KIOS: A smartphone app for self-monitoring for patients with bipolar disorder.

OBJECTIVES: This study examined the use of a self-monitoring/self-management smartphone application (app) for patients with bipolar disorder. The app was specifically designed with patient-centered computational software system based on concepts from nonlinear systems (chaos) theory. METHODS: This was a randomized, active comparator study of use of the KIOS app compared to an existing free app that has high utilization rates known as eMoods, over 52 weeks, and performed in three academic centers. Patients were evaluated monthly utilizing the Bipolar Inventory of Symptoms Schedule (BISS). The primary outcome measure was the persistence of using the app over the year of the study. RESULTS: Patients assigned to KIOS persisted in the study longer than those assigned to eMoods; 57 patients (87.70%) in the KIOS group versus 42 (73.69%) in the eMoods group completed the study (p = 0.03). By 52 weeks, significantly more of KIOS group (84.4%) versus eMoods group (54%) entered data into their programs (χ2 = 14.2, df = 1, p = 0.0002). Patient satisfaction for KIOS was greater (F = 5.21, df = 1, 108, p = 0.025) with a standardized effect size (Cohen's d) of 0.41. There was no difference in clinical outcome at the end of the study between the two groups. CONCLUSIONS: This is the first randomized comparison study comparing two apps for the self-monitoring/self-management of bipolar disorder. The study revealed greater patient satisfaction and greater adherence to a patient-centered software program (KIOS) than a monitoring program that does not provide feedback (eMoods).

Long-Term Lithium Therapy and Thyroid Disorders in Bipolar Disorder: A Historical Cohort Study.

Lithium has been a cornerstone treatment for bipolar disorder (BD). Despite descriptions in the literature regarding associations between long-term lithium therapy (LTLT) and development of a thyroid disorder (overt/subclinical hypo/hyperthyroidism, thyroid nodule, and goiter) in BD, factors such as time to onset of thyroid abnormalities and impact on clinical outcomes in the course of illness have not been fully characterized. In this study we aimed to compare clinical characteristics of adult BD patients with and without thyroid disorders who were on LTLT. We aimed to identify the incidence of thyroid disorders in patients with BD on LTLT and response to lithium between patients with and without thyroid disorders in BD. The Cox proportional model was used to find the median time to the development of a thyroid disorder. Our results showed that up to 32% of patients with BD on LTLT developed a thyroid disorder, of which 79% developed hypothyroidism, which was corrected with thyroid hormone replacement. We did not find significant differences in lithium response between patients with or without thyroid disorders in BD. Findings from this study suggest that patients with BD and comorbid thyroid disorders when adequately treated have a response to lithium similar to patients with BD and no thyroid disorders.

Cardiometabolic and endocrine comorbidities in women with bipolar disorder: A systematic review.

INTRODUCTION: Bipolar Disorder (BD) is known to be equally distributed among males and females. The well-documented increased risk of medical comorbidities in patients with BD, in comparison to BD patients without medical comorbidities, shows a negative impact on the course of illness. There is some evidence suggesting that women with BD have higher psychiatric and medical comorbidities in comparison to men with BD, however there is no evidence in comparison to women without BD or other major psychiatric illness. These comorbidities, along with various psychosocial factors, are known to affect the course of BD. METHODS: We aimed to systematically review the literature on cardiovascular, metabolic and endocrine comorbidities in women with BD in comparison to men with BD and control women. A comprehensive search of electronic databases including PubMed, PsycINFO, Embase, and SCOPUS was conducted, and a total of 61 identified studies were included in this review. RESULTS: Women with BD had higher rates of cardiovascular risk factors/mortality, diabetes mellitus II and thyroid disorders compared to women in the general population. In comparison to men with BD, women with BD had comparable cardiovascular risk but higher prevalence of metabolic and thyroid disorders. LIMITATIONS: Gender specific data was limited in multiple studies. CONCLUSIONS: Results present a need for gender-specific screening and interventions for various medical comorbidities in patients with BD.

Real-World Clinical Practice Among Patients With Bipolar Disorder and Chronic Kidney Disease on Long-term Lithium Therapy.

PURPOSE: Long-term lithium therapy (LTLT) has been associated with chronic kidney disease (CKD). We investigated changes in clinical characteristics, pharmacotherapeutic treatments for medical/psychiatric disorders, and outcomes among patients with bipolar disorder (BD) and CKD on LTLT in a 2-year mirror-image study design. METHODS: Adult BD patients on LTLT for ≥1 year who enrolled in the Mayo Clinic Bipolar Disorder Biobank and developed CKD (stage 3) were included, and our study was approved by the Mayo Clinic Institutional Review Board. The primary outcome was the time to the first mood episode after CKD diagnosis among the lithium (Li) continuers and discontinuers. Cox proportional hazards models were used to estimate the time to the first mood episode. We tested for differences in other medication changes between the Li continuers and discontinuers group using Mantel-Haenszel χ2 tests (linear associations). RESULTS: Of 38 BD patients who developed CKD, 18 (47%) discontinued Li, and the remainder continued (n = 20). The median age of the cohort was 56 years (interquartile range [IQR], 48-67 years), 63.2% were female, and 97.4% were White. As compared with continuers, discontinuers had more psychotropic medication trials (6 [IQR, 4-6] vs 3 [IQR, 2-5], P = 0.02), a higher rate of 1 or more mood episodes (61% vs 10%, P = 0.002), and a higher risk of a mood episode after CKD diagnoses (Hazard Ratio, 8.38; 95% confidence interval, 1.85-38.0 [log-rank P = 0.001]]. CONCLUSIONS: Bipolar disorder patients on LTLT who discontinued Li had a higher risk for relapse and a shorter time to the first mood episode, suggesting a need for more thorough discussion before Li discontinuation after the CKD diagnosis.

Treatment-Resistant Bipolar Depression: Therapeutic Trends, Challenges and Future Directions.

Introduction: Bipolar disorder (BD) is a chronic mental illness impacting 1-2% of the population worldwide and causing high rates of functional impairment. Patients with BD spend most of their time in depressive episodes and up to one-third of patients do not respond to adequate doses of medications. Although no consensus exists for definition of treatment-resistant bipolar depression (TRBD), failure of symptoms improvement despite an adequate trial of two therapeutic agents is a common theme of TRBD. In this paper, we review the evidence base of therapeutic interventions, challenges, and potential future directions for TRBD. Methods: We conducted a literature search for randomized controlled trials on PubMed for the treatment of TRBD and ongoing trials for the treatment of TRBD/bipolar depression on clinicaltrials.gov. Results: Several therapeutic agents have been investigated for TRBD. Adjunctive pramipexole and modafinil have data supporting short-term efficacy in TRBD, along with limited data for racemic intravenous ketamine. Celecoxib augmentation of escitalopram and treatment with metformin in patients with insulin resistance showed promising results. Right unilateral electroconvulsive therapy displayed statistically significant response rate and improvement, but not remission compared to pharmacotherapy. Trials for transcranial magnetic stimulation (TMS) have failed to show a significant difference from sham treatment in TRBD. Future Trends: Pharmacological treatments with novel mechanisms of actions like brexpiprazole and vortioxetine are being investigated following successes in unipolar depression. Modified TMS protocols such as accelerated TMS are under investigation. Innovative approaches like psychedelic-assisted psychotherapy, interleukin-2, fecal microbiota transplantation and multipotent stromal cells are being studied. Conclusion: Evidence on current treatment modalities for TRBD is limited with low efficacy. More research is needed for successful treatment of TRBD. Effective therapies and innovative approaches to treatment are being investigated and could show promise.

Pharmacologic treatment and management of bipolar disorder in adolescents.

INTRODUCTION: The importance of the appropriate therapeutic interventions in children and adolescents with bipolar disorder (BD) cannot be overstated since treatment choices and their consequences may have effects into adulthood. AREAS COVERED: Randomized clinical trials (RCTs) investigating treatment of mania, bipolar depression, and maintenance in adolescents with BD are reviewed. When RCTs are not available or are inadequate, naturalistic data or open studies are also reviewed. EXPERT OPINION: Efficacy and safety of pharmaceutical agents in adolescents with BD appear to mirror adults with BD. Lithium/mood stabilizers are preferred first-line agents over antipsychotic medications, but the latter are second-line agents particularly in bipolar depression. When lithium is used, serum levels approaching 1.0 mEq/L are reasonable since younger people appear to require/tolerate higher levels. Among the antipsychotics, quetiapine appeared to be minimally better than risperidone while risperidone was associated with greater adverse events. Antipsychotics with antidepressant activity in adults also appear to have antidepressant effects in youths. Use of antidepressants in bipolar depression is generally not recommended although it may be reasonable in specific clinical situations. The similarities between adolescent and adult outcomes suggest that it is reasonable to utilize adult data to aid with clinical decision making in adolescents with BD.

Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis.

OBJECTIVE: To compare the efficacy and discontinuation of augmentation agents in adult patients with treatment-resistant depression (TRD). We conducted a systematic review and network meta-analyses (NMA) to combine direct and indirect comparisons of augmentation agents. METHODS: We included randomized controlled trials comparing one active drug with another or with placebo following a treatment course up to 24 weeks. Nineteen agents were included: stimulants, atypical antipsychotics, thyroid hormones, antidepressants, and mood stabilizers. Data for response/remission and all-cause discontinuation rates were analyzed. We estimated effect-size by relative risk using pairwise and NMA with random-effects model. RESULTS: A total of 65 studies (N = 12,415) with 19 augmentation agents were included in the NMA. Our findings from the NMA for response rates, compared to placebo, were significant for: liothyronine, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine, and lisdexamfetamine. For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine). Compared to placebo, ziprasidone, mirtazapine, and cariprazine had statistically significant higher discontinuation rates. Overall, 24% studies were rated as having low risk of bias (RoB), 63% had moderate RoB and 13% had high RoB. LIMITATIONS: Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons. CONCLUSIONS: This NMA suggests a superiority of the regulatory approved adjunctive atypical antipsychotics, thyroid hormones, dopamine compounds (modafinil and lisdexamfetamine) and lithium. Acceptability was lower with ziprasidone, mirtazapine, and cariprazine. Further research and head-to-head studies should be considered to strengthen the best available options for TRD.

New Antipsychotic Medications in the Last Decade.

PURPOSE OF REVIEW: Over the last ten years, the treatment of psychosis has seen a near explosion of creative development in both novel agents and new delivery modalities. The current review summarizes these developments over the past decade (2011-2020). We performed a systematic review utilizing PubMed and PsychInfo with the aim of identifying all the RCT and related analyses in adults with psychosis (schizophrenia and mania). RECENT FINDINGS: We identified 11 significant developments: the introduction of new antipsychotics cariprazine, brexpiprazole, lumateperone, and pimavanserin; introduction of new delivery methods: subcutaneous long-acting risperidone, aripiprazole lauroxil, transdermal asenapine, and inhaled loxapine; and the introduction of new approaches such as olanzapine/samidorphan for olanzapine-associated weight gain, examination of the TAAR1 agonist SEP 363,856 as a test of concept, and the combination of Xanomeline/Trospium, an M1 and M4 muscarinic receptor agonist in conjunction with a peripheral anticholinergic. Last decade has seen a tremendous development in second-generation antipsychotics which provides unprecedented treatment options for clinicians in treating psychosis.

Self-report screening instruments differentiate bipolar disorder and borderline personality disorder.

BACKGROUND: Bipolar disorder (BD) and borderline personality disorder (BPD) share overlapping phenomenology and are frequently misdiagnosed. This study investigated the diagnostic accuracy of the Mood Disorder Questionnaire (MDQ) and McLean Screening Instrument for Borderline Personality Disorder (MSI) in a clinical inpatient setting and whether individual screening items could differentiate BD from BPD. METHODS: 757 sequential inpatients admitted to a Mood Disorder Unit completed both the MDQ and MSI. Screen positive for the MDQ was defined as ≥7/13 symptoms endorsed with concurrence and at least moderate impact. Screen positive for the MSI was defined as a score of ≥7. The clinical discharge summary diagnosis completed by a board-certified psychiatrist was used as the reference standard to identify concordance rates of a positive screen with clinical diagnosis. Individual items predicting one disorder and simultaneously predicting absence of other disorder by odds ratio (OR>and <1) were identified. RESULTS: Both screening instruments were more specific than sensitive (MDQ 83.7%/ 67.8%, MSI 73.2% / 63.3%). MDQ individual items (elevated mood, grandiosity, increased energy, pressured speech, decreased need for sleep, hyperactivity) were significant predictors of BD diagnosis and non-predictors of BPD diagnosis. Whereas MSI subitem, self-harm behaviors/suicidal attempts predicted BPD in the absence of BD; distrust and irritability were additional predictors of BPD. CONCLUSION: While this study is limited by the lack of structured diagnostic interview, these data provide differential symptoms to discriminate BD and BPD. Further work with larger datasets and more rigorous bioinformatics machine learning methodology is encouraged to continue to identify distinguishing features of these two disorders to guide diagnostic precision and subsequent treatment recommendations.

Long-term lithium therapy and risk of chronic kidney disease in bipolar disorder: A historical cohort study.

AIMS: Long-term lithium therapy (LTLT) has been associated with kidney insufficiency in bipolar disorder (BD). We aimed to investigate the risk factors of chronic kidney disease (CKD) development and progression among BD patients receiving LTLT. METHODS: We included adult patients with BD on LTLT (≥1 year) who were enrolled in the Mayo Clinic Bipolar Biobank, Rochester, Minnesota. We reviewed electronic medical records to extract information related to lithium therapy and kidney-related data to assess changes in the estimated glomerular filtration rate (eGFR). CKD severity was assessed based on eGFR. RESULTS: Among 154 patients who received LTLT, 41 patients (27%) developed CKD, of whom 20 (49%) patients continued lithium (continuers) and 19 (46%) discontinued it (discontinuers). The median time to stage 3 CKD development was 21.7 years from the start of Li treatment. Type-2 diabetes mellitus and benzodiazepine use were independent predictors for CKD development in the survival analysis, after controlling for age. The subsequent CKD progression rate did not differ between continuers and discontinuers (mean GFR 48.6 vs. 44.1, p = 0.13) at the end of follow-up duration (mean duration: 3.5 ± 4.4 years for continuers and 4.9 ± 5.3 years for discontinuers). CONCLUSION: CKD was observed in one fourth of patients with BD receiving LTLT. There was no significant difference in the progression of CKD among Li continuers versus discontinuers, at the mean follow-up duration of 4.2 years, after the CKD diagnosis. Progression of CKD could be influenced by existing comorbidities and may not necessarily be due to lithium alone.

Efficacy and Tolerability of Lamotrigine in Borderline Personality Disorder: A Systematic Review and Meta-Analysis.

Background: Patients with Borderline Personality Disorder (BPD) have a high prevalence of mood disorders. Lamotrigine (LAM) is often used as an off-label therapeutic option for BPD. We aimed to conduct a systematic review and meta-analysis to assess the efficacy and tolerability of LAM for the treatment of BPD. Methods: We comprehensively searched electronic databases for eligible studies from the inception of databases to September 2019. Outcomes investigated were BPD dimensions, tolerability, and adverse events. Quality assessments were completed for the included studies. Data were summarized using random-effects model. Results: Of the 619 records, five studies, including three randomized controlled trials (RCT; N = 330) were included for the qualitative analysis. A meta-analysis conducted on two RCTs measuring LAM efficacy at 12 weeks, showed no statistically significant difference at 12 weeks (SMD: -0.04; 95% CI: -0.49, 0.41; p = 0.87; I2 = 38%) and at study endpoints (SMD: 0.18, 95%CI: -0.89, 1.26; p = 0.74; I2 = 86%) as compared to placebo. Sensitivity analysis on three RCTs measuring impulsivity/aggression showed no statistically significant difference between LAM and placebo (SMD: -1.84, 95% CI: -3.94, 0.23; p = 0.08; I2 = 95%). LAM was well tolerated, and quality assessment of the included trials was good. Conclusions: Our results suggest there is limited data regarding efficacy of lamotrigine in BPD. There was no consistent evidence of lamotrigine's efficacy for the core symptom domains of BPD. Future studies should focus on examining targeted domains of BPD to clarify sub-phenotypes and individualized treatment for patients with BPD.

An Update on the Efficacy and Tolerability of Oral Ketamine for Major Depression: A Systematic Review and Meta-Analysis.

Background: Intravenous Ketamine has shown robust antidepressant efficacy although other routes of administration are currently needed. We conducted a systematic review and meta-analysis of studies evaluating the efficacy and tolerability of oral ketamine for depression. Methods: A comprehensive search of major electronic databases from inception to April 2020 was performed. Studies of oral ketamine for depression, from case series to randomized clinical trials, were eligible. Randomized controlled trials were included in a meta-analysis, focusing on response, remission, time to effect, and side effects. Results: A total of 917 articles were identified with 890 studies screened, yielding a total of 10 studies included in our systematic review.Three randomized controlled trials (RCTs) (N = 161, mean age 37.9 ± 9.5 years, 58.6% females) were included in the meta-analysis. Pooled analysis suggested a significant antidepressant effect of oral ketamine (SMD: -0.75; 95% CI: -1.08, -0.43; p<0.0001; I2 = 0%) although remission rates (RR:2.77; 95% CI:0.96, 8.00; p = 0.06) and response rates (RR:2.58; 95% CI:0.94,7.08; p = 0.07) were marginal compared to placebo at the endpoint. Oral ketamine antidepressant effects seemed to take effect at the 2nd week (SMD: -0.71; 95% CI: -1.08, -0.35; p = 0.001; I2 = 0%). There were no significant differences in the overall side-effects between oral ketamine and the placebo group (RR 1.28, 95% CI: 0.89-1.83; p = 0.19). Conclusion: This focused meta-analysis of oral ketamine suggests a marginal efficacy for major depressive disorder without increased risk of adverse events. Further larger sample studies are needed to confirm these preliminary findings, analyzing differential response/remission rates by affective disorder, optimal dosing strategies, and its long-term effects.

A study of psychiatric morbidity among school going adolescents.

AIM: This study aims to study the prevalence of psychiatric morbidity among adolescents and compare its distribution in the urban and rural areas. STUDY DESIGN: This was a cross-sectional study. MATERIALS AND METHODS: One thousand adolescents aged 11 to 16 years studying in various private and government schools in urban and rural areas in district Patiala, Punjab were studied. Stratified cluster sampling was used considering the type of school as strata and sections of each standard as clusters. The study was conducted in two steps; in the first step, self-designed sociodemographic questionnaire and socioeconomic status scale, Parekh's method of socioeconomic classification for rural area, and Kuppuswamy's revised method of social classification for urban areas. To study the psychiatric morbidity, the strength and difficulties questionnaire (SDQ) self-report version and parent version was used. Students who scored borderline or abnormal on SDQ, were further evaluated in second stage by clinical interview, detailed case history, and mental state examination; psychiatric disorders were diagnosed following International Classification of Diseases-10 (ICD-10) criteria. STATISTICAL ANALYSIS USED: Chi-square, Student's t-test. RESULTS: The prevalence ranges from 17.94 in the private school in the urban area and 20.96% in government schools in the urban area to 20.61% in private schools in the rural area and 22.17 in government school of the rural area. The overall prevalence of psychiatric disorders is higher among adolescents in the rural area (21.38%) as compared to the urban area (19.43%). Rural adolescents had significantly higher rates of somatoform disorders (4.45%), conduct disorder (3.78%), dysthymia (1.11%), and other mood disorders (0.89%) whereas higher rates of depression (3.88%), anxiety (3.67%), and hyperkinetic disorders (3.02%) were found in urban counterparts. CONCLUSION: An alarming number of adolescents suffer from different emotional and behavioral problems, but there is no excess of formal mental illness reaching the psychiatrist. This should help us formulate a rational basis for deploying our resources for the treatment and prevention of mental illness in tomorrow's adults.