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Objectives: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients., Methods: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models., Results: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment., Conclusions: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype., (© 2018 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.)

Objective: Research on neurocognitive impairment in adult patients with comorbid bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD) is very scarce. This study assessed the neurocognitive profile of a comorbid group (BD+ADHD) compared with that of pure BD (pBD) group, pure ADHD (pADHD) group and healthy controls (HCs)., Methods: This was a three-site study comprising 229 subjects: 70 patients with pBD, 23 with BD+ADHD, 50 with pADHD, and 86 HCs. All patients with BD had been euthymic for at least 6 months. Neuropsychological performance was assessed using a comprehensive neurocognitive battery., Results: Our results showed that all the clinical groups had poorer performance than the HCs in all the neurocognitive domains except for executive functions. No significant differences were observed between the pBD and BD+ADHD groups in any of the cognitive domains, with these two groups showing greater impairment than the pADHD group in executive functions and visual memory., Conclusions: Our results, although preliminary, suggest that the BD+ADHD group showed the same neurocognitive profile as pBD patients, most likely reflecting the same neurobiological basis. On the other hand, the pADHD group showed a more selective moderate impairment in attention., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Although it is well established that euthymic patients with bipolar disorder can have cognitive impairment, substantial heterogeneity exists and little is known about the extent and severity of impairment within the bipolar II disorder subtype. Therefore, the main aim of this study was to analyze cognitive variability in a sample of patients with bipolar II disorder., Methods: The neuropsychological performance of 116 subjects, including 64 euthymic patients with bipolar II disorder and 52 healthy control subjects, was examined and compared by means of a comprehensive neurocognitive battery. Neurocognitive data were analyzed using a cluster analysis to examine whether there were specific groups based on neurocognitive patterns. Subsequently, subjects from each cluster were compared on demographic, clinical, and functional variables., Results: A three-cluster solution was identified with an intact neurocognitive group (n = 29, 48.3%), an intermediate or selectively impaired group (n = 24, 40.0%), and a globally impaired group (n = 7, 11.6%). Among the three clusters, statistically significant differences were observed in premorbid intelligence quotient (p = 0.002), global functional outcome (p = 0.021), and leisure activities (p = 0.001), with patients in the globally impaired cluster showing the lowest attainments. No differences in other clinical characteristics were found among the groups., Conclusions: These results confirm that neurocognitive variability is also present among patients with bipolar II disorder. Approximately one-half of the patients with bipolar II disorder were cognitively impaired, and among them 12% were severely and globally impaired. The identification of different cognitive profiles may help to develop cognitive remediation programs specifically tailored for each cognitive profile., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The aim of this study was to elucidate the factors associated with the occurrence of mixed episodes, characterized by the presence of concomitant symptoms of both affective poles, during the course of illness in bipolar I disorder patients treated with an antidepressant, as well as the role of antidepressants in the course and outcome of the disorder., Method: We enrolled a sample of 144 patients followed for up to 20 years in the referral Barcelona Bipolar Disorder Program and compared subjects who had experienced at least one mixed episode during the follow-up (n=60) with subjects who had never experienced a mixed episode (n=84) regarding clinical variables., Results: Nearly 40% of bipolar I disorder patients treated with antidepressants experienced at least one mixed episode during the course of their illness; no gender differences were found between two groups. Several differences regarding clinical variables were found between the two groups, but after performing logistic regression analysis, only suicide attempts (p<0.001), the use of serotonin norepinephrine reuptake inhibitors (p=0.041), switch rates (p=0.010), and years spent ill (p=0.022) were significantly associated with the occurrence of at least one mixed episode during follow-up., Conclusions: The occurrence of mixed episodes is associated with a tendency to chronicity, with a poorer outcome, a higher number of depressive episodes, and greater use of antidepressants, especially serotonin norepinephrine reuptake inhibitors., (© 2011 John Wiley and Sons A/S.)

Objectives: Via an international panel of experts, this paper attempts to document, review, interpret, and propose operational definitions used to describe the course of bipolar disorders for worldwide use, and to disseminate consensus opinion, supported by the existing literature, in order to better predict course and treatment outcomes., Methods: Under the auspices of the International Society for Bipolar Disorders, a task force was convened to examine, report, discuss, and integrate findings from the scientific literature related to observational and clinical trial studies in order to reach consensus and propose terminology describing course and outcome in bipolar disorders., Results: Consensus opinion was reached regarding the definition of nine terms (response, remission, recovery, relapse, recurrence, subsyndromal states, predominant polarity, switch, and functional outcome) commonly used to describe course and outcomes in bipolar disorders. Further studies are needed to validate the proposed definitions., Conclusion: Determination and dissemination of a consensus nomenclature serve as the first step toward producing a validated and standardized system to define course and outcome in bipolar disorders in order to identify predictors of outcome and effects of treatment. The task force acknowledges that there is limited validity to the proposed terms, as for the most part they represent a consensus opinion. These definitions need to be validated in existing databases and in future studies, and the primary goals of the task force are to stimulate research on the validity of proposed concepts and further standardize the technical nomenclature.

Objective: Although there are some randomized controlled trials that highlight the positive role of family-focused treatment added to pharmacotherapy in bipolar disorder, no trials using contemporary methodologies have analyzed the specific effect of working with caregiver-only groups. The aim of this study was to assess the efficacy of a psychoeducational group intervention focused on caregivers of euthymic bipolar patients., Method: A total of 113 medicated euthymic bipolar outpatients who lived with their caregivers were randomized into an experimental and a control group. Caregivers in the experimental group received twelve 90-min group psychoeducation sessions focused on knowledge of bipolar disorder and training in coping skills. The patients did not attend the groups. Caregivers assigned to the control group did not receive any specific intervention. Patients were assessed monthly during both the intervention and the 12 months of follow-up. The primary outcome was time to any mood recurrence., Results: Psychoeducation group intervention focused on the caregivers of bipolar patients carried a reduction of the percentage of patients with any mood recurrence (chi2 = 6.53; p = 0.011) and longer relapse-free intervals (log-rank chi(2) = 4.04; p = 0.044). When different types of episodes were analyzed separately, the effect was significant for both the number of patients who experienced a hypomanic/manic recurrence (chi2 = 5.65; p = 0.017) and the time to such an episode (log-rank chi2 = 5.84; p = 0.015). The differences in preventing depressive and mixed episodes were not significant., Conclusions: A psychoeducation group intervention for the caregivers of bipolar patients is a useful adjunct to usual treatment for the patients in reducing the risk of recurrences, particularly mania and hypomania, in bipolar disorder.

Objectives: To review the definition of non-adherence, its clinical and economic impact and identify its role and impact in clinical practice., Methods: A selective review of the literature as conducted of articles and literature known to the authors., Results: There is a paucity of studies examining specifically treatment non-adherence and its consequences in bipolar disorder. Few studies have systematically examined ways in which treatment adherence can impact treatment and improve outcome., Conclusion: Non-adherence is common in the management of bipolar disorder. Clinicians and Researchers alike need to remain alert and be aware of issues related to non-adherence--in particular suicide. Like other course-modifiers non-adherence has to be considered, sought and addressed, and this is perhaps best done by including psychoeducation in routine clinical care.

Objective: To determine the effect on the serum lithium levels of a psychoeducational program in patients with bipolar disorder., Method: This is a subanalysis of data obtained from a larger study on the efficacy of group psychoeducation in the prophylaxis of recurrences in bipolar disorders. Data on plasma lithium levels were obtained at five time points: baseline, 6, 12, 18 and 24 months. Serum lithium levels of patients who had received psychoeduction (psychoeducated) (N = 49) and non-psychoeducated patients (N = 44) were compared., Results: Mean serum lithium levels were significantly higher and more stable for the psychoeducation group., Conclusions: As changes in serum lithium level may be a powerful predictor of recurrence for bipolar patients, the addition of group psychoeducation to standard pharmacological treatment may be beneficial to optimize serum lithium levels and, thereby improve outcome.

Objectives: Although pharmacological treatment is at present essential for treating bipolar patients, a number of psychological interventions have recently been shown to be efficacious as add-on therapies for the prophylactic treatment of bipolar illness. The study aimed critically to examine the efficacy of several tested patient-focused therapies., Methods: A systematic review of the literature on this topic was performed, using MEDLINE, PSYCLIT and CURRENT CONTENTS. 'Bipolar', 'Psychotherapy', 'Psychoeducation', 'Interpersonal' and 'Cognitive-behavioral' were entered as keywords., Results: To date, psychoeducation and cognitive-behavioral therapy are the psychological interventions that have been shown to be more efficacious in the prophylaxis of new recurrences. There remains a need for studies investigating the role and efficacy of psychological interventions during acute phases of the illness., Conclusions: As their therapeutic goals are complementary, a combination of psychotherapy and pharmacotherapy may allow patients to achieve better symptomatic and functional recovery. Further research is needed to determine which patients may be better candidates for psychological interventions and to estimate the relative effects of the different components of psychological approaches on outcome., (Blackwell Munksgaard, 2004)

Background: The co-occurrence of personality and bipolar disorders is quite common. Bipolar patients with personality disorders have been described as having poorer outcome than 'pure' bipolar patients. However, from a combined-approach point of view, a little has been done to improve the course of these patients. Psychoeducation has shown its efficacy in the prevention of relapses in the bipolar population but, to date, no data is available on its efficacy in the management of bipolar patients with personality disorders., Method: The present study shows a subanalysis from a single-blind randomized prospective clinical trial on the efficacy of group psychoeducation in bipolar I patients. Bipolar patients fulfilling DSM-IV criteria for any personality disorder were randomized to either psychoeducational treatment or a non-structured intervention. There were 22 patients in the control group and 15 in the psychoeducation group. All patients received naturalistic pharmacological treatment as well. The follow-up phase comprised 2 years where all patients continued receiving naturalistic treatment without psychological intervention and were assessed monthly for several outcome measures., Results: At the end of the follow-up phase (2 years), a 100% of control group patients fulfilled criteria for recurrence versus a 67% in the psychoeducation group (p < 0.005). Patients included in the psychoeducation group had a higher time-to-relapse and a significantly lower mean number of total, manic and depressive relapses. No significant differences regarding the number of patients who required hospitalization were found but the mean duration of days spent in the hospitalization room was significantly higher for the patients included in the control group., Conclusion: Psychoeducation may be a useful intervention for bipolar patients with comorbid personality disorders. Further studies should address the efficacy of specifically tailored interventions for this common type of patients.

Objective: Cognitive impairment in bipolar disorder may be a stable characteristic of the illness, although discrepancies have emerged with regard to what dysfunctions remain during remission periods. The aim of this study was to ascertain whether euthymic bipolar patients would show impairment in verbal learning and memory and in executive functions compared with healthy controls. Secondly, to establish if there was a relationship between clinical data and neuropsychological performance., Methods: Forty euthymic bipolar patients were compared with 30 healthy controls through a battery of neuropsychological tests assessing estimated premorbid IQ, attention, verbal learning and memory, and frontal executive functioning. The effect of subsyndromal symptomatology was controlled., Results: Remitted bipolar patients performed worse than controls in several measures of memory and executive function, after controlling for the effect of subclinical symptomatology, age and premorbid IQ. Verbal memory impairment was related to global assessment of function scores, as well as to a longer duration of illness, a higher number of manic episodes, and prior psychotic symptoms., Conclusions: Results provide evidence of neuropsychological impairment in euthymic bipolar patients, after controlling for the effect of subsyndromal depressive symptoms, suggesting verbal memory and executive dysfunctions. Cognitive impairment seems to be related to a worse clinical course and poor functional outcome.

Introduction: This prospective open-label study assessed the impact of add-on quetiapine in the treatment of rapid cycling bipolar patients., Methods: Fourteen rapid cycling bipolar patients were treated with quetiapine, which was added to their ongoing medication regimen for 112 +/- 33 days. At the beginning of the study, five were manic, three were in a mixed state, three were depressed, two hypomanic and one was euthymic. Patients were assessed prospectively with a modified version of the Clinical Global Impression Scale for Bipolars (CGI-BP), the Young Scale for mania (YMRS) and the Hamilton Scale for Depression (HDRS)., Results: A significant reduction of the following scale scores was observed: a 1.8 point reduction for the general CGI-BP (p = 0.013), a -1.3 point for the mania subscale (p = 0.016), a -1.01 point for the YMRS (p = 0.025). Improvement in depressive symptoms was not significant, neither in the CGI-BP (-1 point, p = 0.074) nor in the HDRS (-5.2 points, p = NS). The most common side-effect was sedation (n = 6, 43%). Doses of quetiapine were significantly reduced by the end of the study (443 +/- 235 mg/day versus 268 +/- 190 mg/day, p = 0.008) and they also differed according to the initial episode to be treated (720 +/- 84 mg/day for mania, and 183 +/- 29 mg/day for depression, p = 0.023)., Conclusions: Quetiapine could possibly be an effective treatment for rapid cycling bipolar patients. Adequate doses for acute episodes could significantly differ according to the episode polarity and the length of treatment.

Objectives: To ascertain the clinical implications of psychiatric comorbidity in the course and outcome of bipolar I patients., Methods: One hundred and twenty-nine bipolar I outpatients in remission [Young Mania Rating Scale (Y-MRS) < 7, Hamilton Depression Rating Scale (HDRS) < 9] were assessed by means of the Structured Clinical Interview for DSM-III-R axis I and axis II (SCID-I and SCID-II) in order to detect all possible psychiatric comorbid diagnoses. The sample was split according to the presence of psychiatric comorbidity and the groups were compared., Results: Psychiatric comorbidity was detected in 31% of the sample. A higher number of mixed features, depressive episodes and suicide attempts and a predominance of depressive onset amongst comorbid bipolar patients were the most relevant differences between the two groups., Conclusions: There is an association between depression, suicidality and comorbidity in bipolar I disorder. As comorbidity had a clear relevance in the course and outcome of bipolar illness, this issue should be specifically assessed in clinical practice.