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Background: Chronic low-grade inflammation is believed to contribute, at least in a subset of patients, to the development of bipolar disorder (BD). In this context, the most investigated biological marker is the acute phase response molecule, C-reactive protein (CRP). While the genetic diversity of CRP was amply studied in various pathological settings, little is known in BD. Methods: 568 BD patients along with 163 healthy controls (HC) were genotyped for the following single-nucleotide polymorphisms (SNPs) on the CRP gene: intron rs1417938 (+ 29) T/A, 3′-UTR rs1130864 (+ 1444) G/A, and downstream rs1205 (+ 1846) (C/T). The statistical analysis was performed using Chi-square testing and consisted of comparisons of allele/genotype frequencies between patients and controls and within patient sub-groups according to BD clinical phenotypes and the presence of thyroid disorders. Results: We found that the frequencies of the studied SNPs were similar in BD and HC groups. However, the CRP rs1130864 A allele carrier state was significantly more frequent: (i) in BD patients with thyroid disorders than in those without ( pc = 0.046), especially among females ( pc = 0.01) and independently of lithium treatment, (ii) in BD patients with rapid cycling than in those without ( pc = 0.004). Conclusions: Overall, our findings suggest the possibility that CRP genetic diversity may contribute to the development of auto-immune comorbid disorders and rapid cycling, both proxy of BD severity. Such findings, if replicated, may allow to predict complex clinical presentations of the disease, a possible step towards precision medicine in psychiatry. [ABSTRACT FROM AUTHOR]

Objectives: To compare the relative influence (RI) of individual predictors for lifetime attempted suicide between adults with bipolar I (BDBD-I) and bipolar II disorder (BDBD-II).Methods: We conducted an analysis of data from 1465 enrollees in the Mayo Clinic Bipolar Disorder Biobank. Demographic and clinical variables and history of attempted suicide were ascertained using standardized questionnaires. Height and weight were assessed to determine body mass index (BMI); obesity was defined as BMI ≥30kg/m2. The frequencies of these variables were compared between persons with and without self-reported lifetime suicide attempts both overall, and within BD-I and BD-II subgroups. Gradient boosting machine (GBM) models were used to quantify the RI of study variables on the risk of lifetime attempted suicide.Results: Nearly one-third of patients reported having a lifetime suicide attempt. Attempted suicide rates were higher in patients with BD-I than BD-II, but absolute differences were small. Lifetime attempted suicide was associated with female sex, BD-I subtype, psychiatric and substance use comorbidities, binge eating behavior, lifetime history of rapid cycling, other indicators of adverse illness course, and early age of bipolar illness onset in the entire cohort. Differences in the rank-ordering of RI for predictors of attempted suicide between BD-I and BD-II patients were modest. Rapid cycling was a strong risk factor for attempted suicide, particularly in men with BD-I.Limitations: Actively psychotic or suicidal patients needing psychiatric hospitalization were initially excluded, but were approached after these acute psychiatric problems resolved.Conclusions: The prevalence of lifetime attempted suicide was significantly higher in BD-I than BD-II in this large, cross-sectional cohort. Predictors of attempted suicide were similar in BD-I and BD-II subgroups. [ABSTRACT FROM AUTHOR]

Background This study aims at testing for paths from childhood abuse to clinical indicators of complexity in bipolar disorder (BD), through dimensions of affective dysregulation, impulsivity and hostility. Method 485 euthymic patients with BD from the FACE-BD cohort were included from 2009 to 2014. We collect clinical indicators of complexity/severity: age and polarity at onset, suicide attempt, rapid cycling and substance misuse. Patients completed questionnaires to assess childhood emotional, sexual and physical abuses, affective lability, affect intensity, impulsivity, motor and attitudinal hostility. Results The path-analysis demonstrated significant associations between emotional abuse and all the affective/impulsive dimensions (p < 0.001). Sexual abuse was moderately associated with emotion-related dimensions but not with impulsivity nor motor hostility. In turn, affect intensity and attitudinal hostility were associated with high risk for lifetime presence of suicide attempts (p < 0.001), whereas impulsivity was associated with a higher risk of lifetime presence of substance misuse (p < 0.001). No major additional paths were identified when including Emotional and Physical Neglect in the model. Conclusions This study provides refinement of the links between early adversity, dimensions of psychopathology and the complexity/severity of BD. Mainly, dimensions of affective dysregulation, impulsivity/hostility partially mediate the links between childhood emotional to suicide attempts and substance misuse in BD. [ABSTRACT FROM AUTHOR]

Objectives We examined differences in treatment outcome between Diagnostic and Statistical Manual Fourth Edition (DSM-IV)-defined rapid cycling and average lifetime-defined rapid cycling in subjects with bipolar II disorder. We hypothesized that, compared with the DSM-IV definition, the average lifetime definition of rapid cycling may better identify subjects with a history of more mood lability and a greater likelihood of hypomanic symptom induction during long-term treatment. Methods Subjects ≥18 years old with a bipolar II major depressive episode (n=129) were categorized into DSM-IV- and average lifetime-defined rapid cycling and prospectively treated with either venlafaxine or lithium monotherapy for 12 weeks. Responders (n=59) received continuation monotherapy for six additional months. Results These exploratory analyses found moderate agreement between the two rapid-cycling definitions (κ=0.56). The lifetime definition captured subjects with more chronic courses of bipolar II depression, whereas the DSM-IV definition captured subjects with more acute symptoms of hypomania. There was no difference between rapid-cycling definitions with respect to the response to acute venlafaxine or lithium monotherapy. However, the lifetime definition was slightly superior to the DSM-IV definition in identifying subjects who went on to experience hypomanic symptoms during continuation therapy. Conclusions Although sample sizes were limited, the findings suggest that the lifetime definition of rapid cycling may identify individuals with a chronic rapid-cycling course and may also be slightly superior to the DSM-IV definition in identifying individuals with hypomania during relapse-prevention therapy. These findings are preliminary in nature and need replication in larger, prospective, bipolar II studies. [ABSTRACT FROM AUTHOR]

Improved upstream titres in therapeutic monoclonal antibody (mAb) production have shifted capacity constraints to the downstream process. The consideration of membrane-based chromatographic devices as a debottlenecking option is gaining increasing attention with the recent introduction of high-capacity bind and elute membranes. We have evaluated the performance and scalability of the Sartobind ® Rapid A affinity membrane (1 mL) for high-productivity mAb capture. For scalability assessment, a 75 mL prototype device was used to process 100 L of clarified cell culture harvest (CH) on a novel multi-use rapid cycling chromatography system (MU-RCC). MabSelect™ PrismA (4.7 mL) was used as a benchmark comparator for Protein A (ProtA) resin studies. Results show that in addition to a productivity gain of >10×, process and product quality attributes were either improved or comparable to the benchmark. Concentrations of eluate pools were 7.5× less than that of the benchmark, with the comparatively higher bulk volume likely to cause handling challenges at process scale. The MU-RCC system is capable of membrane operation at pilot scale with comparable product quality profile to the 1 mL device. The Sartobind ® Rapid A membrane is a scalable alternative to conventional ProtA resin chromatography for the isolation and purification of mAbs from harvested cell culture media., Competing Interests: S.Y., R.B. (Ryszard Braczkowski), S.-H.C., L.F., and I.B.B. are employees of CSL Innovation Pty Ltd. and have NO conflicts of interest to declare. All were involved in the review of the manuscript and in the decision to publish the results. R.B. (Ricarda Busse) and Y.L. declare the following conflicts of interest: both authors are employees of Sartorius Stedim, the manufacturer and supplier of the Sartobind&reg; Rapid A membrane used in this study, and were involved in the review of the manuscript and in the decision to publish the results.

Objective: In patients with bipolar disorder (BD), rapid cycling (RC) presents a risk for a more severe illness, while euthymia (EUT) has a better prognosis. This study focused on the progression of RC and EUT, which are contrasting phenomenology, and aimed to clarify the influence of patient backgrounds and prescription patterns on these different progressions, using a large sample from the first and second iterations of a multicenter treatment survey for BD in psychiatric clinics (MUSUBI)., Methods: In the cross-sectional study (MUSUBI), a questionnaire based on a retrospective medical record survey of consecutive BD cases ( N  = 2,650) was distributed. The first survey was conducted in 2016, and the second one in 2017. The questionnaire collected information on patient backgrounds, current episodes, and clinical and prescribing characteristics., Results: In the first survey, 10.6% of the participants had RC and 3.6% had RC for two consecutive years, which correlated with BP I (Bipolar disorder type I), suicidal ideation, duration of illness, and the use of lithium carbonate and antipsychotic medications. Possible risk factors for switching to RC were comorbid developmental disorders and the prescription of anxiolytics and sleep medication. Moreover, 16.4% of the participants presented EUT in the first survey, and 11.0% presented EUT for two consecutive years. Possible factors for achieving EUT included older age; employment; fewer psychotic symptoms and comorbid personality disorders; fewer antidepressants, antipsychotics, and anxiolytics, and more lithium prescriptions., Conclusion: RC and EUT generally exhibit conflicting characteristics, and the conflicting social backgrounds and factors contributing to their outcomes were distinctive. Understanding these clinical characteristics may be helpful in clinical practice for management of patients with BD., Competing Interests: MK has received grant funding from the Japanese Ministry of Health, Labor and Welfare, the Japan Society for the Promotion of Science, SENSHIN Medical Research Foundation, the Japan Research Foundation for Clinical Pharmacology, and the Japanese Society of Clinical Neuropsychopharmacology and speaker’s honoraria from Sumitomo Dainippon Pharma, Otsuka, Meiji-Seika Pharma, Eli Lilly, MSD K.K., Pfizer, Janssen Pharmaceutical, Shionogi, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical, Lundbeck, and Ono Pharmaceutical, and participated in an advisory/review board for Otsuka, Sumitomo Dainippon Pharma, Shionogi, and Boehringer Ingelheim. YK has received consultant fees from Pfizer and Meiji-Seika Pharma and speaker’s honoraria from Meiji-Seika Pharma, MSD, Eli Lilly, Janssen Pharmaceutical, Dainippon Sumitomo Pharma, Mitsubishi Tanabe Pharma, Yoshitomi Yakuhin, Otsuka Pharmaceutical, Takeda Pharmaceutical, Lundbeck Japan, and Eisai. TA has received speaker’s honoraria from Eli Lilly, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma and Eisai. HU has received manuscript fees or speaker’s honoraria from Eisai Co., Ltd., Janssen Pharmaceutical, Kyowa Pharmaceutical, Meiji Seika Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, Dainippon Sumitomo Pharma, Takeda Pharmaceutical, Lundbeck Japan, and Yoshitomi Yakuhin. KE has received speaker’s honoraria from Eli Lilly, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Kyowa, Yoshitomi Yakuhin, and Takeda Pharmaceutical. EK has received speaker’s honoraria from Daiichi Sankyo, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Pharmaceutical, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, UCB, and Viatris. SH has received manuscript fees or speaker’s honoraria from Eli Lilly, Janssen Pharmaceutical, Kyowa Pharmaceutical, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Shionogi, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, and Yoshitomi Yakuhin. EG has received manuscript fees or speaker’s honoraria from Eli Lilly, Janssen Pharmaceutical, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Takeda Pharmaceutical, Eisai, Ono Pharmaceutical, Kyowa Pharmaceutical Industry, and Sumitomo Dainippon Pharma. RY has received speaker’s honoraria from Eli Lilly, Dainippon Sumitomo, Otsuka, and Esai. AN has received speaker’s honoraria from Pfizer, Eli Lilly, Otsuka, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida, Dainippon Sumitomo, and NTT Docomo, and participated in an advisory board for Takeda, Meiji Seika, Tsumura, and Yoshitomi Yakuhin. TKik has received consultant fees from Takeda Pharmaceutical and the Center for Cognitive Behavioral Therapy and Training. TT has received consultant fees from Pfizer and speaker’s honoraria from Eli Lilly, Meiji-Seika Pharma, MSD, Janssen Pharmaceutical, Dainippon Sumitomo Pharma, Mitsubishi Tanabe Pharma, Yoshitomi Yakuhin, Mochida Pharmaceutical, Otsuka Pharmaceutical, Kyowa Pharmaceutical, and Takeda Pharmaceutical. KW has received manuscript fees or speaker’s honoraria from Daiichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Kyowa Pharmaceutical, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Pfizer, Shionogi, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, and Yoshitomi Yakuhin, has received research/grant support from Daiichi Sankyo, Eisai, MSD, Mitsubishi Tanabe Pharma, Meiji Seika Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, and is a consultant for Boehringer Ingelheim, Daiichi Sankyo, Eisai, Eli Lilly, Kyowa Pharmaceutical, Lundbeck Japan, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, and Viatris. NY-F has received grant/research support or honoraria from, and received speaker’s honoraria of Dainippon-Sumitomo Pharma, Mochida Pharmaceutical, MSD, and Otsuka Pharmaceutical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Takano, Kato, Adachi, Kubota, Azekawa, Ueda, Edagawa, Katsumoto, Goto, Hongo, Miki, Tsuboi, Yasui-Furukori, Nakagawa, Kikuchi, Watanabe, Kinoshita and Yoshimura.)

The pathophysiology of bipolar disorder, especially the underlying mechanisms of the bipolarity between manic and depressive states, has yet to be clarified. Microglia, immune cells in the brain, play important roles in the process of brain inflammation, and recent positron emission tomography studies have indicated microglial overactivation in the brain of patients with bipolar disorder. We have recently developed a technique to induced microglia-like (iMG) cells from peripheral blood (monocytes). We introduce a novel translational approach focusing on bipolar disorder using this iMG technique. We hypothesize that immunological conditional changes in microglia may contribute to the shift between manic and depressive states, and thus we herein analyzed gene profiling patterns of iMG cells from three patients with rapid cycling bipolar disorder during both manic and depressive states, respectively. We revealed that the gene profiling patterns are different between manic and depressive states. The profiling pattern of case 1 showed that M1 microglia is dominant in the manic state compared to the depressive state. However, the patterns of cases 2 and 3 were not consistent with the pattern of case 1. CD206, a mannose receptor known as a typical M2 marker, was significantly downregulated in the manic state among all three patients. This is the first report to indicate the importance of shifting microglial M1/M2 characteristics, especially the CD206 gene expression pattern between depressive and manic states. Further translational studies are needed to dig up the microglial roles in the underlying biological mechanisms of bipolar disorder. [ABSTRACT FROM AUTHOR]

Objective To examine the safety and effectiveness of antidepressant versus mood stabilizer monotherapy in rapid versus non-rapid cycling bipolar II disorder. Method Subjects ≥18 years old with bipolar II depression ( n = 129) were randomized to double-blind venlafaxine or lithium carbonate monotherapy for 12 weeks. Responders ( n = 59) received continuation monotherapy for six additional months. Results Rapid cycling did not affect frequency of response or change over time in depressive symptoms. Rapid cycling status did not affect frequency of depressive relapse or sustained treatment response. Rapid cyclers were more likely to experience hypomanic symptoms ( P = 0.005) during continuation monotherapy; however, rates were similar in venlafaxine (17.6%) and lithium (42.9%) ( P = 0.31). Conclusion Rapid cycling status may not be associated with an increased risk of diminished response or greater depressive relapse during venlafaxine, relative to lithium monotherapy, in bipolar II subjects. Additional randomized studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported that patients with bipolar disorder (BD) present with cognitive impairments during mood episodes as well as euthymic phase. However, it is still unknown whether reported neurocognitive abnormalities can objectively identify individual BD patients from healthy controls (HC).Methods: A total of 21 euthymic BD patients and 21 demographically matched HC were included in the current study. Participants performed the computerized Cambridge Neurocognitive Test Automated Battery (CANTAB) to assess cognitive performance. The least absolute shrinkage selection operator (LASSO) machine learning algorithm was implemented to identify neurocognitive signatures to distinguish individual BD patients from HC.Results: The LASSO machine learning algorithm identified individual BD patients from HC with an accuracy of 71%, area under receiver operating characteristic curve of 0.7143 and significant at p=0.0053. The LASSO algorithm assigned individual subjects with a probability score (0-healthy, 1-patient). Patients with rapid cycling (RC) were assigned increased probability scores as compared to patients without RC. A multivariate pattern of neurocognitive abnormalities comprising of affective Go/No-go and the Cambridge gambling task was relevant in distinguishing individual patients from HC.Limitations: Our study sample was small as we only considered euthymic BD patients and demographically matched HC.Conclusion: Neurocognitive abnormalities can distinguish individual euthymic BD patients from HC with relatively high accuracy. In addition, patients with RC had more cognitive impairments compared to patients without RC. The predictive neurocognitive signature identified in the current study can potentially be used to provide individualized clinical inferences on BD patients. [ABSTRACT FROM AUTHOR]

Objective This study aimed to examine differences in the clinical presentation of very-early-onset ( VEO) and early-onset ( EO) bipolar disorder ( BD) not fully explored previously. Methods We selected two groups of subjects with BD from the Maritime Bipolar Registry based on age at onset of first major mood episode ( VEO with onset prior to age 15 years; EO ranging from 15 to 18 years) and compared them with a reference group (onset after 18 years of age). There were 363 subjects (240 with bipolar I disorder and 123 with bipolar II disorder; mean age 44.2 ± 12.8 (SD) years), with 41 subjects in the VEO and 95 in the EO groups. Results In comparison with the EO and reference groups, more subjects in the VEO group developed major depression as an index episode (88% for the VEO group versus 61% for the EO group and 54% for the reference group), and had an unremitting clinical course (65% versus 42% and 42%, respectively), rapid cycling (54% versus 34% and 28%, respectively), and comorbid attention-deficit hyperactivity disorder (17% versus 1% and 3%, respectively); a higher proportion of the VEO group had first-degree relatives with affective disorders compared with the EO and reference groups (0.41 versus 0.32 and 0.29, respectively), and they had lower scores on the Global Assessment of Functioning scale (mean scores of 64 versus 70 and 70). Overall, the EO group was similar to the reference group on most measures, except for increased suicidal behavior VEO 53%, EO 44% and reference group 25%). The results of polychotomous logistic regression also support the view that VEO BD represents a rather specific subtype of BD. Conclusions Our results suggest the recognized correlates of early-onset BD may be driven by subjects at the lowest end of the age at onset spectrum. [ABSTRACT FROM AUTHOR]

Background Bipolar II disorder (BP II) is a chronic, frequently co-morbid, and complex disorder with similar rates of attempted suicide to BP I. However, case identification for BP II studies that is based on clinician diagnosis alone is prone to error. This paper reports on differences between clinical and research diagnoses and then describes the clinical characteristics of a carefully defined BP II cohort. Methods A cohort of rigorously defined BP II cases were recruited from a range of primary and secondary health services in the North of England to participate in a programme of cross-sectional and prospective studies. Case identification, and rapid cycling, comorbidities and functioning were examined. Results Of 355 probable clinical cases of BP II disorder, 176 (∼50%) met rigorous diagnostic criteria. The sample mean age was ∼44 years, with a mean duration of mood disorder of ∼18 years. Two thirds of the cohort were female ( n =116), but only 40% were in paid employment. Current and past year functioning was more impaired in females and those with rapid cycling. Limitations This paper describes only the preliminary assessments of the cohort, so it was not possible to examine additional factors that may contribute to the explained variance in functioning. Conclusions This carefully ascertained cohort of BP II cases show few gender differences, except for levels of functional impairment. Interestingly, the most common problem identified with using case note diagnoses of BP II arose because of failure to record prior episodes of mania, not failure to identify hypomania. [ABSTRACT FROM AUTHOR]

In the only bipolar cycling in vitro model, rat hippocampal slices are treated with the sodium pump inhibitor ouabain, which induces epileptiform activity, followed by refractory activity loss that recovers and cycles back to epileptiform activity. Thus, clinical cycling seen in patients with bipolar disorder is modeled on a cellular level as alternating hyperactivity and hypoactivity interspersed with normal activity. In this study, we tested the ability of cariprazine a new antipsychotic candidate to block ouabain-induced changes in rat hippocampal slices. Cycling of population spikes and epileptiform bursts was evoked using an extracellular stimulation electrode located in the Schaeffer collaterals of 400-µm-thick rat hippocampal slices treated with ouabain (3.3 μM) alone or in combination with cariprazine (1, 5, 25, and 50 µM). Responses were recorded using an extracellular electrode placed in the cell body layer of the CA1 region. Cariprazine 25 and 50 µM delayed ouabain-induced epileptiform burst onset and subsequent activity loss. Lower cariprazine concentrations were ineffective. Cariprazine delays the onset of ouabain-induced epileptiform bursts and the loss of spiking activity similarly to that previously demonstrated with the mood stabilizer lithium. These results suggest that cariprazine may have therapeutic potential for treatment of bipolar disorder. [ABSTRACT FROM AUTHOR]

Background The use of antidepressants in rapid-cycling bipolar disorder has been controversial. We report the first randomized clinical trial with modern antidepressants on this topic. Methods As part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we analyzed, as an a priori secondary outcome, rapid cycling as a predictor of response in 68 patients randomized to continue vs. discontinue antidepressant treatment, after initial response for an acute major depressive episode. Outcomes assessed were percent time well and total number of episodes. All patients received standard mood stabilizers. Results In those continued on antidepressants (AD), rapid cycling (RC) subjects experienced 268% (3.14/1.17) more total mood episodes/year, and 293% (1.29/0.44) more depressive episodes/year, compared with non-rapid cycling (NRC) subjects (mean difference in depressive episodes per year RC vs. NRC was 0.85±0.37 (SE), df=28, p =0.03). In the AD continuation group, RC patients also had 28.8% less time in remission than NRC patients (95% confidence intervals (9.9%, 46.5%), p =0.004). No such differences between RC and NRC subjects were seen in the AD discontinuation group ( Table 1 ). Analyses within the rapid-cycling subgroup alone were consistent with the above comparisons between RC and NRC subjects, stratified by maintenance antidepressant treatment, though limited by sample size. Conclusions In an a priori analysis, despite preselection for good antidepressant response and concurrent mood stabilizer treatment, antidepressant continuation in rapid-cycling was associated with worsened maintenance outcomes, especially for depressive morbidity, vs. antidepressant discontinuation. [ABSTRACT FROM AUTHOR]

Objectives To examine the independent effects of sex on the risk of rapid cycling and other indicators of adverse illness course in patients with bipolar I disorder ( BP-I) or bipolar II disorder ( BP- II). Methods We analyzed data from the first 1,225 patients enrolled in the Mayo Clinic Individualized Medicine Biobank for Bipolar Disorder. Demographic and clinical variables were ascertained using standardized questionnaires; height and weight were assessed to determine body mass index ( BMI). Rates of rapid cycling, cycle acceleration, and increased severity of mood episodes over time were compared between women and men overall and within subgroups defined by bipolar disorder subtype ( BP-I or BP- II). Multiple logistic regression analysis was used to assess the independent effect of sex on the risk of these indicators of adverse illness course. Results Women had significantly higher rates of rapid cycling than men. Overall rates of rapid cycling were higher in patients with BP- II than BP-I; and sex differences in the rate of rapid cycling were more pronounced in patients with BP- II than BP-I, although the power to detect statistically significant differences was reduced due to the lower sample size of subjects with BP- II. Female sex was a significant predictor of rapid cycling, cycle acceleration, and increased severity of mood episodes over time after adjusting for age, bipolar disorder subtype, BMI, having any comorbid psychiatric disorder, and current antidepressant use. Conclusions Female sex was associated with significantly higher risk of rapid cycling, cycle acceleration, and increased severity of mood episodes over time in a sample of 1,225 patients with bipolar disorders. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to investigate the clinical factors associated with the development of rapid cycling, as well as to elucidate the role of antidepressants. Methods The present study ( NCT01503489) is a prospective, naturalistic cohort study conducted in a sample of 289 patients diagnosed with bipolar disorder followed and treated for up to 14 years. The patients were divided into two groups on the basis of the development of a rapid cycling course (n = 48) or no development of such a course (n = 241), and compared regarding sociodemographic, clinical, and outcome variables. Results Among the 289 patients, 48 (16.6%) developed a rapid cycling course during the follow-up. Several differences were found between the two groups, but after performing Cox regression analysis, only atypical depressive symptoms (p = 0.001), age at onset (p = 0.015), and number of suicide attempts (p = 0.030) persisted as significantly associated with the development of a rapid cycling course. Conclusions The development of rapid cycling during the course of bipolar disorder is associated with a tendency to chronicity, with a poorer outcome, and with atypical depressive symptomatology. Our study also suggests that the development of rapid cycling is associated with a higher use of antidepressants. [ABSTRACT FROM AUTHOR]

Background: Disturbances related to the arachidonic acid cascade and prostaglandin metabolism may be involved in the pathophysiology of bipolar disorder, as supported by a recent genome-wide association study meta-analysis; however, evidence from clinical studies on a transcriptional level is lacking. Two enzymes in the arachidonic acid cascade are the prostaglandin D synthase (PTGDS), which catalyzes the conversion of prostaglandin H2 to prostaglandin D2 (PGD2), and the aldo-keto reductase family 1 member C3 (AKR1C3), which catalyzes the reduction of PGD2. We aimed to test the hypothesis that mRNA expression of PTGDS and AKR1C3 is deregulated in rapid-cycling disorder patients in a euthymic or current affective state compared with healthy control subjects, and that expression alters with affective states. Methods: PTGDS and AKR1C3 mRNA expression in peripheral blood mononuclear cells was measured in 37 rapid-cycling bipolar disorder patients and 40 age- and gender-matched healthy control subjects using reverse transcription quantitative real-time polymerase chain reaction. Repeated measurements of PTGDS and AKR1C3 mRNA expression were obtained in various affective states during 6-12 months and compared with repeated measurements in healthy control subjects. Results: Adjusted for age and gender, PTGDS mRNA expression was down-regulated in rapid-cycling bipolar disorder patients in a euthymic, depressive, and manic/hypomanic state compared with healthy control subjects. No difference in PTGDS mRNA expression was observed between affective states. AKR1C3 mRNA expression did not differ between bipolar disorder patients in any affective state or in comparison with healthy control subjects. Conclusions: The results suggest a role for aberrantly-regulated PTGDS mRNA expression in rapid-cycling bipolar disorder. The sample size was limited; replication of the findings in larger, independent samples is warranted to further explore the role of the arachidonic acid cascade and prostaglandin metabolism as a potential therapeutic target in bipolar disorder. [ABSTRACT FROM AUTHOR]

Background Obesity seems to show a two-way relationship with bipolar disorder (BD), representing not only a possible vulnerability factor but also a consequence of chronic mood dysregulation associated with an overall poor prognosis. Increased impulsivity has been described across all stages and phases of BD as being also associated with a worse prognosis. Although obesity and impulsivity are common features among rapid cycling bipolar disorder (RC-BD) patients, there is a lack of understanding about the clinical implications of these conditions combined in BD. Methods To explore and integrate available evidence on shared clinical associations between obesity and impulsivity in RC-BD a systematic search of the literature in the electronic database of the National Library of Medicine (PubMed) has been conducted. Results One hundred and fourteen articles were included in our systematic review. Among RC-BD patients, substance abuse disorders (SUDs), anxiety disorders (ADs), predominantly depressive polarity, chronic exposure to antidepressants, psychotic symptoms, suicidality, and comorbid medical conditions are strongly associated with both obesity and impulsivity. Limitations Heterogeneity of published data, inconsistent measurements of both obesity and impulsivity in RC-BD and an absence of control for RC-BD in epidemiological surveys. Consequently, their combined impact on the severity of RC-BD is yet to be recognized and remains to be poorly understood. Conclusion In RC-BD patients the co-occurrence of obesity and impulsivity is associated with an unfavorable course of illness, specific shared clinical correlates, negative psychosocial impact, and overall worse prognosis. There is a need to examine obesity and impulsivity as modulating factors and markers of severity in RC-BD. [ABSTRACT FROM AUTHOR]

Abstract: Background: There is some controversy but growing evidence that childhood onset bipolar disorder may be more prevalent and run a more difficult course in the United States than some European countries. Methods: We update and synthesize course of illness data from more than 960 outpatients with bipolar disorder (average age 40) from 4 sites in the U.S. and 3 sites in Netherlands and Germany. After giving informed consent, patients reported on parental history, childhood and lifetime stressors, comorbidities, and illness characteristics. Results: Almost all aspects of bipolar disorder were more adverse in patients from the US compared with Europe, including a significantly higher prevalence of: bipolar disorder in one parent and a mood disorder in both parents; childhood verbal, physical, or sexual abuse; stressors in the year prior to illness onset and the last episode; childhood onsets of bipolar illness; delay to first treatment; anxiety disorder, substance abuse, and medical comorbidity; mood episodes and rapid cycling; and nonresponse to prospective naturalistic treatment. Limitations: Selection bias in the recruit of patients cannot be ruled out, but convergent data in the literature suggest that this does not account for the findings. Potential mechanisms for the early onset and more adverse course in the U.S. have not been adequately delineated and require further investigation. Conclusions: The data suggest the need for earlier and more effective long-term treatment intervention in an attempt to ameliorate this adverse course and its associated heavy burden of psychiatric and medical morbidity. [Copyright &y& Elsevier]

Thyroid hormone (TH) augmentation, although commonly used for major depression, is sparingly used for bipolar disorder (BD) after the failure of mood-stabilizing agents. While the exact mechanisms of thyroid hormone action in BD remains unclear, central thyroid hormone deficit has been postulated as a mechanism for rapid cycling. This systematic review-conducted in accordance with the PRISMA guidelines-of eight studies synthesizes the evidence for TH augmentation in BD. A systematic search of the Ovid MEDLINE, Embase, PsycINFO, and Cochrane databases was conducted for randomized controlled trials (RCT), open-label trials, and observational studies of levothyroxine (LT4) and triiodothyronine (T3) for BD. Open-label studies of high dose LT4 augmentation for bipolar depression and rapid cycling showed improvement in depression outcomes and reduction in recurrence, respectively. However, an RCT of high-dose LT4 did not show benefit in contrast to placebo. An RCT comparing LT4, T3, and placebo showed benefit only in rapid-cycling bipolar women. A meta-analysis could not be completed due to significant differences in study designs, interventions, and outcomes. Our systematic review shows mixed evidence and a lack of high-quality studies. The initial promise of supratherapeutic LT4 augmentation from open-label trials has not been consistently replicated in RCTs. Limited data are available for T3. The studies did not report significant thyrotoxicosis, and TH augmentation were well tolerated. Therefore, TH augmentation, especially with supratherapeutic doses, should be reserved for highly treatment-resistant bipolar depression and rapid-cycling BD.