Mood Episodes Research Articles

Late-life parkinsonism in bipolar disorder.

Parkinsonism is a frequently encountered symptom in individuals with bipolar disorder (BD). It can be drug-induced, co-occurring with Parkinson's disease (PD), or a genuine motor abnormality of BD itself. This study aims to address the primary pathophysiology of parkinsonism in BD. Sixteen patients with BD and parkinsonism were recruited from consecutive patients who were referred to a neurology clinic at a tertiary psychiatric centre. The patients underwent clinical assessments, dopamine transporter single-photon computed tomography (DAT-SPECT), cardiac 123I-metaiodo-benzylguanidine (MIBG) scintigraphy, and morphometric magnetic resonance imaging (MRI). The positivity or negativity of Lewy body disease (LBD) biomarkers was determined based on the visual assessment of DAT-SPECT and heart-to-mediastinum ratio on cardiac MIBG scintigraphy. Four out of the 16 participants received 300-600 mg of levodopa. Thirteen patients were diagnosed with BD type 1, and 12 had experienced >5 previous mood episodes. Parkinsonism developed more than 10 years after the onset of BD and after the age of 50 years in all patients. Four cases were positive for LBD biomarkers. Six patients with negative LBD biomarkers showed reduced striatal uptake with z-scores below -2.0. MRI morphometry revealed varying degrees of brain atrophy in most patients. Three of the four patients did not respond to 600 mg of levodopa. The results of this study indicate that the majority of parkinsonism observed in BD is not a consequence of PD/LBD. Instead, it may represent a genuine motor abnormality of BD in late life.

Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrum.

Psychotic major depressive disorder (MDD), a subtype of MDD characterised by psychotic symptoms that occur exclusively during mood episode, is clinically significant yet underexplored genetically due to its rarity. This study comprehensively examines the genetic basis of psychotic MDD and elucidates its position within the mood-psychotic spectrum. This population-based cohort study used Swedish and Danish registry data for over 5.1M individuals born between 1958 and 1993/1996. Specialist-diagnosed psychotic MDD was defined using ICD-10 sub-codes of MDD, F32.2/F32.3. We estimated familial aggregation/coaggregation using generalised estimating equations, heritability and genetic correlations using structural equation modelling. We also analysed ∼30,000 genotyped MDD cases from the UK Biobank and a Swedish cohort to explore which polygenic risk score (PRS) may predispose individuals to psychotic MDD. With over 10,000 psychotic MDD identified from the two nationwide patient registers, this study highlights the familial aggregation of psychotic MDD, co-aggregation with mood and psychotic disorders, and its stronger genetic correlation with schizophrenia compared to non-psychotic MDD. The familial risks increased with closer biological relatedness, suggesting genetic influence. Pedigree-heritability of psychotic MDD was 30.17% (95% CI 23.53-36.80%). While the genetic correlation between psychotic and non-psychotic MDD was high (0.82, 95% CI 0.73-0.92), the psychotic subgroup showed a higher genetic correlation with schizophrenia than non-psychotic MDD (0.67 vs 0.46, p-value 7.55∗10-4). Within 30,000 genotyped MDD cases, individuals with psychotic MDD had higher mean PRS for schizophrenia and BD but a lower MDD PRS than non-psychotic MDD. PRS for BD type-I was associated with increased odds of psychotic MDD, while BD type-II PRS showed no significant association with psychotic MDD. This study provides evidence for the genetic basis of psychotic MDD, underscoring its unique position bridging the spectrum of mood and psychotic disorders. These findings advance our understanding of the aetiology of psychotic MDD and contribute to the limited body of evidence on this phenotype by utilising large-scale population-based data. European Research Council; US National Institutes of Mental Health; European Union Horizon 2020 Program; Swedish Research Council; Research Council of Norway; Swedish Foundation for Strategic Research; Hjärnfonden.

Disrupted Relatedness and Shifting Perceptions of Others: Changing Moods Over Time for People Diagnosed with Bipolar Disorder

For people diagnosed with bipolar disorder, the relationship between mood episodes and interpersonal life is critical. Yet little is known about how their experience of other people changes during and between episodes of depression and mania. This longitudinal study aimed to investigate the experience of interpersonal change during depression, mania and euthymia (stability). Semi-structured interviews were conducted with three women at two time points and were analysed using longitudinal interpretative phenomenological analysis. One longitudinal theme, “Changing sense of others impacts relatedness,” demonstrates profound changes in participants’ experiences of other people within and between episodes. During depression, participants experienced other people as critical and threatening, making interactions impossible, whereas during mania they felt liberated from the expectations of others, who were seen as either subservient or irrelevant. For some participants, interpersonal disruption persisted during euthymia, making social interactions challenging. The findings highlight distinct forms of disrupted relatedness during depression and mania which were cumulative, impacting participants’ ability to relate to others and reconnect during stable periods. This points to the clinical value of those affected by bipolar disorder gaining insight into their trajectory of interpersonal change, along with a focus on rebuilding relationships and relational connection during euthymic phases.

Impact of Comorbid Substance Use in Patients with Bipolar Disorder

The presence of addictive comorbidity complicates all psychiatric pathologies, affecting both their management and prognosis due to the numerous complications that punctuate their course. This is particularly true for bipolar disorder. This study explores the relationship between bipolar disorder and substance use, emphasizing the impact on management and prognosis. Using a sample of 40 male patients with bipolar disorder type I, this study investigates clinical parameters, and prognostic elements associated with comorbid substance use. The results reveal a prevalence of 42.5% of substance abuse among bipolar patients. Significant differences were observed in Global Functioning Score (72.78 versus 83.33, p = 0.018), mean number of hospitalizations (5.12 versus 1.45; p=0.010), annual relapses (p=0.044), and the quality of interval of mood episode (p=0.028) between bipolar patients with and without substance use. The study underscores the need for active screening and tailored interventions to address this comorbidity, providing valuable insights for comprehensive patient care and therapeutic recommendations.

Outpatient Management of Bipolar Disorder in Older Adults.

Old age bipolar disorder (OABD), increasingly common as the population ages, presents unique diagnostic and treatment challenges. This selective review focuses on issues especially relevant to outpatient management. People with OABD may have similar frequency and severity of mood episodes compared to younger adults. Depression predominates, and mixed symptoms in both depressive and manic episodes are common. Comorbidity and excess mortality are high, with a particular bidirectional association with cerebrovascular disease. Lithium may outperform valproic acid and second-generation antipsychotics in efficacy. Tolerability and long-term safety can be improved with relatively lower target drug therapeutic levels. Outpatient clinicians treating OABD should take an active role in the recognition and management of medical comorbidities. A careful history and examination might reveal subtle signs of bipolar disorder or mixed features and change treatment. A primary target for treatment is to reduce polypharmacy when appropriate. Further trials are needed to make specific and clear recommendations in OABD.

Imagery-based cognitive therapy to reduce emotional dysregulation and mood instability in bipolar disorder: a case-series study.

Bipolar disorder (BD) has a significant impact on functioning in the absence of acute mood episodes. This has been associated with subsyndromal symptoms, co-morbidities, and emotional dysregulation. The present study aims to evaluate the acceptability and preliminary efficacy of imagery-based cognitive therapy (ImCT) in a French community setting. We were particularly interested in the link between mental imagery and emotional dysregulation as this may clarify the mechanisms involved in the potential efficacy of the therapy and ultimately improve its relevance. Ten participants underwent ImCT, with weekly assessments of mood fluctuations, anxiety, and emotional dysregulation conducted over 1 month (i.e. pre-therapy, post-therapy and 1-month follow-up). Recovery, post-traumatic stress symptoms and self-compassion were measured at baseline and post-therapy. Attrition rates and satisfaction were measured. All participants who completed therapy (n=8) reported high levels of satisfaction. Five of them showed reliable individual improvement on emotion dysregulation scores. At the group level, a significant decrease in mood fluctuation with a large effect size was found post-therapy. ImCT showed good acceptability among participants who completed the study. Importantly, our study is the first to provide an indication that ImCT may alleviate subsyndromal mood symptoms but also emotional dysregulation in individuals with BD. This latter finding is particularly relevant given the scarcity of validated psychosocial interventions targeting emotional dysregulation in BD.

Efficacy and Tolerability of Cariprazine as Monotherapy for Acute Bipolar Depression: A Systematic Review and Meta-analysis

Background: Bipolar depression (BDep) presents a significant clinical challenge with limited treatment options. The second-generation antipsychotics are increasingly utilized as primary or adjunct treatments. The use of cariprazine as monotherapy was approved by the US- Food and Drug Administration for acute BDep in 2019. Aim: The aim of this study is to evaluate the efficacy and tolerability of cariprazine as monotherapy for acute BDep compared to placebo. Methods: We conducted a systematic review of randomized placebo-controlled trials assessing cariprazine as monotherapy for acute BDep. The inclusion criteria encompassed English language studies comparing cariprazine as monotherapy to placebo, with outcomes measured within 6–12 weeks. The primary outcome measures included response and remission rates. The secondary outcomes included standardized mean differences (SMDs) in Montgomery Åsberg Depression Rating Scale (MADRS) and Hamilton Rating Scale for Depression (HAM-D) score changes from baseline to endpoint, dropout rates, and dropout rates due to adverse effects. The binary and continuous outcomes were analyzed using the Mantel–Haenszel and inverse variance methods, respectively, with RevMan 5.4 software. This study was done as the part of a network meta-analysis registered with PROSPERO (CRD42017077575). Results: Only four studies were eligible for the meta-analysis, encompassing 1747 patients. Cariprazine demonstrated significantly higher response rates (odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.18–1.79) and remission rates (OR = 1.52, 95% CI: 1.20–1.93) compared to placebo. SMDs showed that cariprazine was more efficacious (MADRS: SMD −0.24, 95% CI: −0.34 to −0.14, and HAM-D: SMD −0.21, 95% CI: −0.31 to −0.11). There was no significant difference in overall dropout rates and dropout rates due to adverse effects between cariprazine and the placebo arm. Hence, tolerability was comparable to placebo. Heterogeneity was not significant (I 2 = 0). Conclusion: Cariprazine monotherapy was found to be efficacious in acute BDep, with a significant number of patients attaining remission. It is comparable to a placebo in terms of tolerability profile. Future studies are required to understand its efficacy and safety as a prophylactic for preventing mood episodes in BDep.

Accurately predicting mood episodes in mood disorder patients using wearable sleep and circadian rhythm features

Wearable devices enable passive collection of sleep, heart rate, and step-count data, offering potential for mood episode prediction in mood disorder patients. However, current models often require various data types, limiting real-world application. Here, we develop models that predict future episodes using only sleep-wake data, easily gathered through smartphones and wearables when trained on an individual’s sleep-wake history and past mood episodes. Using mathematical modeling to longitudinal data from 168 patients (587 days average clinical follow-up, 267 days wearable data), we derived 36 sleep and circadian rhythm features. These features enabled accurate next-day predictions for depressive, manic, and hypomanic episodes (AUCs: 0.80, 0.98, 0.95). Notably, daily circadian phase shifts were the most significant predictors: delays linked to depressive episodes, advances to manic episodes. This prospective observational cohort study (ClinicalTrials.gov: NCT03088657, 2017-3-23) shows sleep-wake data, combined with prior mood episode history, can effectively predict mood episodes, enhancing mood disorder management.

Thyroid hormone levels in patients with bipolar disorder: a systematic review and meta-analysis

PurposeTo investigate the difference in blood (serum/plasma) thyroid hormone (TH) levels, including thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3), free thyroxine (FT4), and free triiodothyronine (FT3), in bipolar disorder (BD) during different mood episodes (depression and mania) compared with healthy control (HC) and between manic episodes (BD-M) and depressive episodes (BD-D).MethodsAs of September 1, 2024, the electronic databases PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, China Science and Technology Journal Database, Wanfang Database, and Clinical Trials. Gov were systematically searched with no language limitations. Standardized mean differences (SMD) with 95% confidence interval (CI) were summarized using a random effects model. The chi-squared-based Q test and the I2 test assessed the size of heterogeneity.ResultsThe 21 studies included a total of 3696 participants, Of the 2942 BD patients, 1583 were in depressive episodes 1359 were in manic episodes. The status of measuring blood TH levels included 2 studies in plasma and 19 in serum. Combined with the results of the sensitivity analyses, we obtained the following relatively reliable results: serum T3 (SMD: -0.63, 95%CI: -1.09 to -0.17) and FT3 (SMD: -0.42, 95%CI: -0.83 to -0.00) levels decreased significantly in BD-D compared to HC; serum T3 (SMD: -0.91, 95%CI: -1.49 to -0.32) levels decreased significantly and serum FT4 (SMD: 0.37, 95%CI: 0.14 to 0.60) levels increased significantly in BD-M than in HC; serum T3 (SMD: 0.87, 95%CI: 0.24 to 1.49) and FT3 (SMD: 0.27, 95%CI: 0.13 to 0.42) levels demonstrated a significant elevation in BD-M compared to BD-D. In the group of euthyroidism, apart from serum FT4 (SMD: 0.21, 95%CI: -0.15 to 0.58) levels showed no significant difference between BD-M and HC, other results above remained consistent.ConclusionSerum T3 and FT3 levels decreased significantly in BD-D compared to HC. Serum T3 levels decreased significantly and serum FT4 levels increased significantly in BD-M compared to HC. Serum T3 and FT3 levels increased significantly in BD-M than in BD-D. The temporality of changes in TH levels and BD progression demands further longitudinal studies to illustrate.Trial registrationNumber and date of registration for prospectively registered trials No. CRD42022378530.

Associations between lifetime reproductive events among postmenopausal women with bipolar disorder.

The premenstrual phase of the menstrual cycle, childbirth and perimenopause often coincide with a worsening of mood symptoms in women with bipolar disorder (BD). To date, findings from the limited number of studies investigating associations between these events among women with BD have been inconsistent. This study aimed to investigate associations between episodes in relation to the perimenopause and (i) premenstrual symptoms and (ii) postpartum mood episodes in a large sample of postmenopausal women with BD. Among 567 postmenopausal women with BD, recruited as part of the UK Bipolar Disorder Research Network, relationships between reproductive event-associated mood symptoms/episodes were examined. Multivariate binary analyses were carried out to identify if history of premenstrual symptoms and/or postpartum episodes predicted the occurrence of mood episodes in relation to the perimenopause, controlling for potential confounders including number of mood episodes per illness year. History of premenstrual symptoms was associated with experiencing any type of mood episode, and depression specifically, during the perimenopause (OR 6.189, p < 0.001 and OR 2.709, p = 0.019 respectively). History of postpartum depression within 6 weeks of delivery was associated with depressive episodes during the perimenopause (OR 2.635, p = 0.027). Postpartum mania was not a significant predictor. Our findings suggest that women with BD with a history of premenstrual symptoms and postpartum depression are potentially at increased risk of experiencing episodes of depression in relation to the perimenopause. There are clinical and self-management implications in identifying a subgroup of women with BD who may be particularly vulnerable to episodes of mood disturbance during reproductive events.

The efficacy of valproate in acute mania, bipolar depression and maintenance therapy for bipolar disorder: an overview of systematic reviews with meta-analyses.

This study aims to conduct an overview on the comparative efficacy of valproate in acute mania, bipolar depression and maintenance treatment of bipolar disorder (BD). We performed an overview of systematic reviews with meta-analyses of randomised controlled trials (RCTs), registered in PROSPERO (CRD42024497749). We searched Medline and Cochrane Database of Systematic Reviews. Summary measures comparing valproate with placebo or other active drugs were described. We included 26 systematic reviews. For acute mania (31 RCTs, n=4376), valproate showed a significantly better response than placebo in two high-quality systematic reviews (RR=1.42; 95% CI: 1.19 to 1.71) (OR=2.05; 95% CI: 1.32 to 3.20). No significant differences with lithium were found in most outcomes. Valproate had similar efficacy to quetiapine and lower efficacy compared with risperidone, with conflicting results when compared with olanzapine. In bipolar depression (7 RCTs, n=399), valproate was more effective than placebo in reducing depressive symptoms (OR=2.80; 95% CI: 1.26 to 6.18) and achieving remission (OR=2.4; 95% CI: 1.09 to 5.29) (OR=2.15; 95% CI: 0.82 to 5.6), considering the results of three high-quality systematic reviews. No significant difference was observed with lithium, lurasidone, quetiapine or olanzapine plus fluoxetine, but valproate showed superior efficacy to aripiprazole, ziprasidone and agomelatine. In maintenance treatment (11 RCTs, n=1063), valproate was superior to placebo in preventing relapse of any mood episode in two high-quality systematic reviews (RR=0.63; 95% CI: 0.48 to 0.83) (RR=0.63; 95% CI: 0.47 to 0.83). No significant difference was found with lithium, olanzapine or lamotrigine. This overview highlights favourable results for valproate compared with placebo in all phases of BD, as well as presenting specific results in comparison with other active drugs. However, these results must be interpreted considering the methodological limitations of our study.

Mood disorders and 5-HTR2A genetic variants – the moderator effect of inflammation on expression of affective polarity phenotype

BackgroundAlthough repeatedly confirmed, the molecular nature of gene-environment (GxE) interactions has rarely been investigated in the clinical context of mood disorders. This study assesses the relationship between HTR2A genetic variants and the modulatory effect of inflammation in a collective cohort of patients with major depressive disorder (MDD) and bipolar disorder (BD), as a unified group with two distinct phenotypes.MethodsThe study included 138 patients with acute mood episodes (BD = 83; MDD = 55). HTR2A rs6313 and rs6314 genotyping was performed while measuring platelet-derived indicators of inflammation (platelet count (PLT), mean platelet volume (MPV), plateletcrit, and platelet distribution width) and the MPV/PLT ratio.ResultsThe HTR2A rs6313 variant is a significant predictor of the polarity phenotype in mood disorders, with the MPV/PLT ratio moderating this relationship, but only under low-inflammatory conditions. In more pronounced inflammatory states, genetic influences lose their predictive role.ConclusionsTo our knowledge, this is the first study to investigate the complex interplay between platelet-derived indicators of inflammation and HTR2A variants in the context of mood disorders. Without pro-inflammatory conditions, mood disorders seem to be more genetically determined. Under pro-inflammatory conditions, phenotypic presentation is less dependent on genetic factors. GxE interactions in mood disorders are multifaceted, context-dependent and relevant for assessing their clinical presentation and course.

Seasonal mood variation in youth and young adults with bipolar spectrum disorder: A longitudinal prospective analysis

ObjectiveTo determine whether there are latitude and seasonal differences in the prevalence of mood episodes (depression and mania) in youth and young adults with Bipolar Spectrum Disorder (BD). MethodsMood polarity was prospectively evaluated in 413 participants with BD. Participants were enrolled in the Course and Outcome of Bipolar Youth (COBY) study at three sites (University of California Los Angeles-UCLA, Brown University, and the University of Pittsburgh Medical Center-UPMC) and interviewed on average every 7 months for an average of 91.9 months (range: 6–228 months), with a total of 274,123 weekly mood ratings. Associations between light exposure and mood polarity were estimated using generalized linear mixed models with time-varying covariates, considering the latitude and seasonality of the study sites and other potential confounders. ResultsAverage age at intake and at last assessment was 12.6 ± 3.3 and 27.2 ± 4.8 years-old, respectively. There were significantly more depressive episodes during winter than during summer, spring, and autumn. Considering latitude, UCLA showed significantly lower prevalence of depressive episodes, and an absence of seasonal pattern of depression, compared to the Brown/UPMC sites. For the entire sample, there were more manic/hypomanic episodes during summer than during winter. However, there were no significant between site seasonal differences in the prevalence of manic/hypomanic episodes. ConclusionsDepressive episodes are more prevalent during the winter and although less significant, manic/hypomanic episodes during the summer. Awareness and interventions to prevent or ameliorate the effects of seasonal variations in mood changes in BD are warranted.

Aripiprazole once-monthly for the treatment of adult patients with earlier-stage bipolar I disorder: a post hoc analysis of data from a double-blind, placebo-controlled, 52-week randomized withdrawal trial

BackgroundIncreased awareness of the factors contributing to the diagnostic disparities seen in bipolar disorder between individuals of different heritage is needed to achieve equity in diagnosis and treatment. One such inequity is the provision of earlier treatment. Earlier treatment of patients diagnosed with bipolar disorder may prolong time to recurrence of mood episodes and reduce functional impairment and other poor outcomes associated with disease progression. The aim of this post hoc analysis was to study the efficacy and safety of long-acting injectable aripiprazole once-monthly 400 mg (AOM 400) in patients with earlier-stage bipolar I disorder (BP-I). Data from a 52-week multicenter, double-blind, placebo-controlled, randomized withdrawal trial of AOM 400 versus placebo in patients with BP‑I (NCT01567527) were analyzed. Those patients in the lowest quartiles for age (18–≤32 years; n = 70) or disease duration (0.13–≤4.6 years; n = 67) at baseline were categorized with earlier-stage BP-I. The primary endpoint was time from randomization to recurrence of any mood episode. Other endpoints included proportion of patients with recurrence of any mood episode, and change from baseline in Young Mania Rating Scale (YMRS) and Montgomery–Åsberg Depression Rating Scale (MADRS) total scores.ResultsMaintenance treatment with AOM 400 significantly delayed time to recurrence of any mood episode versus placebo in patients aged 18–≤32 years (hazard ratio [HR]: 2.46 [95% confidence interval (CI) 1.09, 5.55]; p = 0.0251) or with disease duration 0.13–≤4.6 years (HR: 3.21 [95% CI 1.35, 7.65]; p = 0.005). This was largely driven by a lower proportion of patients in the AOM 400 group with YMRS total score ≥15 or clinical worsening. Changes from baseline in MADRS total score in both earlier-stage groups indicated AOM 400 did not worsen depression versus placebo. The safety profile of AOM 400 was consistent with the original study. Note that the original study included patients who had previously been stabilized on AOM 400 monotherapy, which may have enriched the population with patients who respond to and tolerate AOM 400.ConclusionsIn this post hoc analysis, AOM 400 prolonged time to recurrence of any mood episode versus placebo in earlier-stage BP-I. These findings support early initiation of maintenance treatment with AOM 400.

A pre-post trial to examine biological mechanisms of the effects of time-restricted eating on symptoms and quality of life in bipolar disorder

BackgroundThe primary objective of this trial is to examine the mechanisms of time-restricted eating (TRE) as an adjunct to psychiatric care for people with bipolar disorder (BD) with sleep or circadian disruptions. This study builds on prior studies of circadian disruption in BD as well as growing evidence that TRE improves circadian functioning.MethodsOne-hundred fifty participants diagnosed with BD 1 or II will be recruited via advertising in the local community. Main inclusion criteria include: obtaining medical treatment for BD; current sleep or circadian problems; self-reported eating period of ≥ 12 h; no eating disorder or other health conditions that would hinder or limit the safety of following TRE; and not currently experiencing a mood episode, acute suicidality, psychosis, alcohol or substance use disorder. Participants will be asked to complete a baseline period in which daily food intake is logged online for two weeks. After baseline, participants will be asked to follow TRE for 8 weeks and to continue to complete daily food logging during this time. Symptom severity interviews will be conducted by phone or videoconference at baseline, mid-intervention (6 weeks post-baseline), end of intervention (10 weeks post-baseline), and 6 months post-baseline. Self-rated symptom severity and quality of life data will be gathered online at the same time points as symptom severity interviews, and at 16 weeks post-baseline (6 weeks after the TRE period ends). To assess potential mechanisms of change, we will examine the change in diurnal amplitude of ‘clock’ gene expression as a primary mediator at 8 weeks compared to baseline. We will further test whether diurnal amplitude of clock gene expression is predictive above and beyond the role of two covariate potential mediators, glucose tolerance and inflammation at 8 weeks relative to baseline. To provide an index of whether TRE successfully decreases emotional lability, participants will be asked to complete 5 mood assessments per day for 7 days at baseline and at 10 weeks. These mood assessments will be optional.DiscussionThe planned research will provide novel and important information on whether TRE improves sleep/circadian rhythm problems, along with reductions in mood symptoms and improvements in quality of life, for individuals with BD.Trial registrationClinicalTrials.gov ID: NCT06555406.

Ten Years of Bipolar Telehealth: Program Evaluation of a Team-Based Telemental Health Clinic.

Objectives: Telemental health via videoconferencing (TMH-V) can overcome many of the barriers to accessing quality mental health care. Toward this end, in 2011, the U.S. Department of Veterans Affairs (VA) established the National Bipolar Disorders TeleHealth (BDTH) Program to provide expert mental health consultation and treatment to Veterans with bipolar spectrum disorders. Methods: Initial analyses of BDTH services suggested that participants had positive changes in quality-of-care indices and clinical outcomes; however, that evaluation was based on a limited sample of both participants and VA medical centers. We were able to confirm and expand upon those early results by using nearly eight times the number of participants and more than twice as many medical centers. Results: For the 2,456 Veterans who completed the intake to our program, there were significant improvements in some of the quality metrics (e.g., lithium use) and a 54% reduction in positive suicide screens (p < 0.05). The Veterans who completed the initial and postprogram assessments (n = 815) reported a 16.6% reduction in manic symptoms (p < 0.001), a 29.3% reduction in depressive symptoms (p < 0.001), and a 21.2% reduction in mood episodes (p < 0.001). Additionally, these Veterans demonstrated significant improvements (p < 0.001) in mental health-related quality of life between the two assessments. Conclusions: These analyses provide further support for the general effectiveness and safety of telemental health via videoconferencing. Future research should examine the generalizability of these findings across various subgroups (e.g., minority patients, patients in rural areas), populations, and health care systems.

Extended-Release Lithium Treatment for Adolescents with Bipolar Disorder with or Without Comorbid Autism Spectrum Disorder: Protocol of a Longitudinal Prospective Naturalistic Study for the Assessment of Efficacy and Tolerability.

Background: Lithium is the gold-standard treatment for Bipolar Disorder (BD) in both adults and adolescents, effectively managing mood episodes and reducing suicide risk. While its efficacy in neurotypical youth is well established, its use in adolescents with Autism Spectrum Disorder (ASD) and comorbid BD remains under-researched. Here, we present the protocol for a study aiming to evaluate the efficacy and tolerability of Extended-Release Lithium Salts in treating adolescents with BD and comorbid ASD compared to neurotypical BD patients. Methods: This longitudinal prospective naturalistic comparative study will enroll lithium-naïve adolescents aged 12-18 with BD, with or without comorbid ASD, from the Department of Child and Adolescent Psychiatry and Psychopharmacology. Participants will be followed for six months while receiving Extended-Release Lithium Salts treatment. Primary outcomes will include mood instability, suicidality, emotional dysregulation, and aggression, assessed through a range of clinical rating scales and diagnostic tools at baseline, three months, and six months. Secondary outcomes will focus on the safety and tolerability of Extended-Release Lithium Salts, with measures including side effect ratings, physical exams, and laboratory tests. Results: We hypothesize that Extended-Release Lithium Salts will demonstrate non-inferiority in treating BD symptoms in adolescents with comorbid ASD compared to those without ASD. Conclusions: This study is poised to fill a significant gap in the literature by providing critical data on the use of lithium for adolescents with BD and ASD. Findings will inform clinical practice and future research, potentially guiding more personalized treatment approaches for this complex and vulnerable population.

Digital phenotyping in bipolar disorder: Using longitudinal Fitbit data and personalized machine learning to predict mood symptomatology.

Effective treatment of bipolar disorder (BD) requires prompt response to mood episodes. Preliminary studies suggest that predictions based on passive sensor data from personal digital devices can accurately detect mood episodes (e.g., between routine care appointments), but studies to date do not use methods designed for broad application. This study evaluated whether a novel, personalized machine learning approach, trained entirely on passive Fitbit data, with limited data filtering could accurately detect mood symptomatology in BD patients. We analyzed data from 54 adults with BD, who wore Fitbits and completed bi-weekly self-report measures for 9 months. We applied machine learning (ML) models to Fitbit data aggregated over two-week observation windows to detect occurrences of depressive and (hypo)manic symptomatology, which were defined as two-week windows with scores above established clinical cutoffs for the Patient Health Questionnaire-8 (PHQ-8) and Altman Self-Rating Mania Scale (ASRM) respectively. As hypothesized, among several ML algorithms, Binary Mixed Model (BiMM) forest achieved the highest area under the receiver operating curve (ROC-AUC) in the validation process. In the testing set, the ROC-AUC was 86.0% for depression and 85.2% for (hypo)mania. Using optimized thresholds calculated with Youden's J statistic, predictive accuracy was 80.1% for depression (sensitivity of 71.2% and specificity of 85.6%) and 89.1% for (hypo)mania (sensitivity of 80.0% and specificity of 90.1%). We achieved sound performance in detecting mood symptomatology in BD patients using methods designed for broad application. Findings expand upon evidence that Fitbit data can produce accurate mood symptomatology predictions. Additionally, to the best of our knowledge, this represents the first application of BiMM forest for mood symptomatology prediction. Overall, results move the field a step toward personalized algorithms suitable for the full population of patients, rather than only those with high compliance, access to specialized devices, or willingness to share invasive data.

Association of circulating monocyte number and monocyte–lymphocyte ratio with cardiovascular disease in patients with bipolar disorder

BackgroundCardiovascular disease (CVD) is the leading cause of excessive and premature mortality in patients with bipolar disorder (BD). Despite immune cells participating considerably in the pathogenesis of CVD, limited data are available regarding leukocyte phenotypes in patients with BD and CVD. This study aimed to evaluate associations between circulating leukocyte subset and CVD among patients with BD.MethodsA total of 109 patients with BD-I and cardiologist-confirmed CVD diagnosis (i.e., case) were matched with 109 BD-I patients without CVD (i.e., control) according to the age (± 2 years), sex, and date of most recent psychiatric admission because of acute mood episode (± 2 years). Leukocyte subset data were retrieved from complete blood count tests performed on the next morning after the most recent acute psychiatric admission.ResultsDuring the most recent acute psychiatric hospitalization, circulating monocyte counts in the case group were significantly higher than those in the age- and sex-matched controls (p = 0.020). In addition, monocyte–lymphocyte ratios (MLRs) in the case group were significantly higher than those in the control group (p = 0.032). Multiple logistic regression showed that together with serum levels of uric acid and manic symptoms, circulating monocyte counts (95% CI, OR: 1.01–1.05) and MLRs (95% CI, OR: 1.01–1.09) were significantly associated with CVD in patients with BD, respectively.ConclusionsMonocyte activation in an acute manic episode may play a critical role in the pathogenesis of CVD among patients with BD. Future research is required to investigate markers of monocyte activation and indices of cardiovascular structure and function across the different mood states of BD.

Alterations of striatal phosphodiesterase 10 A and their association with recurrence rate in bipolar I disorder

Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [18F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = –0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target.