A New Treatment Program: Focused Integrated Team-based Treatment Program for Bipolar Disorder (FITT-BD).

OBJECTIVE: Bipolar disorder (BD) is complicated by a dynamic, chronic course along with multiple comorbid psychiatric and medical conditions, making it challenging for clinicians to treat and patients to thrive. To efficiently manage the complexity of BD and help patients recover, we developed a Focused Integrated Team-based Treatment Program for Bipolar Disorder (FITT-BD). The purpose of this paper is to describe how we developed this clinic and the lessons we learned. METHODS: We developed FITT-BD by integrating strategies from stepped care, collaborative care, and learning health care systems. We describe the rationale, details, and lessons learned in developing FITT-BD. RESULTS: By integrating stepped care, collaborative care, and a learning health care system approach, FITT-BD aims to reduce barriers to care, leverage the expertise of a multidisciplinary treatment team, ensure patient-centeredness, and use assessments to inform and continuously improve outcomes in real time. We learned that there are challenges in the creation of a web-based application that tracks the treatment of patients within a network of hospitals. CONCLUSIONS: The success of FITT-BD will be determined by the degree to which it can increase treatment access, improve treatment adherence, and help individuals with BD achieve their treatment goals. We expect that FITT-BD will improve outcomes in the context of ongoing clinical care. PUBLIC HEALTH SIGNIFICANCE: The treatment of BD is challenging and complex. We propose a new treatment model for BD: FITT-BD. We expect that this program will be a patient-centered approach that improves outcomes in the context of ongoing clinical care for patients with BD.

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Decreased Psychological Well-Being in Patients With Bipolar Disorder in Remission.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Outpatients with bipolar disorder in remission demonstrated substantially impaired psychological well-being, despite low levels of depressive symptoms, compared with a normative community sample.

Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY: NCT0127253.

A Blockchain-Based Spatial Crowdsourcing System for Spatial Information Collection Using a Reward Distribution.

Due to the increasing relevance of spatial information in different aspects of location-based services, various methods are used to collect this information. The use of crowdsourcing due to plurality and distribution is a remarkable strategy for collecting information, especially spatial information. Crowdsourcing can have a substantial effect on increasing the accuracy of data. However, many centralized crowdsourcing systems lack security and transparency due to a trusted party's existence. With the emergence of blockchain technology, there has been an increase in security, transparency, and traceability in spatial crowdsourcing systems. In this paper, we propose a blockchain-based spatial crowdsourcing system in which workers confirm or reject the accuracy of tasks. Tasks are reports submitted by requesters to the system; a report comprises type and location. To our best knowledge, the proposed system is the first system that all participants receive rewards. This system considers spatial and non-spatial reward factors to encourage users' participation in collecting accurate spatial information. Privacy preservation and security of spatial information are considered in the system. We also evaluated the system efficiency. According to the experiment results, using the proposed system, information accuracy increased by 40%, and the minimum time for reviewing reports by facilities reduced by 30%. Moreover, we compared the proposed system with the current centralized and distributed crowdsourcing systems. This comparison shows that, although our proposed system omits the user's history to preserve privacy, it considers a consensus-based approach to guarantee submitted reports' accuracy. The proposed system also has a reward mechanism to encourage more participation.

Illness stage and predominant polarity in bipolar disorder: Correlation with burden of illness and moderation of treatment outcome.

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.

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study.

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

The association between lithium use and neurocognitive performance in patients with bipolar disorder.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1-5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p < 0.001], CVLT trials 1-5 [F = 29.81; p < 0.001], CVLT delayed recall [F = 15.27; p < 0.001], and TMT-B [F = 6.64, p = 0.012] was detected. The cross-sectional and longitudinal (on a subset of 88 patients) investigations suggest that lithium may be beneficial to neurocognitive functioning in patients with BD and that at the very least it does not seem to significantly impair cognition when used therapeutically.

The impact of binge eating behavior on lithium- and quetiapine-associated changes in body weight, body mass index, and waist circumference during 6 months of treatment: Findings from the bipolar CHOICE study.

BACKGROUND: Lithium and quetiapine can cause weight gain, but their comparative longer term anthropometric effects are unknown, as are the potential moderating effects of baseline binge-eating (BE) behavior. METHODS: We assessed 6 month changes in body weight, body mass index (BMI) and waist circumference in 482 adults with DSM-IV bipolar disorders who participated in a comparative effectiveness study of lithium and quetiapine with evidence-based adjunctive treatment (Bipolar CHOICE). Anthropometric measurements were obtained at baseline, and at 2, 4, 6, 8, 12, 16, 20, and 24 weeks. BE behavior was defined as affirmative responses to MINI items M1 and M3 at baseline. Data were analyzed using a mixed model repeated measures approach, adjusted for baseline values of dependent measures. RESULTS: On average, body weight and BMI increased over 6 months with lithium and quetiapine. However, those treated with quetiapine experienced greater increases from baseline in body weight (peak change, + 3.6 lbs. vs. + 1.4 lbs.) and BMI (peak change, + 0.6 kg/m2 vs. + 0.3 kg/m2), starting at 2 weeks (group x time, F8,3052 = 2.9, p = 0.003 for body weight, F8,3052 = 3.0, p = 0.002 for BMI). Significant increases in waist circumference were observed only with quetiapine. The relationship between drug treatment and changes in body weight (group x time x binge eating status, F1,2770 = 2.0, p = 0.002), BMI (F1,2767 = 2.0, p = 0.002), and waist circumference (women only, F25,1621 = 2.9, p < 0.0001) were moderated by BE behavior. The largest increases over 24 weeks in body weight and BMI, and waist circumference in women, occurred for quetiapine-treated patients with baseline binge-eating, relative to quetiapine-treated patients without binge eating and lithium-treated patients with or without baseline binge-eating. LIMITATIONS: Bipolar CHOICE was not designed to study anthropometric outcomes. CONCLUSIONS: Greater changes in body weight, BMI, and waist circumference occurred with quetiapine- versus lithium-based treatment over 6 months of treatment. The effects of study drugs on these anthropometric measures were moderated by BE behavior at baseline.

Developing Dimensional, Pandiagnostic Inhibitory Control Constructs With Self-Report and Neuropsychological Data.

Trait markers, or intermediate phenotypes linking different units of analysis (self-report, performance) from the Research Domain Criteria (RDoC) matrix across populations is a necessary step in identifying at-risk individuals. In the current study, 150 healthy controls (HC) and 456 individuals with bipolar disorder (BD) Type I or II, NOS (not otherwise specified) or Schizoaffective BD completed self-report neuropsychological tests of inhibitory control (IC) and executive functioning. Bifactor analyses were used to examine the factor structure of these measures and to evaluate for invariance across groups. Bifactor analyses found modest convergence of items from neuropsychological tests and self-report measures of IC among HC and BD. The factor scores showed evidence of a general IC construct (i.e., subdomain) across measures. Importantly, invariance testing indicated that the same construct was measured equally well across groups. Groups differed on the general factor for three of the four scales. Convergence on a general IC factor and invariance across diagnosis supports the use of combined dimensional measures to identify clinical risk and highlights how prospective RDoC studies might integrate units of analysis.

Bipolar depression and suicidal ideation: Moderators and mediators of a complex relationship.

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

Complex polypharmacy in bipolar disorder: Side effect burden, adherence, and response predictors.

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

Divalproex and its effect on suicide risk in bipolar disorder: A systematic review and meta-analysis of multinational observational studies.

BACKGROUND: Divalproex has become the most prevalent mood stabilizer for bipolar disorder. However, little is known its effects in the prevention of suicide in patients with bipolar disorder, and recent FDA announcement indicated an increased risk of suicidality when using anti-epileptic agents such as divalproex. The aim of this study is to investigate the effect of divalproex on suicide risk in patients with bipolar disorder. METHODS: A search strategy was used for the PubMed, Embase, ProQuest, ScienceDirect, Cochrane Library, ClinicalKey, Web of Science, and ClinicalTrials.gov until June 13th, 2018. Peer-reviewed observationally clinical studies in humans, investigating the association of divalproex and suicidality in patients with bipolar disorder were included. A random-effects meta-analysis was implemented to calculate the relative risk (RR) and 95% confidence intervals (CIs) for suicidality among patients receiving divalproex and those without. RESULTS: Total 6 studies were included in the final meta-analysis. There was no significant difference in the incidence rates (reported as [RR]; 95% CI) of suicide attempts (0.921; 0.383-2.215) or completed suicides (0.607; 0.180-2.043) between participants receiving divalproex vs. no medication. There was no significant difference in the incidence rates of suicide attempts (0.815; 0.453-1.466) or completed suicides (1.009; 0.410-2.484) between participants receiving divalproex and carbamazepine. LIMITATIONS: The significantly heterogeneous sample sources and study design amount the included trials. CONCLUSIONS: Treatment with divalproex did not reduce or increase the incidence of suicide-related events in patients with bipolar disorder.

Salivary melatonin onset in youth at familial risk for bipolar disorder.

Melatonin secretion and polysomnography (PSG) were compared among a group of healthy adolescents who were at high familial risk for bipolar disorder (HR) and a second group at low familial risk (LR). Adolescent participants (n = 12) were a mean age 14 ± 2.3 years and included 8 females and 4 males. Saliva samples were collected under standardized condition light (red light) and following a 200 lux light exposure over two consecutive nights in a sleep laboratory. Red Light Melatonin onset (RLMO) was defined as saliva melatonin level exceeding the mean of the first 3 readings plus 2 standard deviations. Polysomnography was also completed during each night. HR youth, relative to LR, experienced a significantly earlier melatonin onset following 200 lux light exposure. Polysomnography revealed that LR youth, relative to HR, spent significantly more time in combined stages 3 and 4 (deep sleep) following red light exposure. Additionally, regardless of the group status (HR or LR), there was no significant difference in Red Light Melatonin Onset recorded at home or in the laboratory, implying its feasibility and reliability.

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Mood, Dimensional Personality, and Suicidality in a Longitudinal Sample of Patients with Bipolar Disorder and Controls.

OBJECTIVE: To evaluate the effects of mood and anxiety symptoms in relation to personality dimensions and clinical features such as trauma and substance use on suicidal behaviors in a longitudinal sample of individuals with bipolar illness (BP) and healthy controls (HC). METHODS: Mood, personality, and clinical features were assessed in 151 individuals with BP I and 119 HC. Clinical data were collected at baseline and at 2-year follow-up. Personality traits were measured using the NEO PI-R. RESULTS: In bivariate analyses, personality measures were significantly different between BP and HC, and between BP based on suicide attempt history. However, in regression analyses, baseline measures of depression, mania, anxiety, trauma, education, and age of BP onset correlated with personality domains, while a history of suicide attempts did not. Logistic regressions showed that prospective depression or mania, and a pattern of mixed mood features and chronicity of illness, along with two Neuroticism facet scores (N4-Self-Consciousness and N6-Vulnerability) were predictive of suicide ideation (SI) in the 2-year follow-up period. CONCLUSIONS: While dimensions of personality, trauma, and substance use clearly correlated with suicidal behaviors in BP, in multivariate models emerging mood symptoms were the most robust predictors of suicidality. These results reinforce the importance and attributable role of mood and anxiety symptoms in evaluating suicidal risk.

Patterns of changes in bipolar depressive symptoms revealed by trajectory analysis among 482 patients with bipolar disorder.

INTRODUCTION: Depressive episodes are often prevalent among patients with bipolar disorder, but little is known regarding the differential patterns of development over time. We aimed to determine and characterize trajectories of depressive symptoms among adults with bipolar disorder during 6 months of systematic treatment. METHODS: The pragmatic clinical trial, Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (CHOICE), randomized 482 outpatients with bipolar disorder to lithium or quetiapine. Depressive symptoms were rated at up to 9 visits using the Montgomery-Asberg Depression Rating Scale (MADRS). Growth mixture modeling was utilized to identify trajectories and multinomial regression analysis estimated associations with potential predictors. RESULTS: Four distinct trajectories of depressive symptoms were identified. The responding class (60.3%) with a rapid reduction and subsequent low level; the partial-responding class (18.4%) with an initial reduction followed by an increase during the remaining weeks; the fluctuating class (11.6%) with a fluctuation in depressive symptoms; and the non-responding class (9.7%) with sustained moderate-severe depressive symptoms. Bipolar type I predicted membership of the non-responding class and randomization to quetiapine predicted membership of either the responding or the non-responding class. CONCLUSION: Approximately 30% experienced a partial or fluctuating course, and almost 10% had a chronic course with moderate-severe depression during 6 months. Patients diagnosed with bipolar type 1 had higher risk of being categorized into a class with a worse outcome. While no differences in average overall outcomes occurred between the lithium and quetiapine groups, trajectory analysis revealed that the lithium group had more variable courses.

Comorbid anxiety in bipolar CHOICE: Insights from the bipolar inventory of symptoms scale.

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

A Preliminary Study of Central Nervous System Arousal and Sleep Quality in Bipolar Disorder.

Sleep disturbances are commonly reported in patients with bipolar I disorder (BPI) and are risk factors for mood episodes. In other populations, central nervous system (CNS) hyperarousal is associated with sleep initiation and maintenance problems, and CNS hypoarousal is associated with increased sleep drive. However, it is unclear whether CNS arousal levels are a useful index of sleep disruption in BPI. This study aimed to investigate daytime CNS arousal levels in relation to perceived sleep quality in BPI. Resting EEG, mood state, and self-reported sleep quality data were collected from 34 individuals with BPI. CNS hyperarousal was associated with pervasive poor subjective sleep quality including increased sleep disturbances, increased sleep latency, and reduced global sleep quality. CNS hypoarousal was associated with greater daytime sleepiness, indicating reduced arousal. These preliminary findings suggest that CNS arousal may be a useful index for identifying individuals at high risk for relapse into a mood episode. A limitation of this study is the use of self-report instruments for sleep quality assessment. Future research should investigate the temporal relationship of CNS arousal to sleep disturbances using objective measurements of sleep quality such as polysomnography. If these findings are replicated, measures of CNS arousals may allow for identification of high-risk patients with BPI.

Risk Factors Associated With Antidepressant Exposure and History of Antidepressant-Induced Mania in Bipolar Disorder.

OBJECTIVE: Despite their widespread use in bipolar disorder, there is controversy surrounding the inclusion of antidepressant medications in the disorder's management. We sought to identify which demographic, socioeconomic, and clinical factors are associated with antidepressant exposure in bipolar disorder and which bipolar disorder patients are most likely to report a history of antidepressant-induced mania (AIM) when exposed to antidepressants. METHODS: Our study included subjects with bipolar I disorder (n = 309), bipolar II disorder (n = 66), and bipolar disorder not otherwise specified (n = 27) and schizoaffective disorder, bipolar type (n = 14), from a longitudinal, community-based study. Subjects were evaluated using the Diagnostic Interview for Genetic Studies, modified for DSM-IV criteria. We applied multivariate logistical regression modeling to investigate which factors contribute to antidepressant exposure in bipolar disorder patients. We also used a logistic regression modeling approach to determine which clinical factors in bipolar disorder patients are associated with a history of AIM. Data were gathered from February 2006 through December 2010. RESULTS: Our results suggest that the risk factors most strongly associated with antidepressant exposure are female sex (OR = 2.73, P = .005), older age (OR = 1.03, P = .04), greater chronicity of illness (OR = 2.29, P = .04), and, to a lesser extent, white race (OR = 0.44, P = .051). Factors associated with reduced antidepressant exposure include history of affective psychosis (OR = 0.36, P = .01) and a greater number of previous manic episodes (OR = 0.98, P = .03). In subjects who reported a history of AIM, regression analysis revealed that the only statistically significant factor associated with AIM history was female sex (OR = 3.74, P = .02). CONCLUSIONS: These data suggest that there are certain identifiable factors associated with antidepressant exposure in bipolar disorder patients, and some of these, specifically female sex, are also associated with a history of AIM. These data may be useful in designing prospective trials to identify interventions that can reduce the risk of this adverse outcome.