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BACKGROUND AND OBJECTIVE: Antidepressant use in older adults (≥ 65 years) is understudied in large population-based samples, particularly in recent years and regarding user characteristics. We aimed to describe the trends, patterns, and associated user characteristics of all antidepressant prescriptions redeemed by older adults at community pharmacies in Denmark during 2015-2019.METHODS: This register-based study used a cross-sectional design to characterize antidepressant prescription trends and patterns, and a cohort design to describe user characteristics associated with antidepressant prescription initiation. We used descriptive statistics to characterize trends and patterns, and Poisson regression for analyzing user characteristics.RESULTS: During the years 2015-2019, 17.9% of 1.2 million older adults redeemed 4.84 million antidepressant prescriptions, where 48.5% were selective serotonin reuptake inhibitors, followed by noradrenergic and specific serotonergic antidepressants (26.2%), serotonin-norepinephrine reuptake inhibitors (12.7%), tricyclic antidepressants (11.2%), and others (1.4%). Amitriptyline and nortriptyline, considered potentially inappropriate medications, were among the 10 most frequently redeemed antidepressants. Only 60.5% of prescriptions had a treatment indication of depression. Prescription-proportion trends by drug classes and individual antidepressants remained consistent. A higher incidence rate ratio (IRR) and 95% confidence interval (CI) of initiating antidepressants was associated with female sex (IRR 1.20, 95% CI 1.07-1.34), older age (e.g., 81-85 years vs. 65-70 years: IRR 1.74, 95% CI 1.44-2.11), living in rural areas (North Denmark vs. Capital Region: IRR 1.31, 95% CI 1.09-1.58), and having somatic and psychiatric diagnoses (e.g., per one psychiatric diagnosis: IRR 1.10, 95% CI 1.05-1.15), while a lower ratio was associated with being non-Western (vs. Danish: IRR 0.50, 95% CI 0.28-0.89) and having hospital contacts for psychiatric treatment (per each contact: IRR 0.96, 95% CI 0.93-1.00).CONCLUSION: SSRIs were the most commonly redeemed antidepressants, with consistent trends in Danish older adults. Besides clinical conditions, sociodemographics, e.g., sex, age, ethnicity, and place of residence, may influence antidepressant use.

ImportanceWhether ketamine is as effective as electroconvulsive therapy (ECT) among patients with major depressive episode remains unknown.ObjectiveTo systematically review and meta-analyze data about clinical efficacy and safety for ketamine and ECT in patients with major depressive episode.Data SourcesPubMed, MEDLINE, Cochrane Library, and Embase were systematically searched using Medical Subject Headings (MeSH) terms and text keywords from database inception through April 19, 2022, with no language limits. Two authors also manually and independently searched all relevant studies in US and European clinical trial registries and Google Scholar.Study SelectionIncluded were studies that involved (1) a diagnosis of depression using standardized diagnostic criteria, (2) intervention/comparator groups consisting of ECT and ketamine, and (3) depressive symptoms as an efficacy outcome using standardized measures.Data Extraction and SynthesisData extraction was completed independently by 2 extractors and cross-checked for errors. Hedges g standardized mean differences (SMDs) were used for improvement in depressive symptoms. SMDs with corresponding 95% CIs were estimated using fixed- or random-effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed.Main Outcomes and MeasuresEfficacy outcomes included depression severity, cognition, and memory performance. Safety outcomes included serious adverse events (eg, suicide attempts and deaths) and other adverse events.ResultsSix clinical trials comprising 340 patients (n = 162 for ECT and n = 178 for ketamine) were included in the review. Six of 6 studies enrolled patients who were eligible to receive ECT, 6 studies were conducted in inpatient settings, and 5 studies were randomized clinical trials. The overall pooled SMD for depression symptoms for ECT when compared with ketamine was −0.69 (95% CI, −0.89 to −0.48; Cochran Q, P = .15; I2 = 39%), suggesting an efficacy advantage for ECT compared with ketamine for depression severity. Significant differences were not observed between groups for studies that assessed cognition/memory or serious adverse events. Both ketamine and ECT had unique adverse effect profiles (ie, ketamine: lower risks for headache and muscle pain; ECT: lower risks for blurred vision, vertigo, diplopia/nystagmus, and transient dissociative/depersonalization symptoms). Limitations included low to moderate methodological quality and underpowered study designs.Conclusions and RelevanceFindings from this systematic review and meta-analysis suggest that ECT may be superior to ketamine for improving depression severity in the acute phase, but treatment options should be individualized and patient-centered.

Patients with bipolar disorder (BD) engage in both negative and positive rumination, defined as maladaptive self-focused thinking, and this tendency predicts depressive and manic episodes, respectively. Prior research in patients with major depression implicates regions of the default mode network (DMN) consistent with the self-focused nature of rumination. Little is known about the neural correlates of rumination in bipolar disorder.Fifteen euthymic patients with BD (twelve with Type I) and 17 healthy controls (HC) performed negative and positive rumination induction tasks, as well as a distraction task, followed by a self-related trait judgment task while undergoing functional magnetic resonance imaging (fMRI). Participants also underwent resting state scans. We examined functional connectivity at rest and during the induction tasks, as well as task-based activation during the trait judgment task, in core regions of the DMN.Compared to HC, patients with BD showed greater functional connectivity between the posterior cingulate cortex (PCC) and medial prefrontal cortex (MPFC) at rest and during positive rumination, compared to distraction. They also showed greater activity in the PCC and MPFC during processing of positive traits, following positive rumination. At rest and during negative rumination compared to distraction, patients with BD showed greater functional connectivity between the PCC and inferior parietal lobule than HC.These findings demonstrate that negative and positive rumination are subserved by different patterns of connectivity within the DMN in BD. Additionally, the PCC and MPFC are key regions involved in the processing of positive self-relevant traits following positive rumination.

Objectives Perturbations of the intestinal microbiota have been associated with mental health disorders, including major depressive disorder (MDD). Therefore, faecal microbiota transplantation (FMT) holds promise as a microbiota-modulating treatment for MDD. Yet, to date, there are no published controlled studies evaluating the use of FMT for MDD. This study aimed to address this gap by evaluating the feasibility, acceptability, and safety of FMT for MDD. Methods The study was an 8-week, double-blind, 2:1 parallel group, randomized controlled pilot trial ( n = 15) of enema-delivered FMT ( n = 10) compared with a placebo enema ( n = 5) in adults with moderate-to-severe MDD. Results Recruitment was completed within 2 months, with 0% attrition and 100% attendance at key study appointments. There were no major protocol deviations. The placebo and blinding strategies were considered successful; nurses and participants correctly guessing their treatment allocation at a rate similar to that anticipated by chance. No serious or severe adverse events were reported in either group, and there were no significant differences in mild-to-moderate adverse events between groups (median of 2 adverse events per participant reported in both groups). Furthermore, the 12/15 participants who completed the Week 2 participant satisfaction survey agreed or strongly agreed that the enema delivery was tolerable and that they would have the treatment again if required. Whilst the study was not designed to measure clinical outcomes, exploratory data also suggested that the active FMT treatment may lead to improvements in gastrointestinal symptoms and quality of life in this population, noting that irritable bowel syndrome is commonly comorbid with MDD. Conclusions All feasibility targets were met or exceeded. This study found that enema-delivered FMT is feasible, acceptable, well-tolerated, and safe in patients with MDD. The findings of this study support further research to evaluate clinical efficacy, and the use of this protocol is supported.

Background Fewer than half of patients with major depressive disorder (MDD) respond to psychotherapy. Pre-emptively informing patients of their likelihood of responding could be useful as part of a patient-centered treatment decision-support plan. Methods This prospective observational study examined a national sample of 807 patients beginning psychotherapy for MDD at the Veterans Health Administration. Patients completed a self-report survey at baseline and 3-months follow-up (data collected 2018–2020). We developed a machine learning (ML) model to predict psychotherapy response at 3 months using baseline survey, administrative, and geospatial variables in a 70% training sample. Model performance was then evaluated in the 30% test sample. Results 32.0% of patients responded to treatment after 3 months. The best ML model had an AUC (SE) of 0.652 (0.038) in the test sample. Among the one-third of patients ranked by the model as most likely to respond, 50.0% in the test sample responded to psychotherapy. In comparison, among the remaining two-thirds of patients, Conclusions Patients with MDD could pre-emptively be informed of their likelihood of responding to psychotherapy using a prediction tool based on self-report data. This tool could meaningfully help patients and providers in shared decision-making, although parallel information about the likelihood of responding to alternative treatments would be needed to inform decision-making across multiple treatments.

Suicide is among the leading causes of death in children and adolescents. There are well-known risk factors of suicide, including childhood abuse, family conflicts, social adversity, and psychopathology. While suicide risk is also known to be heritable, few studies have investigated genetic risk in younger individuals.Using polygenic risk score analysis, we examined whether genetic susceptibility to major psychiatric disorders is associated with suicidal behaviors among 11,878 children enrolled in the ABCD (Adolescent Brain Cognitive Development) Study. Suicidal ideation and suicide attempt data were assessed using the youth report of the Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5. After performing robust quality control of genotype data, unrelated individuals of European descent were included in analyses (n = 4344).Among 8 psychiatric disorders we examined, depression polygenic risk scores were associated with lifetime suicide attempts both in the baseline (odds ratio = 1.55, 95% CI = 1.10-2.18, p = 1.27 × 10The largest genetic sample of suicide risk data in U.S. children suggests a significant genetic basis of suicide risk related to attention-deficit/hyperactivity disorder and depression. Further research is warranted to examine whether incorporation of genomic risk may facilitate more targeted screening and intervention efforts.

Background Only a limited number of patients with major depressive disorder (MDD) respond to a first course of antidepressant medication (ADM). We investigated the feasibility of creating a baseline model to determine which of these would be among patients beginning ADM treatment in the US Veterans Health Administration (VHA). Methods A 2018–2020 national sample of n = 660 VHA patients receiving ADM treatment for MDD completed an extensive baseline self-report assessment near the beginning of treatment and a 3-month self-report follow-up assessment. Using baseline self-report data along with administrative and geospatial data, an ensemble machine learning method was used to develop a model for 3-month treatment response defined by the Quick Inventory of Depression Symptomatology Self-Report and a modified Sheehan Disability Scale. The model was developed in a 70% training sample and tested in the remaining 30% test sample. Results In total, 35.7% of patients responded to treatment. The prediction model had an area under the ROC curve (s.e.) of 0.66 (0.04) in the test sample. A strong gradient in probability (s.e.) of treatment response was found across three subsamples of the test sample using training sample thresholds for high [45.6% (5.5)], intermediate [34.5% (7.6)], and low [11.1% (4.9)] probabilities of response. Baseline symptom severity, comorbidity, treatment characteristics (expectations, history, and aspects of current treatment), and protective/resilience factors were the most important predictors. Conclusions Although these results are promising, parallel models to predict response to alternative treatments based on data collected before initiating treatment would be needed for such models to help guide treatment selection.

Background: Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied. Methods: The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool). Results: A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment. Conclusion: This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings.

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.

Objective: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. Methods: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4–0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. Results: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP ( N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) ( p = 0.59). Users of Li+AC ( N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC ( N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p Conclusion: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

Objective: While treatment with antipsychotics and antiepileptics have been associated with an increased risk of diabetes mellitus (DM), lithium may have the opposite effect via inhibition of glycogen synthase kinase-3. The aim of this study was to investigate whether treatment of bipolar disorder with lithium, antipsychotics, or antiepileptics is associated with the risk of DM in a real-world clinical setting. Methods: Using nationwide registers, we identified all patients diagnosed with bipolar disorder in Danish Psychiatric Services from January 1, 1996, to January 1, 2019 (N = 30,451). The risk of developing DM was operationalized via hospital diagnoses and redeemed prescriptions for glucose-lowering drugs. For lithium, antipsychotics, valproate, and lamotrigine, we calculated hazard rate ratios (HRR) for developing DM via adjusted Cox proportional hazards models. Potential cumulative dose–response-like associations were examined using the log-rank test. Results: During follow-up (245,181 person-years), 2107 (6.9%) patients developed DM. Compared with non-users of the respective drugs, we found no clinically or statistically significant difference in the risk of developing DM among patients receiving lithium (n = 11,690; incidence rate of DM/1000 person-years (IR) = 8.87, 95% CI: 8.02–9.90; HRR = 0.94, 95% CI: 0.84–1.06) or lamotrigine (n = 11,785; IR = 7.58, 95% CI: 6.69–8.59; HRR = 0.89, 95% CI: 0.77–1.02), respectively. Conversely, for patients receiving valproate (n = 5171; IR = 12.68, 95% CI: 10.87–14.80; HRR = 1.34, 95% CI: 1.14–1.58) and antipsychotics (n = 22,719; IR = 12.00, 95% CI: 11.14–12.94; HRR = 1.65, 95% CI: 1.45–1.88), respectively, there was increased risk of developing DM. For antipsychotics, we observed a clear cumulative dose–response-like association with the risk of DM. Conclusions: Treatment with valproate and antipsychotics—but not with lithium and lamotrigine—was associated with increased risk of DM in a real-world cohort of patients with bipolar disorder.

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) treat dyslipidaemia and cardiovascular disease by inhibiting cholesterol biosynthesis. They also have immunomodulatory and anti-inflammatory properties. Beyond cardiovascular disease, cholesterol and inflammation appear to be components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Statins may therefore afford some therapeutic benefit in mood disorders. In this paper, we review the pathophysiology of mood disorders with a focus on pharmacologically relevant pathways, using major depressive disorder and bipolar disorder as exemplars. Statins are discussed in the context of these disorders, with particular focus on the putative mechanisms involved in their anti-inflammatory and immunomodulatory effects. Recent clinical data suggest that statins may have antidepressant properties, however given their interactions with many known biological pathways, it has not been fully elucidated which of these are the major determinants of clinical outcomes in mood disorders. Moreover, it remains unclear what the appropriate dose, or appropriate patient phenotype for adjunctive treatment may be. High quality randomised control trials in concert with complementary biological investigations are needed if the potential clinical effects of statins on mood disorders, as well as their biological correlates, are to be better understood.

The goals of this study were to introduce psychological well-being as an important subject of inquiry in bipolar disorder, to compare well-being in a cohort of patients with bipolar disorder with that of a normative sample, and to assess whether common measures of well-being and mood measure empirically distinct phenomena.Participants were outpatients with bipolar I disorder in remission (N=37) from the Enhancing Emotion Regulation in Bipolar Disorder (EERBD) study and a matched community normative sample from the Midlife in the United States (MIDUS) survey (N=6297). The Psychological Well-Being Scale (PWBS) was used to measure psychological well-being. We calculated means and SD of scores on the PWBS and evaluated the differences between the scores of the bipolar I and community samples. We also tested the association between raw and change scores in depression [Hamilton Rating Scale for Depression (HAM-D)] and eudaimonic well-being (PWBS) using Spearman correlation coefficients.The MIDUS survey sample (N=6297) was 48% male, with a mean age of 47 years (SD=13 y). The EERBD sample (N=37) was 27% male, with a mean age of 41 years (SD=11 y). In the bipolar sample, the baseline mean score on the HAM-D was 12.7 (SD=6.0) and the mean score on the Young Mania Rating Scale was 6.1 (SD=6.2). The baseline mean sum score on the PWBS in the normative community MIDUS sample was 100 (SD=14), while that of the bipolar I EERBD sample was 79 (SD=15) at baseline, 84 (SD=13) posttreatment, and 84 (SD=12) at the 3-month follow-up assessment. The effect sizes of the differences at all timepoints were large (Hedges g=1.42 at baseline, 1.11 at the end of treatment, and 1.06 at the 3-mo follow-up). No association was found between the PWBS and depression scores.Outpatients with bipolar disorder in remission demonstrated substantially impaired psychological well-being, despite low levels of depressive symptoms, compared with a normative community sample.

Objectives Societal restrictions imposed to prevent transmission of COVID-19 may challenge circadian-driven lifestyle behaviours, particularly amongst those vulnerable to mood disorders. The overarching aim of the present study was to investigate the hypothesis that, in the routine-disrupted environment of the COVID-19, amongst a sample of people living with mood disorders, greater social rhythm disruption would be associated with more severe mood symptoms. Methods We conducted a two-wave, multinational survey of 997 participants [Formula: see text] who self-reported a mood disorder diagnosis (i.e., major depressive disorder or bipolar disorder). Respondents completed questionnaires assessing demographics, social rhythmicity (The Brief Social Rhythm Scale), depression symptoms (Patient Health Questionnaire-9), sleep quality and diurnal preference (The Sleep, Circadian Rhythms and Mood questionnaire) and stressful life events during the COVID-19 pandemic (The Social Readjustment Rating Scale). Results The majority of participants indicated COVID-19-related social disruption had affected the regularity of their daily routines to at least some extent ( n = 788, 79.1%). As hypothesised, lower social rhythmicity was associated with greater depressive symptoms when tested cross-sectionally (standardised β = −.25, t = −7.94, P = 0.000) and when tested using a 2-level hierarchical linear model across two time points ( b = −0.14, t = −3.46, df = 264, P ≤ 0.001). Conclusions These results are consistent with the social zeitgeber hypothesis proposing that mood disorders are sensitive to life events that disrupt social rhythms.

Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder.

Background Physical activity can mitigate the risk of cardiovascular diseases, but the presence of mood disorders makes it challenging to follow or develop a regular exercise habit. We conducted an online comparative effectiveness study (Healthy Hearts Healthy Minds) to evaluate whether an online psychosocial intervention adjunctive to an activity monitor (Fitbit) can improve adherence to physical activity among individuals with mood disorders who have or are at-risk for cardiovascular disease (CVD). Methods In this paper, we explore design considerations (including both procedural challenges and achievements) of relevance to our study. Results Challenges of this study included navigating a complex IRB review process, integrating two study platforms, automating study procedures, and optimizing participant engagement. Achievements of this study included building trust with collaborators, leveraging existing online communities, generating daily data reports, and conducting patient-centered research. Limitations These design considerations are based on a single online comparative effectiveness study, and other online intervention studies may be presented with other unique challenges that are specific to their study format or aims. Consistent with some of the generalizability challenges facing other online studies, participants in this study were overall highly educated (most had at least a college degree). Conclusions We successfully conducted a large-scale virtual online intervention to increase physical activity of participants with comorbid mood and cardiovascular disorders by overcoming substantial operational and technical challenges. We hope that this exploration of design considerations in the context of our online study can inform upcoming online intervention studies.

BACKGROUND: Although randomized trials show that specific phobia treatments can be effective, it is unclear whether patients experience treatment as helpful in clinical practice. We investigated this issue by assessing perceived treatment helpfulness for specific phobia in a cross-national epidemiological survey.METHODS: Cross-sectional population-based WHO World Mental Health (WMH) surveys in 24 countries (n=112,507) assessed lifetime specific phobia. Respondents who met lifetime criteria were asked whether they ever received treatment they considered helpful and the number of professionals seen up to the time of receiving helpful treatment. Discrete-event survival analysis was used to calculate conditional-cumulative probabilities of obtaining helpful treatment across number of professionals seen and of persisting in help-seeking after prior unhelpful treatment.RESULTS: 23.0% of respondents reported receiving helpful treatment from the first professional seen, whereas cumulative probability of receiving helpful treatment was 85.7% after seeing up to 9 professionals. However, only 14.7% of patients persisted in seeing up to 9 professionals, resulting in the proportion of patients ever receiving helpful treatment (47.5%) being much lower than it could have been with persistence in help-seeking. Few predictors were found either of perceived helpfulness or of persistence in help-seeking after earlier unhelpful treatments.LIMITATIONS: Retrospective recall and lack of information about either types of treatments received or objective symptomatic improvements limit results.CONCLUSIONS: Despite these limitations, results suggest that helpfulness of specific phobia treatment could be increased, perhaps substantially, by increasing patient persistence in help-seeking after earlier unhelpful treatments. Improved understanding is needed of barriers to help-seeking persistence.

Individuals experiencing socioeconomic deprivation consistently demonstrate poorer physical and mental health. Income alone is inadequate as a measure of socioeconomic status (SES); a better measure for assessing the deprivation status of individuals is needed.The New Zealand Index of Socioeconomic Deprivation for Individuals, a validated, eight-item measure of deprivation, was modified to create the United States Index of Socioeconomic Deprivation for Individuals (USiDep). The questionnaire was administered to patients with major depressive disorder participating in two clinical trials. Spearman's correlation coefficients evaluated associations between USiDep scores with income and other measures associated with deprivation.The USiDep was completed by 118 participants, demonstrating adequate internal consistency (Crohnbach's alpha = 0.766) and strong item-total correlations. USiDep scores were moderately correlated with past-year personal income (Spearman's rho = -0.362, p.001) and several other measures related to deprivation, including body mass index, level of education, quality of life, severity of childhood traumatic events, self-reported physical health, and negative life events. Patients scoring 5 on the USiDep (the highest possible score, indicating greater deprivation) had significantly lower rates of remission after 12 weeks of treatment than those scoring ≤ 4 (1/12, 8.3% vs 40/98, 40.8%, respectively, p = .03), whereas the lowest income group showed no significant associations with outcomes.The USiDep is a valid, brief questionnaire for assessing SES that has utility for clinical research and may serve as a predictor of treatment outcomes in clinical trials. Validation of the USiDep in healthy controls and other medically and psychiatrically ill populations is warranted.

Background Mental disorders, including major depressive disorder (MDD), are a leading cause of non-fatal burden of disease globally. Current conventional treatments for depression have significant limitations, and there have been few new treatments in decades. The microbiota-gut-brain-axis is now recognised as playing a role in mental and brain health, and promising preclinical and clinical data suggest Faecal Microbiota Transplants (FMT) may be efficacious for treating a range of mental illnesses. However, there are no existing published studies in humans evaluating the efficacy of FMT for MDD. Methods and design This protocol describes an 8-week, triple-blind, 2:1 parallel group, randomised controlled pilot trial (n = 15), of enema-delivered FMT treatment (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD. There will be a further 26-week follow-up to monitor longer-term safety. Participants will receive four FMT or placebo enemas over four consecutive days. The primary aims of the study are to evaluate feasibility and safety of FMT as an adjunctive treatment for MDD in adults. Changes in gut microbiota will be assessed as a secondary outcome. Other data will be collected, including changes in depression and anxiety symptoms, and safety parameters. Discussion Modification of the microbiota-gut-brain axis via FMT is a promising potential treatment for MDD, but there are no published rigorous clinical trials evaluating its use. If this study finds that our FMT strategy is safe and feasible, a larger fully powered RCT is planned. Further high-quality research in this field is urgently needed to address unmet need. Trial registration Australian and New Zealand Clinical Trials Registry: ACTRN12621000932864

The associations of current and remitted bipolar disorder (BD) with health-related quality of life (HRQOL) have been under-studied, and we aim to address these gaps.The 2012-2013 National Epidemiological Survey on Alcohol and Related Conditions III (NESARC III) surveyed a nationally representative sample of non-institutionalized adults in the US. Using DSM-5 criteria, three groups were operationalized as: 1) adults who met criteria for BD in the past year (i.e., current BD; n = 566 unweighted); and 2) adults who met criteria for BD previously but not in the past year (i.e., BD in remission; n = 187); and 3) adults with no BD in their lifetime (n = 35,556). HRQOL and quality-adjusted life years (QALYs) were compared by these groups. Multivariable-adjusted regression analyses were used to adjust for and examine the role of covariates.Overall, 1.5 % of the study sample, representing 3.6 million adults nationwide, met criteria for current BD, and 0.5 %, representing 1.3 million adults, met criteria for BD in remission. Adults with current BD and BD in remission had lower mental HRQOL and QALYs, as compared to adults who never had BD. However, these differences were no longer significant when adjusted for behavioral co-morbidities (e.g., psychiatric and substance use disorders).Both current BD and BD in remission were adversely associated with HRQOL and QALYs, while these associations were not independent of behavioral co-morbidities. Because behavioral co-morbidities are common in individuals with current BD or those with BD in remission, they should be treated together to improve HRQOL.

Patient-reported helpfulness of treatment is an important indicator of quality in patient-centered care. We examined its pathways and predictors among respondents to household surveys who reported ever receiving treatment for major depression, generalized anxiety disorder, social phobia, specific phobia, post-traumatic stress disorder, bipolar disorder, or alcohol use disorder. Data came from 30 community epidemiological surveys - 17 in high-income countries (HICs) and 13 in low- and middle-income countries (LMICs) - carried out as part of the World Health Organization (WHO)'s World Mental Health (WMH) Surveys. Respondents were asked whether treatment of each disorder was ever helpful and, if so, the number of professionals seen before receiving helpful treatment. Across all surveys and diagnostic categories, 26.1% of patients (N=10,035) reported being helped by the very first professional they saw. Persisting to a second professional after a first unhelpful treatment brought the cumulative probability of receiving helpful treatment to 51.2%. If patients persisted with up through eight professionals, the cumulative probability rose to 90.6%. However, only an estimated 22.8% of patients would have persisted in seeing these many professionals after repeatedly receiving treatments they considered not helpful. Although the proportion of individuals with disorders who sought treatment was higher and they were more persistent in HICs than LMICs, proportional helpfulness among treated cases was no different between HICs and LMICs. A wide range of predictors of perceived treatment helpfulness were found, some of them consistent across diagnostic categories and others unique to specific disorders. These results provide novel information about patient evaluations of treatment across diagnoses and countries varying in income level, and suggest that a critical issue in improving the quality of care for mental disorders should be fostering persistence in professional help-seeking if earlier treatments are not helpful.

Patient-reported outcome measures (PROMs) are self-rated scales and indices developed to improve the detection of the patients’ subjective experience. Given that a considerable number of PROMs are available, it is important to evaluate their validity and usefulness in a specific research or clinical setting. Published guidelines, based on psychometric criteria, do not fit in with the complexity of clinical challenges, because of their quest for homogeneity of components and inadequate attention to sensitivity. Psychometric theory has stifled the field and led to the routine use of scales widely accepted yet with a history of poor performance. Clinimetrics, the science of clinical measurements, may provide a more suitable conceptual and methodological framework. The aims of this paper are to outline the major limitations of the psychometric model and to provide criteria for clinimetric patient-reported outcome measures (CLIPROMs). The characteristics related to reliability, sensitivity, validity, and clinical utility of instruments are critically reviewed, with particular reference to the differences between clinimetric and psychometric approaches. Of note is the fact that PROMs, rating scales, and indices developed according to psychometric criteria may display relevant clinimetric properties. The present paper underpins the importance of the clini­metric methodology in choosing the appropriate PROMs. CLIPROM criteria may also guide the development of new indices and the validation of existing PROMs to be employed in clinical settings.

Bipolar disorders are a complex group of severe and chronic disorders that includes bipolar I disorder, defined by the presence of a syndromal, manic episode, and bipolar II disorder, defined by the presence of a syndromal, hypomanic episode and a major depressive episode. Bipolar disorders substantially reduce psychosocial functioning and are associated with a loss of approximately 10-20 potential years of life. The mortality gap between populations with bipolar disorders and the general population is principally a result of excess deaths from cardiovascular disease and suicide. Bipolar disorder has a high heritability (approximately 70%). Bipolar disorders share genetic risk alleles with other mental and medical disorders. Bipolar I has a closer genetic association with schizophrenia relative to bipolar II, which has a closer genetic association with major depressive disorder. Although the pathogenesis of bipolar disorders is unknown, implicated processes include disturbances in neuronal-glial plasticity, monoaminergic signalling, inflammatory homoeostasis, cellular metabolic pathways, and mitochondrial function. The high prevalence of childhood maltreatment in people with bipolar disorders and the association between childhood maltreatment and a more complex presentation of bipolar disorder (eg, one including suicidality) highlight the role of adverse environmental exposures on the presentation of bipolar disorders. Although mania defines bipolar I disorder, depressive episodes and symptoms dominate the longitudinal course of, and disproportionately account for morbidity and mortality in, bipolar disorders. Lithium is the gold standard mood-stabilising agent for the treatment of people with bipolar disorders, and has antimanic, antidepressant, and anti-suicide effects. Although antipsychotics are effective in treating mania, few antipsychotics have proven to be effective in bipolar depression. Divalproex and carbamazepine are effective in the treatment of acute mania and lamotrigine is effective at treating and preventing bipolar depression. Antidepressants are widely prescribed for bipolar disorders despite a paucity of compelling evidence for their short-term or long-term efficacy. Moreover, antidepressant prescription in bipolar disorder is associated, in many cases, with mood destabilisation, especially during maintenance treatment. Unfortunately, effective pharmacological treatments for bipolar disorders are not universally available, particularly in low-income and middle-income countries. Targeting medical and psychiatric comorbidity, integrating adjunctive psychosocial treatments, and involving caregivers have been shown to improve health outcomes for people with bipolar disorders. The aim of this Seminar, which is intended mainly for primary care physicians, is to provide an overview of diagnostic, pathogenetic, and treatment considerations in bipolar disorders. Towards the foregoing aim, we review and synthesise evidence on the epidemiology, mechanisms, screening, and treatment of bipolar disorders.

Importance: Osteoporosis, a systemic skeletal disorder associated with substantial morbidity and mortality, may be particularly common among individuals with bipolar disorder. Lithium, a first-line mood-stabilizing treatment for bipolar disorder, may have bone-protecting properties.Objective: To evaluate if treatment with lithium is associated with a decrease in risk of osteoporosis among patients with bipolar disorder.Design, Setting, and Participants: This retrospective cohort study included 22 912 adults from the Danish Psychiatric Central Research Register who received an initial diagnosis of bipolar disorder in the period from January 1, 1996, to January 1, 2019. For each patient with bipolar disorder, 5 age- and sex-matched individuals were randomly selected from the general population as reference individuals. Individuals with bipolar disorder prior to January 1, 1996, those with a diagnosis of schizophrenia or schizoaffective disorder prior to being diagnosed with bipolar disorder, and those with osteoporosis prior to the index date were excluded. Of the 114 560 reference individuals included, 300 were diagnosed with bipolar disorder during follow-up and were censored from the reference group from the date of diagnosis forward. For patients with bipolar disorder, treatment periods with lithium, antipsychotics, valproate, and lamotrigine were identified. Analyses were performed between January 2021 and January 2022.Exposures: Bipolar disorder and treatment with lithium, antipsychotics, valproate, and lamotrigine.Main Outcomes and Measures: The primary outcome was osteoporosis, identified via hospital diagnoses and prescribed medications. First, incidence of osteoporosis was compared between patients with bipolar disorder and reference individuals (earliest start of follow-up at age 40 years) using Cox regression. Subsequently, incidence of osteoporosis for patients receiving treatment with lithium, antipsychotics, valproate, and lamotrigine, respectively, was compared with that of patients who were not treated with these medications.Results: A total of 22 912 patients with bipolar disorder (median [IQR] age, 50.4 [41.2-61.0] years; 12 967 [56.6%] women) and 114 560 reference individuals (median [IQR] age, 50.4 [41.2-61.0] years; 64 835 [56.6%] women) were followed up for 1 213 695 person-years (median [IQR], 7.68 [3.72-13.24] years). The incidence of osteoporosis per 1000 person-years was 8.70 (95% CI, 8.28-9.14) among patients and 7.90 (95% CI, 7.73-8.07) among reference individuals, resulting in a hazard rate ratio (HRR) of 1.14 (95% CI, 1.08-1.20). Among patients with bipolar disorder, 8750 (38.2%) received lithium, 16 864 (73.6%) received an antipsychotic, 3853 (16.8%) received valproate, and 7588 (33.1%) received lamotrigine (not mutually exclusive). Patients with bipolar disorder treated with lithium had a decrease in risk of osteoporosis (HRR, 0.62; 95% CI, 0.53-0.72) compared with patients not receiving lithium. Treatment with antipsychotics, valproate, and lamotrigine was not associated with reduced risk of osteoporosis.Conclusions and Relevance: In this study, bipolar disorder was associated with an increase in risk of osteoporosis, and lithium treatment was associated with a decrease in risk of osteoporosis. These findings suggest that bone health should be a priority in the clinical management of bipolar disorder and that the potential bone-protective properties of lithium should be subjected to further study, both in the context of bipolar disorder and in osteoporosis.

International audience; Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD.Methods: Thirteen cohorts from 7 countries included n=5,882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors.Results: We found high rates of functional impairment, ranging from 41-75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning.Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.

Individuals with bipolar disorder (BD) experience cognitive and affective processing deficits that often persist beyond the remission of acute mood symptoms. One possible biological mechanism for these deficits involves the potential effects of chronic low-grade peripheral inflammation on brain function. Peripheral inflammation has been associated with reduced executive functioning and memory performance, as well as altered reward processing in BD, but whether it is also implicated in cognitive-affective processing remains unknown.Peripheral inflammation was measured by serum C-reactive protein (CRP) in 119 adults with BD I or II, age 18-65. All participants completed the Affective Go/No-Go Task, a measure of cognitive-emotional processing. Correlations of CRP with discrimination of and response times to Negative, Positive, and Neutral words were performed before and after adjustment for severity of residual depressive symptoms and other demographic and clinical characteristics associated with inflammation.Increased CRP was significantly associated with reduced negative target discriminability, which was also significantly reduced compared to positive and neutral target conditions. Additionally, greater CRP was associated with faster response times for both negative hits and commissions, as well as positive commissions.This study adds to existing research demonstrating associations between inflammation and cognition or reward sensitivity and motivation separately in BD, by raising the possibility that inflammation is also implicated in the integration of cognitive-affective processing. Assessment of these associations over time is warranted to determine involvement of inflammation and cognitive-emotional processing in course of illness and identify critical periods for possible modulation of inflammation.

Objective In this study, we aimed to determine clinical correlates of false positive assignment (FPA) on commonly used bipolar screening questionnaires.Methods A retrospective chart review was conducted to a total of 3885 psychiatric outpatients. After excluding patients who have bipolar spectrum illnesses, patients who were assigned as having hypomania on the mood disorder questionnaire (MDQ) or the hypomania checklist-32 (HCL-32) were identified as patients who had FPA. Psychiatric diagnoses and severity of emotional symptoms were compared between patients with and without FPA.Results Patients with FPA on the MDQ showed significant associations with presence of major depressive disorder, generalized anxiety disorder, and alcohol-use disorder, while patients with FPA on the HCL-32 showed associations with presence of panic disorder and agoraphobia. FPA on the MDQ was also associated with greater emotional symptoms and lifetime history of suicide attempts. Logistic regression analysis showed that male sex, younger age, presence of alcohol-use disorder, and severity of depression and obsessive-compulsive symptoms were significantly associated with FPA on the MDQ.Conclusion The FPA for the MDQ was associated with clinical factors linked to trait impulsivity, and the FPA for both the MDQ and the HCL-32 could be related to increased anxiety.

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.