Carolina Franco

Clinical and neurocognitive predictors of functional outcome in bipolar euthymic patients: A long-term, follow-up study

OBJECTIVE To identify clinical and neurocognitive predictors of long-term functional outcome in patients with bipolar disorder METHODS A total of 32 subjects who met criteria for bipolar I or II disorder were recruited from the Barcelona Bipolar Disorder Program and were assessed clinically and neuropsychologically at baseline. After an average 4-year follow-up, they were interviewed with the Functioning Assessment Short Test (FAST) to assess functional outcome. Multivariate analyses were applied to identify clinical and neurocognitive predictors of functional outcome. RESULTS The main regression model for predictors of overall psychosocial functioning identified subclinical depressive symptoms (beta=0.516, t=3.51, p=0.002), and free delayed recall in a verbal memory task (beta=-0.314, t=-2.144, p=0.041), accounting for 36% of the variance. Specific predictors of occupational functioning were, again, subthreshold depression (beta=0.435, t=2.8, p=0.009) and a measure of executive function, digits backwards (beta=-0.347, t=-2.23, p=0.034). This model explained around 28% of the variance (corrected R(2)=0.28; F=6.38, gl=2, p=0.004). CONCLUSIONS Subdepressive symptomatology together with neurocognitive impairments related to verbal memory and executive functions are predictor variables of long-term functional outcome in bipolar disorder.

Clinical predictors of functional outcome of bipolar patients in remission.

OBJECTIVES A number of studies have now shown that subjects with bipolar disorder (BD) have significant psychosocial impairment during interepisode intervals. This study was carried out to assess the level of functioning as well as to identify potential predictors of functioning in a well-defined, euthymic bipolar sample. METHODS The study included 71 euthymic bipolar patients and 61 healthy controls. The Functioning Assessment Short Test (FAST) was used to assess multiple areas of functioning such as autonomy, occupational functioning, cognitive functioning, interpersonal relationships, financial issues, and leisure time. Multivariate analysis was used to determine the global and specific clinical predictors of outcome. RESULTS Sixty percent (n = 42) of the patients had overall functional impairment (defined as a FAST total score > 11) compared to 13.1% (n = 8) of the control group (p = 0.001). Bipolar patients showed a worse functioning in all the areas of the FAST. Only four variables-older age, depressive symptoms, number of previous mixed episodes, and number of previous hospitalizations-were associated with poor functioning, on a linear regression model, which accounted for 44% of the variance (F = 12.54, df = 58, p < 0.001). CONCLUSIONS A substantial proportion of bipolar patients experience unfavorable functioning, suggesting that there is a significant degree of morbidity and dysfunction associated with BD, even during remission periods. Previous mixed episodes, current subclinical depressive symptoms, previous hospitalizations, and older age were identified as significant potential clinical predictors of functional impairment.

Functional Impairment and Disability across Mood States in Bipolar Disorder

BACKGROUND Bipolar disorder (BD) represents a chronic and recurrent illness that can lead to severe disruptions in family, social, and occupational functioning. The severity of mood symptomatology has been associated with functional impairment in this population. However, the majority of studies have assessed global functioning without considering specific domains. The main objective of the current study was to assess specific life domains of functioning as well as the overall functioning in patients with BD across different mood states ([hypo] mania, depression, or euthymia) compared with healthy controls by the means of a standardized scale validated for BD. METHODS The sample included 131 subjects with BD (68 in remission, 31 hypo [manic], and 32 depressed) and 61 healthy controls. The Functioning Assessment Short Test was used to assess overall and multiple areas of functional impairment (autonomy, occupational functioning, cognitive functioning, interpersonal relationships, financial issues, and leisure time). RESULTS The results showed significant intergroup differences; depressed patients had the lowest functioning (48.03 ± 12.38) followed by (hypo) manic patients (39.81 ± 13.99). The euthymic group showed least impairment in functioning compared with the depression and (hypo) mania groups (11.76 ± 12.73) but still displayed significant impairment when compared with the healthy control group (5.93 ± 4.43). CONCLUSIONS This study indicates that depressive symptoms are associated with greater negative impact on psychosocial functioning than (hypo) manic symptoms. Further deficits in functioning seem to persist during remission. The results highlight the importance of aggressively treating depression and mania and the need to develop psychosocial interventions targeting to improve functional outcomes.

Effects of atypical antipsychotics on neurocognition in euthymic bipolar patients.

BACKGROUND Different factors may influence cognitive functioning in bipolar disorder such as the effect of subsyndromal symptoms, the history of psychotic symptomatology or substance abuse, negative symptomatology, chronicity, sleep disturbances, and hormonal factors. The effect of pharmacologic treatment on cognition is still uncertain because of an insufficient number of studies examining this issue. OBJECTIVE The aims of this study were to compare neuropsychologic performance of treated bipolar patients with that of controls, including unmedicated patients and healthy subjects, as well as to evaluate possible neurocognitive differences among 3 different atypical antipsychotics. RESEARCH DESIGN AND METHODS A total of 119 subjects were included in the study. Of 79 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition euthymic bipolar patients, 68 were treated with one atypical antipsychotic, quetiapine (n = 12), olanzapine (n = 26), or risperidone (n = 30). Sixteen patients were drug-free. The 4 groups were compared with a sample of drug-naïve patients and a healthy control group (n = 35) on several clinical and neuropsychologic variables, especially on the domains of attention, verbal memory, and executive functions. Euthymia was defined by a score of 6 or less at the Young Mania Rating Scale and a score of 8 or less at the Hamilton Depression Rating Scale for at least 6 months. RESULTS The 5 groups did not differ in age, years of education, sex distribution, or estimated premorbid IQ. The 4 patients groups did not differ in chronicity, age of onset, total number of episodes, and number of hospitalizations. No differences were found regarding antipsychotic dosages between the groups. Bipolar patients performed poorly on most neuropsychologic measures as compared with healthy controls. After controlling for Hamilton Depression Rating Scale symptoms, no significant change in the results was observed. Because many patients with antipsychotic treatment had a history of psychotic symptoms, we performed multivariate analysis of covariance controlling for this variable. Bipolar patients taking 1 of the 3 antipsychotics presented with dose-independent significant deficits in most cognitive tasks compared with healthy controls. After several head-to-head group comparisons, the patients receiving quetiapine showed a better performance in learning task, short-term memory, and recognition task assessed with the California Verbal Learning Test and verbal fluency (P < .05). CONCLUSIONS Our results confirm the findings of previous studies of cognitive deficits in bipolar disorder. Untreated euthymic patients showed better cognitive performance than did patients on atypical antipsychotics. Some iatrogenic-pharmacologic effect, therefore, cannot be excluded, but quetiapine seemed to be less associated with impairment in measures of verbal memory than olanzapine or risperidone. We suggest to use drugs in bipolar disorder with a lower risk of cognitive adverse effects. However, randomized controlled trials are urgently needed to give a definite answer to this critical problem.

Functional Impairment in Patients with Remitted Bipolar Disorder

written informed consent to participate. The data were analyzed using the SPSS 12.0 version software package. The results show that the patients had a total mean FAST score significantly higher than the controls. There were significant differences between the patients and healthy volunteers in almost all specific domains of the FAST. The largest variation and the most affected domain was occupational functioning ( table 1 ). Cognitive functioning and autonomy were the other 2 most affected domains. A moderate impact was observed in the interpersonal relationships, and the weakest effect was found in the financial issue and leisure time domains, possibly reflecting the public mental health care environment and access to disability claims and income. Other studies have also reported high occupational disability rates of bipolar patients [13–15] . Almost 20% of the patients in this sample had a permanent disability. Of those who were employed, a quarter had lower-qualifications jobs, around 20% had lower incomes for the same jobs than nonbipolar subjects, almost 60% reported having problems in finishing their tasks promptly, and a quarter of them mentioned difficulties in achieving the expected performance. Occupational dysfunction is not only bad per se, it has also been reported to be predictive of a short time to relapse [9] . Taking care of their household, living alone, independence and taking their medication were the most frequent difficulties in the autonomy domain. This autonomy handicap might result in an increase in the level of caregiver burden [16] . Euthymic bipolar patients also reported more difficulties in concentration, memory and arithmetic abilities and, to a lesser degree, in problem solving and learning than healthy controls subjects. In our sample almost 20% of the patients experienced some degree of difficulty in handling money; financial problems are generally described during hypomanic episodes. Our study confirms the burden of the cognitive impairment as perceived by euthymic bipolar subjects over time, as recent studies point out [17–21] . Although interpersonal relationships may improve during euthymia, almost a third of our sample reported some degree of difficulty in family and social activities [22] . Partner’s stress, as well as marital and sexual satisfaction are important areas that patients identify as problematic [23] . Several factors such as stigmatization, behavioral changes, high levels of expressed emotion, carry-over effects of manic episodes, decreased income and even side effects of medication have been described as possible explanations [24–25] . Somewhat surprisingly, in this study, the differences between the patients and controls were only marginally significant in leisure time satisfaction, as opposed to other studies [26] . This area of functioning may be one of the most influenced by mood state at the time of the assessment. Bipolar disorder (BD) is a chronic and severe mental disorder. It is the sixth leading cause of disability-adjusted life years in the world among people aged 15–44 [1] . BD represents a major public health problem with severe psychosocial disruptions in addition to an increased mortality [2–4] . A number of studies report that patients with acute depressive and manic symptoms, or even with subsyndromal depressive symptoms, experienced marked impairments in role functioning [5] . Besides that, BD also has significant interepisodic psychosocial impairment and has been reported to be predictive of a short time to relapse [6] . The extent to which individuals return to full functioning during euthymia has been relatively understudied [7–9] . The aim of this naturalistic cross-sectional study was to assess functional impairment in patients with BD, and particularly in 6 specific domains of functioning (autonomy, occupational functioning, interpersonal relationship, cognitive functioning, financial issues and leisure time) during clinical remission. Hence, a sample of 71 consecutive bipolar patients in remission (34 females, 37 males; aged 47.74 8 17.34 years) and 61 healthy controls (matched for gender, age and sociocultural conditions) were enrolled in this study. Among the 71 bipolar patients, mood-stabilizing agents were the most commonly prescribed medication (80.3%), 54.9% received antipsychotics, 26.8% antidepressants and 36.6% anxiolytic sedatives. All patients were recruited from the Bipolar Disorder Program at the University of Barcelona Hospital Clinic. They met DSM-IV criteria for BD (type I or II) by the Structured Clinical Interview for DSM-IV [10] . Remission criteria were defined as a score ! 9 on the 17-item Hamilton Depression Rating Scale and a Young Mania Rating Scale Score ! 7 [11] . Functioning was evaluated by a trained research fellow using the Functioning Assessment Short Test (FAST) [12] . The study was approved by the hospital ethics committee and all subjects gave Published online: August 21, 2008

Six-month functional outcome of a bipolar disorder cohort in the context of a specialized-care program

Rosa AR, Reinares M, Amann B, Popovic D, Franco C, Comes M, Torrent C, Bonnín CM, Solé B, Valentí M, Salamero M, Kapczinski F, Vieta E. Six‐month functional outcome of a bipolar disorder cohort in the context of a specialized‐care program. Bipolar Disord 2011: 13: 679–686.

Has number of previous episodes any effect on response to group psychoeducation in bipolar patients? A 5‐year follow‐up post hoc analysis

Colom F, Reinares M, Pacchiarotti I, Popovic D, Mazzarini L, Martínez-Arán A, Torrent C, Rosa A, Palomino-Otiniano R, Franco C, Bonnin CM, Vieta E. Has number of previous episodes any effect on response to group psychoeducation in bipolar patients? A 5-year follow-up post hoc analysis. Objective: One of the main utilities of staging in bipolar disorder is enhancing the formulation of pharmacological and non-pharmacological treatment strategies. Hence, it is essential to ascertain whether the number of previous episodes influences treatment response. Hereby, we present a 5-year post hoc study on the efficacy of group psychoeducation for bipolar disorders according to the number of previous episodes. Methods: For this subanalysis, we have compared the 5-year outcome of 120 euthymic psychoeducated versus non-psychoeducated bipolar patients according to the number of previous episodes at study entry. Results: Patients with more than seven episodes at study entry did not show any significant improvement with psychoeducation according to time to recurrence. Patients with more than 14 episodes did not benefit from psychoeducation in terms of a reduction of time spent ill. Patients with 7 or 8 episodes showed a benefit in terms of fewer days spent in hypomania, depression, mixed episodes or any episodes but not mania, while patients with 9–14 episodes showed a benefit in terms of fewer days spent in hypomania and depression but not in mixed states or mania. Only patients who presented up to 6 episodes showed reduction in time spent in any episode polarity. Conclusion: The number of previous episodes clearly worsens response to psychoeducation, perhaps in a more subtle way than that observed with other psychological therapies. Psychoeducation should be delivered as soon as possible in the illness course, supporting the idea of early intervention.

Why do clinicians maintain antidepressants in some patients with acute mania? Hints from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM), a large naturalistic study.

OBJECTIVE Antidepressants are supposed to be withdrawn during a manic episode. The aim of this study was to analyze the characteristics of manic patients who received antidepressants during a manic phase in a large, naturalistic study. METHOD The European Mania in Bipolar Longitudinal Evaluation of Medication was a 2-year prospective observational study of inpatients and outpatients with acute mania/mixed mania (DSM-IV or ICD-10 criteria) conducted in 14 European countries. Of 2,416 manic patients who continued into the maintenance phase of the study, 345 (14%) were taking an antidepressant and 2,071 (86%) were not taking an antidepressant at baseline, week 1, and/or week 2 postbaseline. Demographic and clinical variables were collected at baseline and each study visit up to 24 months. Outcome measures included the Clinical Global Impressions-Bipolar Disorder scale (CGI-BP overall, mania, and depression scores) at 12 weeks and 24 months, the 5-item Hamilton Depression Rating Scale (HDRS-5), and the Young Mania Rating Scale (YMRS) at 12 weeks only. The present study was conducted from December 2002 to June 2004. RESULTS More antidepressant maintenance use was seen in patients with mixed episodes (P < .001), rapid cyclers (P < .02), patients with more previous depressive episodes (P < .001), and patients with higher mean HDRS-5 score at baseline (P < .001)-specifically patients with anxiety (P = .013). Patients in the antidepressant group had significantly higher CGI-BP depression scores (P < .001) and a significantly higher rate of depression relapse (P < .001) at both 12 weeks and 24 months. CONCLUSIONS Patients with mania receiving antidepressants are more likely to be outpatients with mixed episodes, anxiety, or rapid cycling and have a higher risk of depression relapse during follow-up.

A systematic review on the role of anticonvulsants in the treatment of acute bipolar depression.

Despite the high morbidity and mortality associated with bipolar depression, the optimal treatment for this phase is still a matter of debate. The aim of the current review was to provide updated evidence about the efficacy and tolerability of anticonvulsants in the treatment of acute bipolar depression. A comprehensive review of randomized controlled trials (RCTs) evaluating the use of anticonvulsants for the treatment of acute bipolar depression up to June 2011 was conducted by means of the PubMed-Medline database. Eligibility criteria included active comparator-controlled or placebo-controlled randomized studies involving monotherapy or combination therapy. A total of 18 RCTs fulfilled the inclusion criteria. Studies supported the efficacy of divalproex as monotherapy in acute bipolar depression but small sample size was a common methodological limitation. Findings were inconclusive for lamotrigine and carbamazepine although overall lamotrigine may have a beneficial but modest effect. Negative results were found for levetiracetam and gabapentin but the evidence base on these agents is scant. All anticonvulsants were generally well tolerated. No double-blind RCTs were found for the use of other anticonvulsants such as oxcarbazepine, licarbazepine, zonisamide, retigabine, pregabalin, tiagabine, felbamate and vigabatrine in the acute treatment of bipolar depression. To sum up, taking into consideration the efficacy and tolerability profiles of anticonvulsants, current evidence supports the use of divalproex and lamotrigine in the treatment of acute bipolar depression. However, available data for most other anticonvulsants are inconclusive and further RCTs with larger sample sizes are needed before drawing firm conclusions.

Ziprasidone in the Treatment of Affective Disorders : A Review

Ziprasidone was the fifth atypical antipsychotic approved by Food and Drug Administration (FDA) for use in bipolar mania and mixed episodes. This atypical antipsychotic has a unique profile, as it acts primarily through serotonergic and dopaminergic receptor antagonism, but also exerts effects as an inhibitor of norepinephrine reuptake. Moreover, one of the advantages of ziprasidone is its safety profile as it is not associated with clinically significant metabolic side effects and little or no effect on prolactin level or anticholinergic side effects. Most of the studies evaluating ziprasidones efficacy and safety are short‐term double‐blind, placebo‐controlled studies in acute mania and mixed episodes. In two of them, ziprasidone was associated to significant improvement in the primary measures assessed. However, an add‐on study, lithium plus ziprasidone showed similar results than lithium monotherapy, although there was a significant advantage for the combination within the first week. In a more recent trial, ziprasidone was compared with placebo and haloperidol as monotherapies, again beating placebo. In that trial, ziprasidone appeared to be safer and better tolerated, although less likely efficacious than haloperidol. Particularly, subjects treated with ziprasidone were less likely to switch to depression. Despite the well‐studied efficacy of ziprasidone in the first weeks of treatment, there are no controlled trials that evaluate the role and efficacy of ziprasidone in long‐term treatment of bipolar disorder (BD). Overall, in the open‐label extension studies, there was a global improvement at all visits compared with baseline scores. Furthermore, ziprasidone appears to offer some antidepressant effect in patients with major depressive episode and resistant to treatment, as demonstrated in add‐on open‐label studies with ziprasidone plus selective serotonin reuptake inhibitor (SSRI).