, and essential hypertension) and four cardiovascular biomarkers (arterial stiffness index, low-density lipoprotein, C-reactive protein, and HbA1c) in 293 participants with BD and 257,380 psychiatrically healthy controls in the UK Biobank.After adjusting for age, we found a two- to three-fold stronger association among women than among men between BD and rates of coronary artery disease, heart failure, and essential hypertension, with a significant sex-by-diagnosis interactions. The association remained significant after controlling for self-reported race, education, income, and smoking status. After controlling for potential confounders, there was no significant association between sex and any cardiovascular biomarkers.These analyses could not disentangle effects of BD from its treatment.Our results underscore the importance of incorporating sex and mental illness in risk estimation tools for CVD, and improving screening for, and timely treatment of, CVD in those with BD. Future research is needed to better understand the contributors and mechanisms of sex differences related to CVD risk in BD.

Background Long-term clinical monitoring in bipolar disorder (BD) is an important therapeutic tool. The availability of smartphones and wearables has sparked the development of automated applications to remotely monitor patients. This systematic review focus on the current state of electronic (e-) monitoring for episode prediction in BD. Methods We systematically reviewed the literature on e-monitoring for episode prediction in adult BD patients. The systematic review was done according to the guidelines for reporting of systematic reviews and meta-analyses (PRISMA) and was registered in PROSPERO on April 29, 2020 (CRD42020155795). We conducted a search of Web of Science, MEDLINE, EMBASE, and PsycINFO (all 2000–2020) databases. We identified and extracted data from 17 published reports on 15 relevant studies. Results Studies were heterogeneous and most had substantial methodological and technical limitations. Models varied widely in their performance. Published metrics were too heterogeneous to lend themselves to a meta-analysis. Four studies reported sensitivity (range: 0.21 - 0.95); and two reported specificity for prediction of mood episodes (range: 0.36 - 0.99). Two studies reported accuracy (range: 0.64 - 0.88) and four reported area under the curve (AUC; range: 0.52-0.95). Overall, models were better in predicting manic or hypomanic episodes, but their performance depended on feature type. Limitations Our conclusions are tempered by the lack of appropriate information impeding our ability to synthesize the available evidence. Conclusions Given the clinical variability in BD, predicting mood episodes remains a challenging task. Emerging e-monitoring technology for episode prediction in BD requires more development before it can be adopted clinically.

Impaired insight into delusions is associated with a lower probability of remission of psychotic depression, independent of illness severity. The relationship between participant characteristics and impaired insight into delusions in remitted psychotic depression, and whether impaired insight is associated with risk of relapse of psychotic depression during continuation pharmacotherapy were examined.Data were analyzed from 126 participants in the STOP-PD II study who experienced sustained remission of psychotic depression during 8-week stabilization treatment with sertraline plus olanzapine and were then randomized to 36 weeks of continuation treatment with sertraline plus either olanzapine or placebo. Insight into delusions was assessed with the Resolution of Delusions Scale (RODS). Linear regression analyses examined the associations between participant characteristics and insight into delusions. Cox proportional-hazards models examined whether i) change in RODS during stabilization treatment; or ii) RODS at the end of stabilization treatment predicted risk of relapse during 36 weeks of continuation treatment.Severity of psychosis before initiation of treatment was the only participant characteristic associated with the change in insight during stabilization treatment. Neither change in insight during stabilization treatment nor insight at the end of stabilization treatment was associated with risk of relapse.Insufficient statistical power and the lack of variability in RODS scores at the time of randomization may have contributed to the absence of a relationship between RODS and risk of relapse.Residual or reemergent insight impairment following acute treatment does not preclude patients from sustaining remission of psychotic depression in a randomized placebo-controlled trial.

Background : Metabolic dysfunction is prevalent in bipolar disorder (BD) and associated with illness severity and treatment outcomes. There is little research exploring this relationship in low and middle-income countries (LMICs) and little is known about the moderating effect of metabolic health on treatment response to anti-inflammatory drugs in BD. Methods : MINDCARE, a randomized-controlled-trial conducted in Pakistan, investigated the efficacy of minocycline and celecoxib in 266 adults with bipolar depression. This secondary analysis evaluated the association between depression severity at baseline and treatment outcome with metabolic parameters including body mass index (BMI), waist circumference (WC), heart rate (HR), systolic blood pressure (s-BP), and diastolic blood pressure (d-BP). Depression severity was measured using the Hamilton Depression Rating Scale-17. The exploratory aim was to assess whether treatment impacted change in metabolic variables. Associations were evaluated using linear regression. Results : Higher BMI (B=-0.38, 95%CI: -0.55 to -0.21) and WC (B=-0.68, 95%CI: -0.97 to -0.39) were associated with lower baseline depression severity in both the unadjusted and the adjusted models. Baseline metabolic parameters were not associated with treatment response to minocycline or celecoxib nor did treatment significantly impact metabolic variables. Limitations : Our sample represents patients in an RCT and may not be fully representative of the overall BD population in Pakistan. Conclusions : Our findings indicate a potential association of poor metabolic health and lower severity of bipolar depression but not treatment outcomes. Future work should evaluate potential relationships of metabolic parameters and BD in diverse populations to increase the transferability of this line of work.

Background Some patients with major depression continue to demonstrate deficits in health-related quality of life (HRQL) following remission. No data exist, however, regarding HRQL in remitted psychotic depression. In this study, we aimed to characterize HRQL in patients with psychotic depression receiving controlled pharmacotherapy. Methods This is a secondary analysis of a randomized controlled trial studying continuation pharmacotherapy of psychotic depression. We compared participants’ HRQL (measured using the SF-36) between baseline and remission and to population norms. We also compared SF-36 scores stratified by age and gender and examined the correlation between SF-36 scores and medical burden, depression score and neuropsychological performance in remission. Results SF-36 scores were significantly lower than population norms at baseline, but improved following remission to the level of population norms. Neither SF-36 scores nor magnitude of SF-36 improvement differed substantially between genders or between younger and older participants. In remission, depression scores were correlated with most SF-36 scales and medical burden was correlated with SF-36 scales measuring physical symptoms. Neuropsychological measures were generally not correlated with SF-36 scores. Limitations This study was a secondary analysis not powered specifically to measure HRQL as an outcome variable and the SF-36 was the only HRQL measure used. Conclusions Participants with remitted psychotic depression demonstrated levels of HRQL comparable to population norms, despite marked impairment in HRQL when acutely ill. This finding suggests that, when treated in a rigorous manner, many patients with this severe illness improve significantly from a clinical and HRQL perspective.

Background Many patients with major depressive disorder (MDD) experience substantial impairment despite the availability of efficacious treatments. We performed a systematic review and meta-analysis to compare antidepressant outcomes in MDD with or without physical or psychiatric comorbidities. Methods Pubmed, EMBASE, and PsycInfo were searched up to May 14th, 2020 using keywords including MDD, antidepressant, medication, and comorbid. 1915 studies were reviewed. Studies that performed a direct and quantitative comparison of antidepressant effect in patients with MDD with or without comorbidities were included. Study characteristics and primary outcomes were extracted. Continuous and dichotomous variables were considered using standardized mean difference (SMD). Heterogeneity was measured using χ2 and I2 tests. Risk of bias was assessed using Cochrane Risk of Bias tool and NIH Quality Assessment Tool. Results 26 studies met selection criteria. Studies of physical (6 studies; I2 = 57.69%, p = 0.04) and psychiatric comorbidities (20 studies; I2 = 75.75%, p Limitations Our limitations included aggregating the comorbidities into physical and psychiatric comorbidities and the high heterogeneity of the studies. Conclusions Our review provides updated evidence demonstrating that patients with MDD and physical or psychiatric comorbidities experience worse antidepressant outcomes.

The prevalence and risk factors of suicidal ideation in bipolar depression in low- and middle-income countries (LMICs) are poorly understood. This study is a secondary, cross-sectional analysis of a randomized controlled trial from Pakistan, a lower middle-income country. Participants included psychiatric outpatients aged 18 to 65 with a known diagnosis of bipolar disorder and currently in a depressive episode. Suicidality was assessed using the suicide item of the 17-item Hamilton Depression Rating Scale (HAM-D) and levels of severity were categorized as absent, mild/moderate, or severe. Biometric data and biomarkers were obtained. Descriptive statistics were used to describe prevalence and logistic regression applied to establish correlates to suicidal ideation. Among the 266 participants, 67% indicated suicidality of any level and 16% endorsed severe suicidality. Lower body mass index (BMI) (OR = 0.93, 95% CI = 0.88–0.98), higher HAM-D score (OR = 1.29, 95% CI = 1.16–1.43), lower C-reactive protein (CRP) level (OR = 0.53, 95% CI = 0.40–0.70), and increased number of inpatient hospitalizations (OR = 1.16, 95% CI = 1.03–1.31) were identified as significant predictors of suicidality in the fully adjusted regression model. Our findings add to the limited literature on suicidality in bipolar disorder in the LMIC context and suggest roles of biological variables such as BMI and CRP level in predicting suicidal ideation and potentially suicidal behaviours in bipolar depression.

Among patients with major depression with psychotic features, little is known about the extent to which those with and without somatic delusions differ.The first 183 participants in the STOP-PD study were divided into two groups based on the presence or absence of somatic delusions and were compared on multiple demographic and clinical characteristics.In the multivariate analysis, those with somatic delusions reported more somatic symptoms, rated their health as worse, and were less likely to have persecutory delusions.Based on the methods we used, we could not detect meaningful differences between subjects with and without somatic delusions. This suggests that the presence of irrational somatic ideation does not define a distinct clinical subgroup among patients with psychotic depression. This finding needs to be replicated.

Introduction To determine the rate and clinical correlates of emergent, persistent, and resolved suicidal ideation during treatment of major depression in the elderly. Methods Based on the course of suicidal ideation before and during 12 weeks of antidepressant treatment, we classified 437 elderly patients (234 treated with paroxetine; 203 with nortriptyline) as either non-suicidal or as having “emergent”, “persistent”, or “resolved” suicidality. We compared the four groups on pretreatment demographic and clinical measures and with respect to depression, anxiety, and akathisia during treatment. Results: Rates of emergent, persistent, and resolved suicidality were 7.8%, 12.6%, and 15.6%, respectively. Patients with persistent suicidal ideation were more likely to have recurrent depression than non-suicidal patients or patients whose suicidality resolved with treatment. At the start of treatment, patients in all three suicidal groups had lower self-esteem than non-suicidal patients. During the course of treatment, emergent suicidality was not associated with akathisia, nor did rates of emergent suicidality differ between paroxetine- and nortriptyline-treated patients. While at baseline the levels of depression and anxiety and agitation were similar in the four groups, patients with resolved suicidality had a favorable treatment response, while patients with emergent and persistent suicidality were more likely to maintain higher depression scores and had higher levels of anxiety and agitation during treatment. Discussion Emergence of suicidal ideation is not common but is clinically significant during treatment of late-life depression and may signal more difficult-to-treat-depression.

Objective: The authors examined elderly patients with major depression to determine the relationship of current age to treatment response course and success rate. Methods: Three studies of elderly depressed patients provided data on antidepressant treatment response in 323 subjects, treated in protocols using either nortriptyline or paroxetine. We grouped the subjects by current age: ‘young-old’ (59–69, N =163), ‘middle-old’ (70–75, N =80), and ‘older-old’ (76–99, N =80). We employed mixed-effect random regression analyses to examine Hamilton Rating Scale for Depression scores over 12 weeks of acute treatment. Results: Older-old patients responded as quickly and successfully as the young- and middle-old. Conclusions: Major depression in the very old can be treated as successfully as in early old age.

Major depressive disorder (MDD) presents with a variety of symptoms and responds to a wide range of treatment interventions. Diagnostic criteria collapse multiple syndromes with distinct etiologies into the same disorder. MDD is typically understood as a malfunction of neurotransmission or brain circuitry regulating mood, pleasure and reward, or executive function. However, research from an evolutionary perspective suggests that the "normal" functioning of adaptations may also generate symptoms meeting diagnostic criteria. Functioning adaptations may be an underappreciated etiological pathway to MDD. Many adaptive functions for depressive symptoms have been suggested: biasing cognition to avoid losses, conserving energy, disengaging from unobtainable goals, signaling submission, soliciting resources, and promoting analytical thinking. We review the potential role of these adaptive functions and how they can lead to specific clusters of depressive symptoms. Understanding MDD from such a perspective reduces the heterogeneity of cases and may help to select the best intervention for each patient. We discuss the implications of different adaptive and maladaptive etiological pathways for the use of antidepressants and various modes of psychotherapy. In particular, instances of MDD caused by functioning adaptations may benefit most from treatments that support the adaptive function, or that target the precipitating causal stressor. We conclude that an evolutionary approach to the study of MDD may be one of the more promising approaches to reduce its heterogeneity and to better match patients and treatment.

Background: Although active maintenance treatments appear superior to placebo in preventing depression recurrence in older adults, few data are available to guide maintenance modality selection to maximize the probability of continued wellness for a given patient. Patients’ temporal patterns of acute treatment response may predict who requires which maintenance therapy to remain well. Methods: Depression levels were observed over 16 weeks of combined nortriptyline (NT) and interpersonal psychotherapy (IPT) in 140 persons aged ≥60 years with recurrent major depression. Subjects were empirically classified into four groups: rapid, sustained responders; delayed, sustained responders; mixed responders without sustained improvement; prolonged nonresponders. Groups were compared on subsequent recovery rates and on time to depression recurrence after randomization to 3 years of combined maintenance therapy (monthly IPT with NT), monotherapy (either IPT or NT alone), or medication clinic with placebo. Pretreatment psychosocial and clinical variables were controlled. Results: Initial response profile predicted ultimate recovery rates, as well as who remained well, given the maintenance treatment received. Rapid initial responders showed lower recurrence risk with either combined or monotherapy, relative to placebo. Specific types of monotherapy appeared equally effective in rapid responders. In initially mixed responders, only combined therapy was superior to placebo. It was marginally superior to monotherapy. For delayed responders, combined therapy was superior to placebo; monotherapy did not differ from the other maintenance conditions. Prolonged nonresponders did not benefit from maintenance treatment. Limitations: Subjects had only recurrent, unipolar depression. Initial response profile groups were established empirically and require replication. Sample sizes in initial response profile by maintenance treatment cells were small. Conclusion: The ability to match patients to maintenance treatments more likely to prevent recurrence may be enhanced by considering the temporal profile of initial response to acute treatment.

Many older patients who recover from an episode of major depression continue to suffer from depressed mood, anxiety, and sleep problems. Our study assesses the impact of these residual symptoms on the risk of recurrence during maintenance treatment of late-life depression.We analyzed data from a randomized clinical trial of maintenance treatment in patients with unipolar depression agedor =70, 116 of whom remitted and remained stable during open pharmacotherapy and interpersonal psychotherapy (IPT) and were randomized to clinical management/pharmacotherapy; clinical management/placebo; monthly maintenance IPT/ pharmacotherapy; or monthly maintenance IPT/placebo. We assessed the impact of overall residual symptoms (based on the Hamilton Depression Rating Scale (HAM-D) total score) and of specific residual symptom clusters - mood symptoms (depressed mood, guilt, suicidality, energy/interests), sleep disturbance (early, middle, late insomnia), and anxiety (agitation, psychic and somatic anxiety, hypochondriasis) measured at randomization. Sleep disturbance was also assessed with the Pittsburgh Sleep Quality Index (PSQI). We used Cox proportional hazards regression models controlling for assignment to antidepressant medication versus placebo to identify predictors of recurrence.Residual anxiety and residual sleep disturbance (as measured by the PSQI but not the HAM-D) independently predicted early recurrence.Use of HAM-D clusters to define residual symptoms; analysis limited to completers of acute and continuation treatment.In patients with late-life depression who have remitted with pharmacotherapy and psychotherapy, the deleterious effect of residual symptoms is due to persisting anxiety and, possibly, residual sleep disturbance.

Background: Late-life depression studies have found that comorbid anxiety, as a symptom or comorbid disorder, is associated with poorer treatment response and increased likelihood of dropout. This study evaluated the impact of comorbid anxiety on response, dropouts, and side effects, in elderly subjects treated for depression. Methods: We analyzed data from a 12-week trial comparing nortriptyline and paroxetine in 116 patients aged 60 and older with depression. Subjects classified as having anxious depression were compared to those with nonanxious depression in terms of treatment response rate, time to response, dropout rate, and early side effects. The analysis was replicated with another study, in which 125 subjects aged 69 and older were treated openly with paroxetine and interpersonal psychotherapy. Results: Anxious and nonanxious groups did not differ in terms of response rates, time to response, dropout rates, or time to dropout. Side effects declined more quickly and more significantly in the anxious group than in the nonanxious group. Limitations: Subjects were treated in a specialty mental health setting, and the findings may not apply in other settings. Conclusions: We found no association between comorbid anxiety and a poorer prognosis during acute treatment of late-life depression. For elderly patients with anxious depression, standardized treatment in the mental health sector is associated with a good response.