Bipolar disorder (BD) frequently coexists with anxiety disorders, creating complex challenges in clinical therapy and management. This study investigates the prevalence, prognostic implications, and treatment strategies for comorbid BD and anxiety disorders. High comorbidity rates, particularly with generalized anxiety disorder, underscore the necessity of thorough clinical assessments to guide effective management. Our findings suggest that anxiety disorders may serve as precursors to BD, especially in high-risk populations, making early detection of anxiety symptoms crucial for timely intervention and prevention. We also found that comorbid anxiety can negatively affect the course of BD, increasing clinical severity, reducing treatment responsiveness, and worsening prognosis. These complexities highlight the need for caution in using antidepressants, which may destabilize mood. Alternatively, cognitive-behavioral therapy presents a promising, targeted approach for managing BD with comorbid anxiety. In summary, this study provides essential insights for clinicians and researchers, enhancing understanding of BD and anxiety comorbidity and guiding more precise diagnostics and tailored interventions to improve overall patient care.

This study reports the effects of acupuncture treatment on depression and anxiety symptoms for 3 different bipolar disorder (BD) pathologies.

Case 1: A 35-year-old man was diagnosed with BD type 2. His depressive symptoms appeared 17 years ago. He did not meet the diagnostic criteria for anxiety disorder (AD) in the Mini International Neuropsychiatric Interview (MINI). Case 2: A 32-year-old woman was diagnosed with BD type 2 with AD. Her depressive symptoms appeared 5 years ago. MINI indicated panic-, social anxiety-, and generalized AD. Case 3: A 42-year-old woman was diagnosed with rapid cycling BD. She developed depressive and hypomanic symptoms and visited our hospital 18 years ago. Acupuncture treatment was performed weekly for 12 weeks. Depression and anxiety symptoms were evaluated using the Himorogi Self-Rating Depression Scale (HSDS) and Himorogi Self-Rating Anxiety Scale (HSAS), respectively.

Case 1: The HSAS score did not improve significantly, but the HSDS score decreased from 22 points at baseline to 9 points at the 12th visit. Case 2: The HSDS score did not improve, and the HSAS score remained high from 26 points at baseline to 25 points at the 12th visit. Case 3: During the acupuncture period, both HSDS and HSAS scores fluctuated greatly, and the patient experienced repeated episodes of depression and hypomania.

The response to acupuncture treatment may differ according to the classification and pathology of BD, and it may be desirable to perform the acupuncture treatment after evaluating the pathology and estimating the prognosis.

Bipolar Disorder (BD) is a highly comorbid condition, and rates of cooccurring disorders are even higher in youth. Comorbid disorders strongly affect clinical presentation, natural course, prognosis, and treatment.

This review focuses on the clinical and treatment implications of the comorbidity between BD and Attention-Deficit/Hyperactivity Disorder, disruptive behavior disorders (Oppositional Defiant Disorder and/or Conduct Disorder), alcohol and substance use disorders, Autism Spectrum Disorder, anxiety disorders, Obsessive-Compulsive Disorder, and eating disorders.

These associations define specific conditions which are not simply a sum of different clinical pictures, but occur as distinct and complex combinations with specific developmental pathways over time and selective therapeutic requirements. Pharmacological treatments can improve these clinical pictures by addressing the comorbid conditions, though the same treatments may also worsen BD by inducing manic or depressive switches.

The timely identification of BD comorbidities may have relevant clinical implications in terms of symptomatology, course, treatment and outcome. Specific studies addressing the pharmacological management of BD and comorbidities are still scarce, and information is particularly lacking in children and adolescents; for this reason, the present review also included studies conducted on adult samples. Developmentally-sensitive controlled clinical trials are thus warranted to improve the prognosis of these highly complex patients, requiring timely and finely personalized therapies.

Depression is the leading cause of disease burden among women worldwide. However, an understanding of symptom profiles among women at risk of mood disorders is limited. We determined distinct profiles of affective symptoms among high risk women, along with their distinguishing characteristics.

Women were recruited from 17 clinical sites affiliated with the National Network of Depression Centers. They completed measures of depression (Patient Health Questionnaire - 9) and anxiety (Generalized Anxiety Disorder - 7) as well as questions regarding demographics, reproductive status, behavioral/mental health history, and life stress/adversity. Latent class analysis and multinomial logistic regression were used to identify and characterize symptom profiles.

5792 women participated, ages 18 to 90 (M = 38). Three latent classes were identified: generally asymptomatic (48%), elevated symptoms of comorbid anxiety and depression (16%), and somatic symptoms (36%). Financial security and greater social support were protective factors that distinguished asymptomatic women. The profile of the class with elevated anxiety/depressive symptoms constituted a complex mix of adverse social determinants and potentially heritable clinical features, including a diagnosis of Bipolar Disorder. Women in the 3rd latent class were characterized by menstrual irregularity and a stronger expression of neurovegetative symptoms, especially sleep disturbance and fatigue.

Limitations included less than optimal racial diversity of our sample and reliance on self-report.

Different symptom profiles may reflect distinct subtypes of women at risk of mood disorders. Understanding the etiology and mechanisms underlying clinical and psychosocial features of these profiles can inform more precisely targeted interventions to address women's diverse needs.

Anxiety symptoms are prevalent in bipolar disorder (BD) even during periods of remission and impede treatment efficacy, prognosis and functional capacity. This highlights a pressing clinical need to identify novel effective anxiety treatments. This systematic review aimed to evaluate the evidence within the field.

Following PRISMA guidelines, we conducted a systematic search on PubMed, PsycInfo, EMBASE and Cochrane Library for randomised controlled trials (RCTs) targeting anxiety in remitted BD patients.

We identified 10 RCTs investigating the effects of psychological or pharmacological treatments on anxiety in remitted BD patients. Two studies of transdiagnostic personalised cognitive behavioural therapy (CBT) found a treatment-related reduction in anxiety. This evidence was preliminary given small sample size and use of self-report measures in a single-blind trial design, respectively. The remaining six psychological intervention trials provided more preliminary evidence due to several methodological challenges. The two pharmacological studies found anxiolytic effects of add-on olanzapine or methylene blue to lithium treatment, respectively. Nevertheless, this evidence should be interpreted with caution given high drop-out rates and substantial side-effects that may have impeded blinding.

We did not conduct a quantitative meta-analysis.

There is preliminary evidence for beneficial effects of modified CBT and add-on pharmacotherapy on residual anxiety in BD. Future trials should pre-screen participants for anxiety, define one clinician-rated anxiety measurement as a primary outcome, and employ intention-to-treat analysis to assess treatment effect. This will advance treatment development and enable personalised approaches to address residual anxiety in BD, which has great clinical relevance.

Over the last three decades burgeoning research has shown that anxiety disorder comorbidity is not only highly prevalent in bipolar disorder (BD), but it also adversely impacts the course, outcome, and treatment of BD. The present review provides an overview of the current trends in research on comorbid anxiety and BDs based on prior reviews and meta-analyses (n = 103), epidemiological surveys, and large-scale clinical studies. The results reiterated the fact that at least half of those with BD are likely to develop an anxiety disorder in their lifetimes and a third of them will manifest an anxiety disorder at any point of time. All types of anxiety disorders were equally common in BD. However, there was a wide variation in rates across different sources, with most of this discrepancy being accounted for by methodological differences between reports. Comorbid anxiety disorders negatively impacted the presentation and course of BD. This unfavourable clinical profile led to poorer outcome and functioning and impeded treatment of BD. Despite the extensive body of research there was paucity of data on aetiology and treatment of anxiety disorder comorbidity in BD. Nevertheless, the substantial burden and unique characteristics of this comorbidity has important clinical and research implications.

Most people with bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of bipolar depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant bipolar depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi-therapy-resistant bipolar depression (MTRBD).AimsTo reach consensus regarding threshold definitions criteria for TRBD and MTRBD.

Based on the evidence of standard treatments available in the latest bipolar disorder treatment guidelines, TRBD and MTRBD criteria were agreed by a representative panel of bipolar disorder experts using a modified Delphi method.

TRBD criteria in bipolar depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy.

The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research.Declaration of interestIn the past 3 years, M.B. has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer and Servier. A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. A.J.C. has in the past 3 years received honoraria for speaking from Astra Zeneca and Lundbeck, honoraria for consulting from Allergan, Janssen, Lundbeck and LivaNova and research grant support from Lundbeck. G.M.G. holds shares in P1Vital and has served as consultant, advisor or CME speaker for Allergan, Angelini, Compass pathways, MSD, Lundbeck, Otsuka, Takeda, Medscape, Minervra, P1Vital, Pfizer, Servier, Shire and Sun Pharma. J.G. has received research funding from National Institute for Health Research, Medical Research Council, Stanley Medical Research Institute and Wellcome. H.G. received grants/research support, consulting fees or honoraria from Gedeon Richter, Genericon, Janssen Cilag, Lundbeck, Otsuka, Pfizer and Servier. R.H.M.-W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. R.M. has received research support from Big White Wall, Electromedical Products, Johnson and Johnson, Magstim and P1Vital. S.N. received honoraria from Lundbeck, Jensen and Otsuka. J.C.S. has received funds for research from Alkermes, Pfizer, Allergan, J&J, BMS and been a speaker or consultant for Astellas, Abbott, Sunovion, Sanofi. S.W has, within the past 3 years, attended advisory boards for Sunovion and LivaNova and has undertaken paid lectures for Lundbeck. D.J.S. has received honoraria from Lundbeck. T.S. has reported grants from Pathway Genomics, Stanley Medical Research Institute and Palo Alto Health Sciences; consulting fees from Sunovion Pharamaceuticals Inc.; honoraria from Medscape Education, Global Medical Education and CMEology; and royalties from Jones and Bartlett, UpToDate and Hogrefe Publishing. S.P. has served as a consultant or speaker for Janssen, and Sunovion. P.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. E.V. received grants/ research support, consulting fees or honoraria from Abbott, AB-Biotics, Allergan, Angelini, Dainippon Sumitomo, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka and Sunovion. L.N.Y. has received grants/research support, consulting fees or honoraria from Allergan, Alkermes, Dainippon Sumitomo, Janssen, Lundbeck, Otsuka, Sanofi, Servier, Sunovion, Teva and Valeant. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has also previously received funding for investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth. P.R.A.S. has received research funding support from Corcept Therapeutics Inc. Corcept Therapeutics Inc fully funded attendance at their internal conference in California USA and all related expenses. He has received grant funding from the Medical Research Council UK for a collaborative study with Janssen Research and Development LLC. Janssen Research and Development LLC are providing non-financial contributions to support this study. P.R.A.S. has received a presentation fee from Indivior and an advisory board fee from LivaNova.

Anxiety in bipolar disorder (BD) exacerbates emotion dysregulation and reduces treatment response. We recently conducted a pilot trial of transdiagnostic CBT to target anxiety and emotion dysregulation in BD adjunctive to pharmacotherapy. Reductions in depression and anxiety symptoms were significantly predicted by baseline levels of neuroticism and perceived affective control, as well as changes over time in emotion regulation skills. The present study investigates mechanism of treatment response by examining the relationship between baseline emotion regulation-related neural circuitry and trial outcomes.

Nineteen patients completed baseline resting state fMRI scans prior to treatment randomization. Functional connectivity between the anterior insula (AI) and regions in the salience network (SN), default mode network (DMN), and executive control network (ECN) were examined as predictors of baseline and treatment-related changes in emotion regulation.

Greater improvements in emotion regulation were predicted by weaker right dorsal AI - right ventrolateral prefrontal cortex (VLPFC; SN) and stronger bilateral dorsal AI - bilateral amygdala functional connectivity. Baseline neuroticism was negatively correlated with right dorsal AI- inferior parietal lobule (ECN) functional connectivity, and baseline deficits in perceived affective control were positively associated with ventral AI - bilateral dACC (SN) connectivity.

Small sample limits interpretability of treatment-specific effects.

Baseline functional connectivity of emotion-regulation related neural circuitry significantly predicted change in emotion regulation-related dimensions associated with anxiety and depression symptom reduction. Future studies are needed to determine if employing methods such as neuromodulation to rehabilitate relevant neural circuitry may improve ultimate treatment outcomes of transdiagnostic CBT for BD and anxiety.

Individuals with bipolar spectrum disorder (BSD) frequently meet criteria for comorbid anxiety disorders, and anxiety may be an important factor in the etiology and course of BSDs. The current study examined the association of lifetime anxiety disorders with prospective manic/hypomanic versus major depressive episodes. Participants were 244 young adults (aged 17-26) with milder forms of BSDs (i.e., bipolar-II, cyclothymia, BD-NOS). First, bivariate analyses assessed differences in baseline clinical characteristics between participants with and without DSM-IV anxiety diagnoses. Second, negative binomial regression analyses tested whether lifetime anxiety predicted number of manic/hypomanic or major depressive episodes developed during the study. Third, survival analyses evaluated whether lifetime anxiety predicted time to onset of manic/hypomanic and major depressive episodes. Results indicated that anxiety history was associated with greater illness severity at baseline. Over follow-up, anxiety history predicted fewer manic/hypomanic episodes, but did not predict number of major depressive episodes. Anxiety history also was associated with longer time to onset of manic/hypomanic episodes, but shorter time to onset of depressive episodes. Findings corroborate past studies implicating anxiety disorders as salient influences on the course of BSDs. Moreover, results extend prior research by indicating that anxiety disorders may be linked with reduced manic/hypomanic phases of illness.

Objective: Bipolar disorder is highly comorbid with anxiety disorders, however current and lifetime comorbidity patterns of each anxiety disorder and their associated features are not well studied. Here, we aimed to conduct a meta-analysis and meta-regression study of current evidence. Method: We searched PubMed to access relevant articles published until September 2015, using the keywords "Bipolar disorder" or "Affective Psychosis" or "manic depressive" separately with "generalized anxiety," "panic disorder," "social phobia," "obsessive compulsive," and "anxiety." Variables for associated features and prevalence of anxiety disorders were carefully extracted. Results: Lifetime any anxiety disorder comorbidity in BD was 40.5%; panic disorder (PD) 18.1%, generalized anxiety disorder (GAD) 13.3%, social anxiety disorder (SAD) 13.5% and obsessive compulsive disorder (OCD) 9.7%. Current any anxiety disorder comorbidity in BD is 38.2%; GAD is 15.2%, PD 13.3%, SAD 11.7%, and OCD 9.9%. When studies reporting data about comorbidities in BDI or BDII were analyzed separately, lifetime any anxiety disorder comorbidity in BDI and BDII were 38% and 34%, PD was 15% and 15%, GAD was 14% and 16.6%, SAD was 8% and 13%, OCD was 8% and 10%, respectively. Current any DSM anxiety disorder comorbidity in BDI or BDII were 31% and 37%, PD was 9% and 13%, GAD was 8% and 12%, SAD was 7% and 11%, and OCD was 8% and 7%, respectively. The percentage of manic patients and age of onset of BD tended to have a significant impact on anxiety disorders. Percentage of BD I patients significantly decreased the prevalence of panic disorder and social anxiety disorder. A higher rate of substance use disorder was associated with greater BD-SAD comorbidity. History of psychotic features significantly affected current PD and GAD. Conclusions: Anxiety disorder comorbidity is high in BD with somewhat lower rates in BDI vs BDII. Age of onset, substance use disorders, and percentage of patients in a manic episode or with psychotic features influences anxiety disorder comorbidity.

To assess differential relationships between lifetime anxiety disorder/current anxiety symptoms and longitudinal depressive severity in bipolar disorder (BD).

Stanford BD Clinic outpatients enrolled during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD Clinical Monitoring Form while receiving naturalistic treatment for up to two years. Baseline unfavorable illness characteristics/current mood symptoms and times to depressive recurrence/recovery were compared in patients with versus without lifetime anxiety disorder/current anxiety symptoms.

Among 105 currently recovered patients, lifetime anxiety disorder was significantly associated with 10/27 (37.0%) demographic/other unfavorable illness characteristics/current mood symptoms/current psychotropics, hastened depressive recurrence (driven by earlier onset age), and a significantly (> two-fold) higher Kaplan-Meier estimated depressive recurrence rate, whereas current anxiety symptoms were significantly associated with 10/27 (37.0%) demographic/other unfavorable illness characteristics/current mood symptoms/current psychotropics and hastened depressive recurrence (driven by lifetime anxiety disorder), but only a numerically higher Kaplan-Meier estimated depressive recurrence rate. In contrast, among 153 currently depressed patients, lifetime anxiety disorder/current anxiety symptoms were not significantly associated with time to depressive recovery or depressive recovery rate.

American tertiary BD clinic referral sample, open naturalistic treatment.

Research is needed regarding differential relationships between lifetime anxiety disorder and current anxiety symptoms and hastened/delayed depressive recurrence/recovery - specifically whether lifetime anxiety disorder versus current anxiety symptoms has marginally more robust association with hastened depressive recurrence, and whether both have marginally more robust associations with hastened depressive recurrence versus delayed depressive recovery, and related clinical implications.

Comorbid anxiety in bipolar disorder (BD) is associated with greater illness severity, reduced treatment response, and greater impairment. Treating anxiety in the context of BD is crucial for improving illness course and outcomes. The current study examined the feasibility, acceptability and preliminary efficacy of the Unified Protocol (UP), a transdiagnostic cognitive behavioral therapy, as an adjunctive treatment to pharmacotherapy for BD and comorbid anxiety disorders.

Twenty-nine patients with BD and at least one comorbid anxiety disorder were randomized to pharmacotherapy treatment-as-usual (TAU) or TAU with 18 sessions of the UP (UP+TAU). All patients completed assessments every four weeks to track symptoms, functioning, emotion regulation and temperament. Linear mixed-model regressions were conducted to track symptom changes over time and to examine the relationship between emotion-related variables and treatment response.

Satisfaction ratings were equivalent for both treatment groups. Patients in the UP+TAU group evidenced significantly greater reductions over time in anxiety and depression symptoms (Cohen's d's>0.80). Baseline levels of neuroticism, perceived affective control, and emotion regulation ability predicted magnitude of symptom change for the UP+TAU group only. Greater change in perceived control of emotions and emotion regulation skills predicted greater change in anxiety related symptoms.

This was a pilot feasibility and acceptability trial; results should be interpreted with caution.

Treatment with the UP+TAU was rated high in patient satisfaction, and resulted in significantly greater improvement on indices of anxiety and depression relative to TAU. This suggests that the UP may be a feasible treatment approach for BD with comorbid anxiety.

To evaluate the length of the interval between the onset and the initial management of bipolar disorder (BD).

We conducted a meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Systematic searches located studies reporting estimates of the age of onset (AOO) and indicators of the age at initial management of BD. We calculated a pooled estimate of the interval between AOO and age at management. Factors influencing between-study heterogeneity were investigated using sensitivity analyses, meta-regression, and multiple meta-regression.

Twenty-seven studies, reporting 51 samples and a total of 9415 patients, met the inclusion criteria. The pooled estimate for the interval between the onset of BD and its management was 5.8 years (standardized difference, .53; 95% confidence interval, .45 to .62). There was very high between-sample heterogeneity ( I² = 92.6; Q = 672). A longer interval was found in studies that defined the onset according to the first episode (compared to onset of symptoms or illness) and defined management as age at diagnosis (rather than first treatment or first hospitalization). A longer interval was reported among more recently published studies, among studies that used a systematic method to establish the chronology of illness, among studies with a smaller proportion of bipolar I patients, and among studies with an earlier mean AOO.

There is currently little consistency in the way researchers report the AOO and initial management of BD. However, the large interval between onset and management of BD presents an opportunity for earlier intervention.

There has been limited consideration and empirical studies on treatment-resistant bipolar disorder (TRBD). This exploratory study was designed to identify factors contributing to TRBD in patients with a bipolar (I or II) disorder. Patients were categorized with "low," "medium," or "high" levels of treatment resistance based on a) the total number of psychiatric medications received and, for a second analysis, b) the number of mood stabilizer medications received. The study identified a number of factors associated with TRBD, such as being female and older and having an older age at illness onset, a higher incidences of family depression, less likelihood of being in paid employment, a higher number of lifetime stressors, medical conditions and comorbid anxiety disorders, a different personality and temperament profile, and more regular use of benzodiazepines. There were few factors associated with TRBD when defined by number of mood stabilizers trialed. Potential explanations for these findings were explored.

Previous studies have supported acceptance and commitment therapy (ACT) for reducing impairment related to various chronic conditions. ACT may possibly be beneficial for bipolar disorder (BD) with co-existing anxiety, which is associated with a poorer treatment outcome. Efforts are needed to identify suitable psychological interventions for BD and co-existing anxiety. In this open clinical trial, we included 26 patients with BD type 1 or 2 at an outpatient psychiatric unit specializing in affective disorders. The intervention consisted of a 12-session manualized group treatment that included psychoeducation, mindfulness, engaging in values-based behaviour, cognitive defusion, acceptance and relapse prevention modules. Participants completed four self-report questionnaires covering anxiety symptoms (Beck Anxiety Inventory - BAI), depressive symptoms (Beck Depression Inventory - BDI-II), quality of life (Quality of Life Inventory - QOLI) and psychological flexibility (Acceptance and Action Questionnaire - AAQ-2) before, during and after the treatment. At post-treatment, the participants reported significant improvements in all outcome measures, with large effects (Cohen's d between 0.73 and 1.98). The mean reduction in anxiety symptoms was 45%. At post-treatment, 96% of the patients were classified as responders on at least one of the outcome measures. A limitation is that the trial is uncontrolled. The results suggest that ACT has the potential to be an effective treatment for BD patients with co-existing anxiety. Further randomized studies are warranted.

New treatment approaches are needed for patients with severe and composite mental disorders who are resistant to conventional treatments. Such treatment-resistant patients often have diagnoses of psychotic or bipolar disorders or severe personality disorders and comorbid conditions. In this study, we evaluate basal exposure therapy (BET), a novel ward-integrated psychotherapeutic approach for these patients. Central to BET is the conceptualization of undifferentiated existential fear as basic to the patients' problem, exposure to this fear, and the therapeutic platform complementary external regulation, which integrates and governs the totality of interventions throughout the treatment process. BET is administered at a locked-door ward with 6 patient beds and 13.5 full-time employees, including a psychiatrist and 2 psychologists. Thirty-eight patients who had completed BET were included, all but two being female, mean age 29.9 years. Fourteen patients had a diagnosis of schizophrenia or schizoaffective disorder (F20/25), eight had bipolar disorder or recurrent depressive disorder (F31/33), eight had diagnoses in the F40-48 domain (neurotic, stress-related, and somatoform disorders), five were diagnosed with emotionally unstable personality disorder (F60.3), and three patients had other diagnoses. Twenty of the patients (53%) had more than one ICD-10 diagnosis. Average treatment time in BET was 13 months, ranging from 2 to 72 months. Time-series data show significant improvements in symptoms and functioning from enrollment to discharge, with effect sizes at 0.76 for the Dissociation Experience Scale, 0.93 for the Brief Symptom Inventory, 1.47 for the Avoidance and Action Questionnaire, and 1.42 and 1.56, respectively, for the functioning and symptom subscales of the Global Assessment of Functioning Scale. In addition, the patients used significantly less antiepileptic, antipsychotic, anxiolytic, and antidepressant medications at discharge than at treatment enrollment. Patient improvement across treatment was associated with the following duration of time in BET, the successful completions of the exposure component of BET, positive changes in experiential avoidance as measured with the Acceptance and Action Questionnaire, and high symptom levels and low levels of functioning at treatment start. The findings indicate that BET may be a promising inpatient psychotherapeutic approach for previously treatment-resistant patients with severe and comorbid conditions.

Several studies have evaluated the efficacy and tolerability of aripiprazole for augmentation of antidepressant therapy for treatment-resistant depression (TRD). Here, we investigated the efficacy of aripiprazole augmentation for TRD including both major depressive disorder and bipolar disorder and the clinical predictors of treatment efficacy in a Japanese population.

Eighty-five depressed Japanese patients who underwent aripiprazole augmentation therapy after failing to respond satisfactorily to antidepressant monotherapy were included in the study. Treatment responses were evaluated based on Clinical Global Impression Improvement scores assessed 8 weeks after initiation of aripiprazole administration. We compared demographic and diagnostic variables, psychiatric medication variables, and clinical variables between remission and nonremission groups.

The aripiprazole augmentation remission rate was 36.5%. Multiple logistic regression analysis indicated that aripiprazole augmentation was significantly more effective for bipolar depression than for major depressive disorder, and both absence of comorbid anxiety disorders and current episode duration >3 months were significantly associated with the efficacy of aripiprazole augmentation.

Polarity of depression, comorbidity of anxiety disorders, and current episode duration may predict the efficacy of aripiprazole augmentation for TRD including both major depressive disorder and bipolar disorder. Among them, comorbidity of anxiety disorders was significantly related to the efficacy for TRD including only major depressive disorder. Additional studies are needed to examine the association between the efficacy of aripiprazole augmentation and bipolarity, and these findings should be validated further in a prospective study.

Bipolar affective disorder has a high rate of comorbidity with a multitude of psychiatric disorders and medical conditions. Among all the potential comorbidities, co-existing anxiety disorders stand out due to their high prevalence.

To determine the lifetime prevalence of comorbid anxiety disorders in bipolar affective disorder under the care of psychiatric services through systematic review and meta-analysis.

Random effects meta-analyses were used to calculate the lifetime prevalence of comorbid generalised anxiety disorder, panic disorder, social anxiety disorder, specific phobia, agoraphobia, obsessive compulsive disorder and posttraumatic stress disorder in bipolar affective disorder.

52 studies were included in the meta-analysis. The rate of lifetime comorbidity was as follows: panic disorder 16.8% (95% CI 13.7-20.1), generalised anxiety disorder 14.4% (95% CI 10.8-18.3), social anxiety disorder13.3% (95% CI 10.1-16.9), post-traumatic stress disorder 10.8% (95% CI 7.3-14.9), specific phobia 10.8% (95% CI 8.2-13.7), obsessive compulsive disorder 10.7% (95% CI 8.7-13.0) and agoraphobia 7.8% (95% CI 5.2-11.0). The lifetime prevalence of any anxiety disorders in bipolar disorder was 42.7%.

Our results suggest a high rate of lifetime concurrent anxiety disorders in bipolar disorder. The diagnostic issues at the interface are particularly difficult because of the substantial symptom overlap. The treatment of co-existing conditions has clinically remained challenging.

Numerous studies have documented a significant association between symptom severity and cognitive functioning in bipolar disorder (BD). These findings advanced speculations about a potential link between the physiological stress associated with illness severity and cognitive dysfunction. To explore this hypothesis, the current study employed heart rate variability (HRV) as a physiological measure that is sensitive to the effects of chronic stress, and a scale of trait anxiety for assessing a psychological condition that is correlated with hyper sympathetic arousal. Analyses indicated that BD patients with High Illness Severity reported more symptoms of trait-anxiety (i.e., State Trait Anxiety Inventory), performed more poorly on a computerized neuropsychological battery (i.e., CNS Vital Signs), and exhibited a more constricted HRV profile (i.e., lower SDNN with elevated LF/HF ratio) than patients with Low Illness Severity. Illness severity was determined by a history of psychosis, illness duration, and number of mood episodes. A third group of healthy controls (n=22) performed better on the neuropsychological battery and exhibited a healthier HRV profile than the BD groups. This study provides preliminary evidence that illness severity and cognitive impairment in BD may be associated with state anxiety and neuro-cardiac alterations that are sensitive to physiological stress.

This study investigated the impact of comorbid obsessive-compulsive disorder (OCD) and four anxiety disorders [panic disorder (PD), agoraphobia, social anxiety disorder (SAD), and generalized anxiety disorder (GAD)] on the clinical outcomes of bipolar disorder.

This study analysed data of 174 patients with bipolar I disorder who participated in the prospective observational study. Participants were assessed every 3 months for 24 months. The primary outcome measure was the achievement of symptomatic remission, defined by a total score on the Young Mania Rating Scale (YMRS) of ≤12 and a total score on the 21-item Hamilton Depression Rating Scale (HAMD-21) of ≤8.

Comorbidity was associated with decreased likelihood of remission. However, the impact of individual disorders on outcome differed according to clinical and treatment situations. Most comorbid anxiety disorders and OCD had a negative effect on remission during the first year of evaluation, as measured by the HAMD-21, and in patients taking a conventional mood stabilizer alone. However, the association with poorer outcome was observed only for a few specific comorbid disorders in the second year (GAD and OCD), as measured by YMRS-defined remission (OCD), and in patients with olanzapine therapy (GAD and OCD).

Follow-up evaluation of comorbid disorders was lacking.

Comorbid anxiety disorders and OCD negatively influenced the clinical course of bipolar disorder. Specifically, OCD had a consistently negative impact on the outcome of bipolar I disorder regardless of clinical situation. Effective strategies for the control of these comorbidities are required to achieve better treatment outcomes.

Poor treatment adherence among patients with bipolar disorder (BD) is a common clinical problem. However, whether adherence is mostly determined by patient characteristics or attitudes, type of treatment or treatment side-effects remains poorly known.

The Jorvi Bipolar Study (JoBS) is a naturalistic prospective 18-month study representing psychiatric in- and outpatients with DSM-IV BD I and II in three Finnish cities. During the 18-month follow-up we investigated the continuity of, attitudes towards and adherence to various types of psychopharmacological and psychosocial treatments among 168 psychiatric in- and outpatients with BD I or II.

One-quarter of the patients using mood stabilizers or atypical antipsychotics discontinued medication during at least one treatment phase of the follow-up autonomously, mostly during depression. When pharmacotherapy continued, adherence was compromised in one-third. Rates of non-adherence to mood stabilizers or antipsychotics did not differ, but the predictors did. One-quarter of the patients receiving psychosocial treatments were non-adherent to them.

Serum concentrations were not estimated.

More than one-half of BD patients either discontinue pharmacotherapy or use it irregularly. Autonomous discontinuation takes place mostly in depression. Although rates of non-adherence do not necessarily differ between mood-stabilizing medications, the predictors for nonadherence do. Moreover, adherence to one medication does not guarantee adherence to another, nor does adherence at one time-point ensure later adherence. Attitudes towards treatments affect adherence to medications as well as to psychosocial treatments and should be repeatedly monitored. Non-adherence to psychosocial treatment should be given more attention.

The high comorbidity rate between bipolar disorder (BP) and anxiety disorder (AD) has been studied in depth. This comorbidity is not as high in Han Chinese in Taiwan. Therefore, we explored the genetic effects BP comorbid with AD.

We recruited 1316 participants: 286 with BP-I, 681 with BP-II, and 349 healthy Controls. Genotypes of the BDNF Val66Met and DRD3 Ser9Gly polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis.

The DRD3 Ser9Gly polymorphism was associated with BP-II comorbid with AD (BPII(+AD)), and the BDNF Val66Met polymorphism was associated with BP-I comorbid with AD (BPI(+AD)). An interaction between the Val/Val genotype of the BDNF Val66Met and Gly/Gly polymorphism of the DRD3 Ser9Gly was found in BPII(+AD), but not in BP-II not comorbid with AD (BPI(-AD)) compared with healthy Controls.

The low comorbidity rate of AD in both BP subtypes, especially BP-I, limit generalizing our findings.

The involvement of the dopaminergic pathway in AD was confirmed, particularly with BP-II rather than BP-I. Because the Val/Val genotype of the BDNF Val66Met polymorphism, rather than the other two polymorphisms, has been associated with anxiety, it seems to affect BP-I comorbid with AD without the involvement of the DRD3 Seg9Gly polymorphism, but may modify the involvement of DRD3 Gly/Gly in BP-II comorbid with AD.

Patients with Bipolar Disorder (BD) have high rates of suicide compared to the general population. The present study investigates the predictive power of baseline clinical, psychological and environmental characteristics as risk factors of prospective suicide events (attempts and completions). Data was collected from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. 3083 bipolar patients were included in this report, among these 140 (4.6%) had a suicide event (8 died by suicide and 132 attempted suicide). Evaluation and assessment forms were used to collect clinical, psychological and socio-demographic information. Chi-square and independent t-tests were used to evaluate baseline characteristics. Potential prospective predictors were selected on the basis of prior literature and using a screening analysis of all risk factors that were associated with a history of suicide attempt at baseline and were tested using a Cox regression analysis. The strongest predictor of a suicide event was a history of suicide attempt (hazard ratio = 2.60, p-value < 0.001) in line with prior literature. Additional predictors were: younger age, a high total score on the personality disorder questionnaire and a high percentage of days spent depressed in the year prior to study entry. In conclusion, the present findings may help clinicians to identify patients at high risk for suicidal behavior upon presentation for treatment.

Previous theories about the etiology of cognitive dysfunction in bipolar disorder (BD) emphasized trait factors such as neurological impairment. State factors, other than mood symptoms, that may exacerbate functional deficits have not yet been considered. The purpose of this study was to examine autonomic nervous system (ANS) arousal following cognitive challenge. The study compared patients with BD and healthy controls (HC) in physiological measures and neuropsychological test scores.

Thirty euthymic patients with BD and 22 HC completed the study. Participants completed mood [Beck Depression Inventory-II (BDI-II) and Young Mania Rating Scale (YMRS)], anxiety (State-Trait Anxiety Inventory), and substance abuse (Drug Abuse Screening Test-20 item and Alcohol Use Disorders Identification Test) measures. They were connected to an electrogram, a sensitive thermometer for measuring finger temperature, and electrodes that measure galvanic skin response. After a five-min baseline measurement in a restful state, participants completed a computerized neuropsychological battery (CNS Vital Signs).

The group with BD reported significantly more mood symptoms (BDI-II, t = 3.71, p < 0.001; YMRS, t = 6.73, p < 0.001) and scored higher on a measure of trait-anxiety (State-Trait Anxiety Inventory, t = 2.91, p < 0.001) than HC. A multivariate analysis of variance revealed higher arousal on all physiological measures in the BD group relative to HC at baseline [F(3,48) = 13.1, p < 0.001] and during cognitive testing [F(3,48) = 11.3, p < 0.001]. The increase in physiological arousal from a restful state to the time of testing was higher for the BD group [F(3,37) = 8.06, p < 0.001]. With respect to cognitive data, HC scored higher than patients with BD across the measures of memory (F = 8.5, p < 0.001), sustained (F = 9.5, p < 0.001) and complex (F = 2.7, p < 0.04) attention, processing speed (F = 10.0, p < 0.001), reaction time (F = 7.8, p < 0.001), cognitive flexibility (F = 19.7, p < 0.001), working memory (F = 10.8, p < 0.001), and social acuity (F = 5.7, p < 0.01), with partial eta-squared from 0.18 to 0.62. Correlational analysis revealed significant associations between various cognitive test scores and changes in physiological arousal from baseline to testing (-0.59 ≤ r ≤ 0.22).

Relative to HC, patients with BD experience larger changes in ANS arousal between a restful baseline and cognitive testing, and achieve lower cognitive test scores. Further research is needed to determine whether acute physiological symptoms of anxiety directly compromise cognitive functioning in BD.

Bipolar disorder (BP), especially bipolar II disorder (BP-II), is highly comorbid with anxiety disorder (AD). Monoaminergic dysfunction has been implicated in the pathogenesis of BP, it may be important to investigate genes such as the catechol-O-methyltransferase (COMT), involved in monoamine metabolism and brain-derived neurotrophic factor (BDNF) genes, modulating the monoamine system. We therefore examined the association of the COMT Val158Met and BDNF Val66Met polymorphisms with BP-II with and without comorbidity of AD, and possible interactions between these genes. Seven hundred and seventy-one participants were recruited: 314 with bipolar-II without AD, 117 with bipolar-II with AD, and 340 healthy controls. The genotypes of the COMT and BDNF polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant effect of the COMT and the BDNF polymorphisms, and a significant interaction effect for the Val/Val genotypes of the BDNF Val66Met polymorphism and the COMsT Val158Met Val/Met and Met/Met genotypes (P=0.007, 0.048) discriminated between BP-II without AD patients and controls. Our findings provide initial evidence that the COMT and BDNF genes interact in bipolar-II without AD. Our findings suggest the involvement of dopaminergic pathway in the pathogenesis of bipolar-II.

Perinatal choline supplementation in rats is neuroprotective against insults such as fetal alcohol exposure, seizures, and advanced age. In the present study we explored whether dietary choline supplementation may also confer protection from psychological challenges, like stress, and act as a natural buffer against stress-linked psychological disorders, like depression. We previously found that choline supplementation increased adult hippocampal neurogenesis, a function compromised by stress, lowered in depression, and boosted by antidepressants; and increased levels of growth factors linked to depression, like brain-derived neurotrophic factor. Together, these were compelling reasons to study the role of choline in depressed mood. To do this, we treated rats with a choline supplemented diet (5 mg/kg choline chloride in AIN76A) prenatally on embryonic days 10-22, on postnatal days (PD) 25-50, or as adults from PD75 onward. Outside of these treatment periods rats were fed a standard diet (1.1 mg/kg choline chloride in AIN76A); control rats consumed only this diet throughout the study. Starting on PD100 rats' anxiety-like responses to an open field, learning in a water maze, and reactivity to forced swimming were assessed. Rats given choline supplementation during pre- or post-natal development, but not adult-treated rats, were less anxious in the open field and less immobile in the forced swim test than control rats. These effects were not mediated by a learning deficit as all groups performed comparably and well in the water maze. Thus, we offer compelling support for the hypothesis that supplemental dietary choline, at least when given during development, may inoculate an individual against stress and major psychological disorders, like depression.

Studies report high comorbidity of lifetime anxiety disorders with bipolar disorders in Western patients, but it is unclear in Taiwan. The authors explored the comorbidity of anxiety disorders in different bipolar disorder subtypes in Han Chinese in Taiwan.

Three hundred twenty-five patients with bipolar disorder (bipolar I: 120; bipolar II: 205) disorder were recruited from two general medical outpatient services. They were evaluated and their diagnoses confirmed by a psychiatrist using the Chinese version of the Modified Schedule of Affective Disorder and Schizophrenia-Lifetime. The exclusion criteria were: any DSM-IV-TR Axis I diagnosis, other than bipolar disorder, being outside the 18-65-year-old age range, any other major and minor mental illnesses except anxiety disorder, any neurological disorders or organic mental disorders.

Thirty-two (26.7%) of patients were comorbid with lifetime anxiety disorder and bipolar I, 80 (39.0%) with lifetime anxiety disorder and bipolar II, 7 (5.8%) were comorbid with two or more anxiety disorders and bipolar I, and 27 (13.2%) with two or more anxiety disorders and bipolar II.

That more than twice as many bipolar II than bipolar I patients reported two or more anxiety disorders implies that the complication is more prevalent in bipolar II patients.

Comorbid anxiety disorders are highly prevalent in bipolar disorder and have been shown to have serious negative impacts on the course of illness. The pharmacological treatment of anxiety can interact with the bipolar disorder and has not been proven effective. As such, many have recommended the psychological treatment of anxiety. This paper reviews the literature on psychological treatments for anxiety comorbid to bipolar disorder.

The Medline, PsychInfo and Web of Science databases were thoroughly examined for relevant treatment studies.

Despite frequent recommendations in the literature, surprisingly few have studied the psychological treatment of comorbid anxiety in bipolar disorders. Nevertheless, preliminary results suggest that comorbid anxiety disorders can be effectively treated in a bipolar clientele using cognitive-behavioral therapy, mindfulness-based cognitive-behavioral therapy or relaxation training. In contrast, interpersonal, family therapy and psychoeducation alone would not seem to be beneficial treatment alternatives for anxiety. Cognitive-behavioral therapy appears to reduce the symptoms of obsessive-compulsive disorder, generalized anxiety disorder, panic disorder, post-traumatic stress disorder and general symptoms of anxiety among patients with bipolar disorder. However, the long-term maintenance of anxiety treatment effects may be somewhat reduced and adaptations may be called for to augment and sustain benefits.

There is an urgent need for randomized controlled trials of different forms of psychotherapy for anxiety disorders comorbid to bipolar disorder. Until such trials are available, the most promising approach would appear to be the sequential or modular CBT-based treatment of the anxiety disorder.

The current report describes individuals with bipolar disorder who attempted or completed suicide while participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.

Baseline and course features of individuals with suicide events are described.

Among the 4360 people with bipolar disorder enrolled, 182 individuals made 270 prospectively observed suicidal acts, including 8 completed suicides. This represents a suicide rate of .014 per 100 person years in STEP-BD, which included frequent clinical visits, evidence based care, and standardized assessment at each patient contact. Approximately 1/3 of those who attempted suicide had more than one attempt during study participation. Those who completed suicide tended to do so early in study participation, and half of them did so on their first attempt.

While this study is limited to description of individuals and precipitants of completed suicides and attempts in STEP-BD, further analyses are planned to explore risk factors and potential interventions for prevention of suicidal acts in persons with bipolar disorder.

Persons with bipolar disorder are at high risk for suicide. Overall rates of suicide events in STEP-BD were lower than expected, suggesting that the combination of frequent clinical visits (i.e., access to care), standardized assessment, and evidence-based treatment were helpful in this population.

Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder. We aimed to examine the prevalence and correlates of comorbid anxiety disorders among youth with bipolar disorder.

As part of the Course and Outcome of Bipolar Youth study, 446 youth, ages 7 to 17 years, who met DSM-IV criteria for bipolar I disorder (n = 260) or bipolar II disorder (n = 32) or met operationalized criteria for bipolar disorder not otherwise specified (n = 154) were included. Subjects were evaluated for current and lifetime Axis I psychiatric disorders at intake using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime version, and standardized instruments were used to assess functioning and family history.

Forty-four percent (n = 194) of the sample met DSM-IV criteria for at least 1 lifetime anxiety disorder, most commonly separation anxiety (24%) and generalized anxiety disorders (16%). Nearly 20% met criteria for 2 or more anxiety disorders. Overall, anxiety disorders predated the onset of bipolar disorder. Subjects with bipolar II disorder were more likely than subjects with bipolar I disorder or bipolar disorder not otherwise specified to have a comorbid anxiety disorder. After adjusting for confounding factors, youth with bipolar disorder with anxiety were more likely to have bipolar II disorder; longer duration of mood symptoms; more severe ratings of depression; and family history of depression, hopelessness, and somatic complaints during their worst lifetime depressive episode than those without anxiety.

Comorbid anxiety disorders are common in youth with bipolar disorder, and they most often predate bipolar disorder onset. Bipolar II disorder, a family history of depression, and more severe lifetime depressive episodes distinguish youth with bipolar disorder with comorbid anxiety disorders from those without. Careful consideration should be given to the assessment of comorbid anxiety in youth with bipolar disorder.

Clinical implications of the high rates of creativity within bipolar disorder (BD) have not been explored. The aim of this review is to outline these implications by (i) reviewing evidence for the link between creativity and BD, (ii) developing a provisional model of mechanisms underpinning the creativity-BD link, (iii) describing unique challenges faced by creative-BD populations, and (iv) systematically considering evidence-based psychosocial treatments in the light of this review. While more research into the creativity-BD nexus is urgently required, treatment outcomes will benefit from consideration of this commonly occurring phenotype.

Impulsivity, a breakdown in the balance between initiation and screening of action that leads to reactions to stimuli without adequate reflection or regard for consequences, is a core feature of bipolar disorder and is prominent in manic episodes. Catecholaminergic function is related to impulsivity and mania. Manic individuals have abnormal dopaminergic reactions to reward and abnormal responses in the ventral prefrontal cortex that are consistent with impulsive behavior. Impulsivity in mania is pervasive, encompassing deficits in attention and behavioral inhibition. Impulsivity is increased with severe course of illness (eg, frequent episodes, substance use disorders, and suicide attempts). In mixed states, mania-associated impulsivity combines with depressive symptoms to increase the risk of suicide. Clinical management of impulsivity in mania involves addressing interpersonal distortions inherent in mania; reducing overstimulation; alertness to medical-, trauma-, or substance-related problems; and prompt pharmacologic treatment. Manic episodes must be viewed in the context of the life course of bipolar disorder.

Prevalence and clinical correlates of dissociative symptoms in general, and depersonalization (DP) in particular, in patients with mood disorders have received limited attention in the literature. Nevertheless, the identification of these symptoms may have important implications in terms of a better definition of clinical endophenotypes. Thus, this study aimed at investigating frequency and clinical correlates of dissociative symptoms, with special attention to DP symptoms, in patients with bipolar disorder (BD) looking specifically at differences between BD-I and BD-II and the comorbidity with panic disorder.

The study sample included 91 adult patients with BD (BD-I=43; BD-II=48) assessed with the Semi-structured Clinical Interview for Temperament (TEMPS-I), the Dissociative Experiences Scale (DES) and the Structured Clinical Interview for Depersonalization-Derealization Spectrum (SCI-DER).

There was no difference in lifetime dissociative experiences or DP symptoms between BD-I and BD-II patients. There was no difference in relation to temperament characteristics. Lifetime DP symptoms, as assessed with the SCI-DER, were associated to an early onset of the BD (beta=-0.436, t=-4.572, p<0.001). Derealization symptoms correlated with panic disorder comorbidity (OR=1.22; 95%CI=1.03-1.46, Wald=5.177, p=0.023).

Our study suggests that lifetime DP symptoms are correlated with an early onset of the BD and derealization symptoms with panic disorder comorbidity, bearing the opportunity to identify patients with a specific profile for a better clinical and neurobiological definition.