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Objective: Treatment of bipolar depression with antidepressants is strongly debated on the basis of the methodologically poor and insufficient data supporting their use and the widely held belief that antidepressants can induce new episodes of abnormal mood elevation or accelerate the rate of cycling. The present study aimed at identifying clinical risk factors for switch into hypomania, mania, or mixed states, within 8 weeks after introduction of an antidepressant or after increasing its dosage, in a prospective, longitudinal design., Method: 221 consecutive DSM-IV-TR depressed bipolar I and II disorder patients were treated with antidepressants, which were added to previously prescribed mood stabilizers and/or atypical antipsychotics. No patient was on antidepressant monotherapy. The patients were enrolled from October 2005 through January 2010. The primary outcome was the assessment of switch to mania or hypomania within 8 weeks after the introduction or dose increase of an antidepressant. Both groups were compared with analysis of variance and χ² procedures., Results: Treatment-emergent affective switch was detected in 54 patients (24.4%) (switch group) while 167 patients (75.6%) (nonswitch group) did not experience a treatment-related switch. The main clinical differences significantly associated with the occurrence of an antidepressant-related switch, after performing logistic regression analysis, were higher rate of previous switches (P < .001) in the switch versus the nonswitch group, lower rate of responses to antidepressants (P < .001) in the switch versus the nonswitch group, and earlier age at onset (P = .026) in the switch versus the nonswitch group., Discussion: Bipolar patients with an earlier age at onset and an illness course characterized by lower rate of response to antidepressants and higher rate of switches into mania or hypomania were found to be the ones with higher switch risk. Nevertheless, a greater number of previous antidepressant exposures was not associated with the occurrence of an antidepressant-associated switch., Trial Registration: clinicaltrials.gov Identifier: NCT01503489., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Objective: Despite the additional complications associated with alcohol misuse in bipolar populations, it is generally the case that studies exploring neurocognitive aspects of bipolar disorder specifically exclude patients with alcohol abuse or dependence. Given the role of cognitive dysfunctions in overall illness outcome, this study addressed the neurocognitive functioning of patients with a history of alcohol abuse or dependence as compared to bipolar patients without such a history and healthy controls., Method: The study sample included 100 subjects: 65 bipolar patients, 30 of whom with a history of alcohol abuse or dependence and 35 without a previous history of alcohol abuse or dependence, based on DSM-IV criteria, and a control group of 35 healthy subjects. Comprehensive neuropsychological tests were carried out during strictly defined clinical remission. Differences between groups were analyzed and a linear regression analysis was undertaken to establish predictors of psychosocial functioning as measured using the Global Assessment of Functioning. Data were collected from September 2006 to July 2007., Results: Bipolar patients with a history of alcohol abuse or dependence obtained lower scores in the interference task of the Stroop test compared to the control group. Both patient groups showed a poorer performance in some verbal memory and executive function measures than healthy controls. Verbal learning impairment was significantly associated with poor psychosocial functioning., Conclusions: Cognitive dysfunctions appeared to be more strongly associated with bipolar disorder than with the "history of alcohol abuse or dependence" factor. Bipolar patients with history of alcohol misuse may have greater difficulties of inhibitory control, probably due to higher impulsivity., (©Copyright 2009 Physicians Postgraduate Press, Inc.)

Objective: Little is known regarding the relationship between treatment adherence and residual cognitive dysfunction in euthymic bipolar disorder patients. This study aimed to investigate whether poor treatment adherence is associated with cognitive impairment in euthymic bipolar patients and whether other factors may be associated with both adherence and cognitive functioning., Method: Euthymic DSM-IV bipolar I or II disorder patients (N = 103: 61 with high levels of treatment adherence and 42 with poor treatment adherence) were assessed using a neuropsychological battery targeting attention, psychomotor speed, verbal memory, and executive functions and compared with 35 healthy controls of similar age, sex distribution, and education. Data were collected from September 2005 to June 2007., Results: Bipolar patients with poor treatment adherence had more hospitalizations than those with high adherence. After controlling for age, gender, estimated IQ score, and Young Mania Rating Scale and 17-item Hamilton Rating Scale for Depression scores, non-treatment-adherent patients performed less well than normal controls in verbal learning and some executive functions. Among treatment-adherent and poorly adherent bipolar disorder patients, performance was similar in attention tasks and short-term and long-term verbal recall, but non-treatment-adherent patients were more impaired in ability to inhibit interferences and in spatial working memory. Poorer treatment adherence also was associated with the bipolar I subtype and with greater illness severity, as indicated by number of manic episodes and hospitalizations and history of psychosis. Pharmacologic factors, such as treatment with lithium, may also influence the relationship between neurocognition and adherence., Conclusions: There is a close relationship between poor treatment adherence and cognitive impairment, but the causal inferences of these findings are uncertain. Poor treatment adherence may worsen the course of bipolar disorder and so indirectly worsen cognitive performance, or cognitive impairment may contribute to poor treatment adherence and reflect more severe illness., (©Copyright 2009 Physicians Postgraduate Press, Inc.)

Objective: To explore the short- and long-term mental health resource utilization and cost of care in a sample of 120 individuals with bipolar disorders who participated in a randomized controlled efficacy trial of group psychoeducation versus unstructured group support., Method: Prospective, independent monitoring of DSM-IV bipolar disorder type I or II patients aged 18 to 65 years was conducted during the intervention phase (6 months) and follow-up phase (5-year postintervention) of a randomized controlled trial reporting clinical outcomes and inpatient and outpatient mental health service utilization, with estimation of cost of treatment per patient. The study was conducted from October 1997 through October 2006., Results: Compared with individuals with bipolar disorder receiving the control intervention, psychoeducated patients had twice as many planned outpatient appointments, but the estimated mean cost of emergency consultation utilization was significantly less. There were trends for psychoeducated patients to opt for self-funded psychotherapy after completing group psychoeducation and to utilize more medications. However, inpatient care accounted for 40% estimated total cost in the control group but only about 15% in the psychoeducation group., Conclusions: This study demonstrates the importance of taking a long-term overview of the cost versus benefits of adjunctive psychological therapy in bipolar disorders. If viewed only in the short-term, the psychoeducation group used more mental health care resources without clear additional health gain. However, extended follow-up demonstrated a long-term advantage for psychoeducated individuals, such that, compared to an unstructured support group intervention, group psychoeducation is less costly and more effective., (©Copyright 2009 Physicians Postgraduate Press, Inc.)

Objective: Little is known regarding the impact of psychotic symptoms on the cognitive functioning of bipolar patients. Findings from previous reports are controversial and mainly focused on current psychotic symptoms. The main aim of this study was to ascertain whether the history of psychotic symptoms was associated with greater cognitive impairment in euthymic bipolar patients., Method: Sixty-five euthymic bipolar disorder patients (DSM-IV criteria; 35 with a history of psychotic symptoms and 30 without such a history) were assessed through a neuropsychological battery targeting attention, psychomotor speed, verbal memory, and executive functions. Thirty-five healthy controls were also included in the study in order to compare the neuropsychological performance among groups. Multivariate analysis of covariance was performed controlling for the effect of residual depressive symptoms as a covariate. The study was conducted from June 2005 to June 2006., Results: Bipolar patients with a history of psychotic symptoms showed a higher number of manic episodes and more hospitalizations than patients without such a history (both p < .001). Regarding neuropsychological performance, patients with a history of psychotic symptoms performed more poorly than those without such a history or controls in all verbal memory measures (p < .005). Furthermore, patients with a history of psychotic symptoms were more impaired on tasks related to executive functions compared to healthy controls (p < .05). History of psychotic symptoms was found to be a predictor of verbal memory impairment., Conclusions: Our findings suggest that the history of psychotic symptoms may partly account for the cognitive dysfunctions seen in euthymic bipolar patients, especially with regard to persistent verbal memory dysfunction, as well as with some executive dysfunctions.

Objective: This study examined the association between family history of completed suicide and suicidal behavior and other clinical variables in subjects with bipolar disorder., Method: 374 outpatients aged from 19 to 88 years (mean +/- SD age = 41.9 +/- 4.1 years) (54.3% female) meeting DSM-IV criteria for bipolar disorder type I or II or schizoaffective disorder, bipolar subtype, were included in the study. Forty-eight subjects with a family history of completed suicide were compared to 326 subjects without a family history of completed suicide regarding several clinical and demographic variables. The study was conducted from 2001 to 2004., Results: There were no statistically significant demographic differences between bipolar disorder subjects with and without a family history of suicide. Bipolar disorder subjects with a family history of suicide showed higher rates of cluster C personality disorders than subjects without a family history of suicide (14.9% vs. 2.5%, OR = 6.72, 95% CI = 2.31 to 19.51, p < .001). Subjects with a family history of suicide also demonstrated a significantly greater lifetime prevalence of suicide attempts (52.2% vs. 25.5%, OR = 3.19, 95% CI = 1.7 to 6.0, p < .001). Results remained significant after controlling for all possible interactions., Conclusion: Family history of completed suicide is a significant risk factor associated with suicidal attempts in patients with bipolar disorder. These findings underscore the importance of identifying patients with a family history of suicide in order to provide prompt treatment and careful follow-up.

Objective: To conduct the first randomized, controlled trial assessing the prophylactic efficacy of gabapentin in bipolar disorder., Method: We conducted a 1-year, double-blind, randomized, comparative, placebo-controlled, parallel-group, multicenter study. As this was a pure prophylactic trial, only euthymic bipolar I and II patients (DSM-IV) were randomly assigned in a 1:1 ratio to gabapentin (N = 13) or placebo (N = 12) added to the current treatment (lithium, valproate, carbamazepine, or any combination but not antipsychotics or antidepressants). Subjects participated in the study for 12 months. The primary efficacy parameter was the Clinical Global Impressions scale for Bipolar Illness, Modified (CGI-BP-M), which was assessed at all visits. Other assessments were the Young Mania Rating Scale (YMRS), Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), Pittsburgh Sleep Quality Index (PSQI), and the systematic collection of reported adverse events. Data were collected from May 1999 to February 2004., Results: The change from baseline to month 12 in mean CGI-BP-M scores between groups was statistically significant (p = .0046). Mean score change from baseline to endpoint in the gabapentin group was -2.1, and the mean score change in the placebo group was -0.6. No emerging manic or depressive symptoms were seen in either group as measured with the YMRS, HAM-D, HAM-A, and PSQI. In the PSQI-6 subscale (use of sleeping medication), the mean score change at month 12 in the gabapentin group was 0.9, and the mean score change in the placebo group was 0.05 (p = .0267). Overall, gabapentin was well tolerated., Conclusion: This small, randomized clinical trial comparing the prophylactic efficacy of adjunctive gabapentin to placebo suggests that, despite lack of acute efficacy, treatment with gabapentin might provide some benefit on the long-term outcome of bipolar disorder.

Introduction: Rapid-cycling (RC) bipolar disorder patients experience high levels of morbidity, typically respond unsatisfactorily to available treatments, and, so, require additional studies of novel treatments. We report on the first controlled study comparing acute and continuous clinical outcomes in RC and non-RC manic patients treated with olanzapine., Method: We analyzed data pooled from 2 placebo-controlled, double-blind, 3- to 4-week trials of olanzapine in mania (N = 254), 1 with an open-label extension up to 1 year (N = 113) and controlled supplementation with lithium or fluoxetine as needed, to compare demographic, clinical, and outcome measures between RC and non-RC subgroups of 254 DSM-IV bipolar I manic subjects., Results: RC (N = 90, 35%) versus non-RC subjects (N = 164, 65%) were younger at intake (p = .02), less often psychotic (p < .0001), and more likely to have familial bipolar disorder (p < .0001), abused substances (p = .01), more previous hospitalizations (p = .004), and many more illness episodes (p < .001). In initial blinded trial outcomes, relative responses (> or = 50% improvement of mania) to olanzapine/placebo were similar in RC and non-RC subjects, though early responses to olanzapine favored RC over non-RC subjects (p = .003), and long-term outcomes favored non-RC subjects (p = .05). Fewer RC subjects achieved strictly defined initial symptomatic remission (p = .014) within a year; RC subjects were more likely to experience recurrences (p = .002), especially of depressive illness (< .001), and had more rehospitalizations (p = .01) and suicide attempts (p = .03)., Conclusions: RC bipolar I patients showed major initial differences and more rapid initial clinical changes, especially toward depression, with less favorable long-term outcomes than non-RC cases during treatment with olanzapine. Inclusion of RC bipolar disorder patients can complicate therapeutic trials, but these patients require further study for differential responsiveness to innovative treatments with methods of assessing clinical response that take their mood instability into account.

Background: Several previous studies have established that low treatment adherence is common among bipolar patients and may explain high rates of recurrence. On the other hand, some patients keep relapsing even when they strictly follow their prescribed somatic treatments. Psychological interventions such as psychoeducation may foster early recognition of prodromal symptoms and minimize the risk of relapse. To date, studies assessing the usefulness of psychoeducation in fully compliant patients are lacking., Method: This was a single-blind, randomized, prospective clinical trial on the efficacy of group psychoeducation in remitted fully compliant DSM-IV bipolar I patients (N = 25) who were compared with a group with similar characteristics (N = 25) who did not receive psychoeducation. All patients received naturalistic pharmacologic treatment. Recruitment began in 1997 and follow-up was completed in January 2002. The follow-up phase comprised 2 years during which all patients continued receiving naturalistic treatment without psychological intervention and were assessed monthly on several outcome measures., Results: At the end of the 2-year follow-up, 23 subjects (92%) in the control group fulfilled criteria for recurrence versus 15 patients (60%) in the psychoeducation group (p < .01). The number of total recurrences and the number of depressive episodes were significantly lower in psychoeducated patients., Conclusion: Although the present study has the limitation of small sample size, psychoeducation showed its efficacy in preventing relapses in bipolar I patients who were adherent to drug treatment. The action of psychoeducation seems to go beyond compliance enhancement and may support a tripod model composed by lifestyle regularity and healthy habits, early detection of prodromal signs followed by prompt drug intervention, and finally treatment compliance.

Background: The safety and efficacy of the combination of risperidone and topiramate in the long-term treatment of mania were assessed in a 12-month, multicenter open study., Method: Subjects (N = 58) who met DSM-IV criteria for bipolar disorder and for a manic episode received both risperidone and topiramate for the treatment of their manic symptoms. Patients with mixed episodes were excluded. Risperidone could be discontinued at any point, but patients had to be on topiramate therapy for at least 12 months to be considered completers. Efficacy was assessed with the Young Mania Rating Scale (YMRS) and a modified version of the Clinical Global Impressions for Bipolar Disorder (CGI-BP-M). Safety was assessed with systematic collection of side effect data, weight, and the Hamilton Rating Scale for Depression (HAM-D) scores, to address the risk of switch into depression., Results: 41 patients (70.7%) completed the study. There was a significant improvement on the YMRS (p <.001) and the CGI-BP-M subscales for manic symptoms (p <.005) and long-term outcome (p <.005) from week 2 onward. Relapse rates were significantly lower during the 12-month study period compared to the precedent year (p <.0001). There was no increase in depressive symptoms as measured by the HAM-D. 37 patients (63.8 %) experienced at least 1 adverse event, the most frequent of which was somnolence (N = 7, 12.1%). At endpoint, the patients' mean weight had decreased an average of 1.1 +/- 0.4 kg., Conclusion: Despite the limitations inherent to the open design, this naturalistic study suggests that the combination of risperidone and topiramate may be a valuable option for the short- and long-term treatment of mania.

Background: The treatment of depressive episodes occurring in bipolar patients taking mood stabilizers is an understudied area of research with outstanding clinical consequences. This study was aimed to assess and compare the efficacy and safety of 2 different antidepressant drugs, paroxetine and venlafaxine, in this indication., Method: Sixty DSM-IV bipolar patients. each presenting with a major depressive episode while receiving mood stabilizers, were randomly assigned to either paroxetine (N = 30) or venlafaxine (N = 30) for 6 weeks in a single-blind manner. They had to score higher than 17 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and have their mood stabilizer blood levels within the therapeutic range. Efficacy was measured by the HAM-D. Reports of side effects were collected at each visit; switch to mania or hypomania was specifically assessed by the Young Mania Rating Scale at 5 of 7 visits., Results: Significant improvements in HAM-D scores were observed in both paroxetine- and venlafaxine-treated patients (Wilcoxon p < .0001). There were no significant differences in either efficacy or safety measures between the 2 drugs. By intention-to-treat analysis, 43% (N = 13) of patients taking paroxetine and 48% (N = 14) taking venlafaxine were considered to be responders. Only 3% (N = 1) of patients switched to hypomania or mania in the paroxetine group, whereas 13% (N = 4) switched in the venlafaxine group., Conclusion: Paroxetine and venlafaxine are both effective and safe in the treatment of depressive breakthrough episodes in bipolar disorder. There was a suggestion of a slightly higher risk for switch to mania or hypomania with venlafaxine.

Background: The goal of this study was to assess the efficacy and safety of risperidone in bipolar and schizoaffective disorders., Method: 541 patients entered this open, multicenter, 6-month study. Patients were entered provided that they fulfilled DSM-IV criteria for bipolar disorder or schizoaffective disorder, bipolar type, during a manic, hypomanic, mixed, or depressive episode. Risperidone was added to any previous mood-stabilizing medication that the patients were taking. Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Hamilton Rating Scale for Depression (HAM-D), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions scale (CGI). Extrapyramidal symptoms (EPS) were assessed using the UKU Side Effect Rating Scale., Results: 430 patients completed the study. Addition of risperidone produced highly significant improvements (p < .0001) on the YMRS and HAM-D at both 6 weeks and 6 months and on the CGI and the scales of the PANSS at both 4 weeks and 6 months. There was a significant reduction in UKU total and subscale scores at 6 months. The mean dose of risperidone was 3.9 mg/day. There was no single case of new-emergent tardive dyskinesia, and there was a very low incidence of exacerbation of mania within the first 6 weeks (2%). Adverse events were few and mostly mild. the most frequent being EPS and weight gain., Conclusion: This large study provides additional evidence that risperidone is effective and well tolerated when combined with mood stabilizers in the treatment of bipolar disorder and schizoaffective disorder, bipolar type. Previous concerns about exacerbation of manic symptoms were not confirmed.

Background: An adequate therapy for psychotic disorders needs to be effective against mood as well as psychotic symptoms. Analyses of data from clinical trials of risperidone in schizophrenia and small open-label studies in mania suggest that risperidone may have this broad efficacy profile. We present data on a 6-week trial of risperidone for the treatment of schizoaffective disorder that was part of a larger, 6-month surveillance study of patients with affective disorders., Method: One hundred two patients suffering from schizoaffective disorder (DSM-IV or ICD-10) entered the trial. Inclusion criteria consisted of a current DSM-IV diagnosis of schizoaffective disorder, bipolar type; DSM-IV manic or mixed psychotic episode; and a Young Mania Rating Scale (YMRS) score > 7 for a mixed episode (> 20 for a manic episode). Assessments included the YMRS, the Positive and Negative Syndrome Scale (PANSS), the Hamilton Rating Scale for Depression (HAM-D), the 4-item Clinical Global Impressions (CGI) scale, and the UKU Side Effect Rating Scale subscale for neurologic side effects. For patients entering the study, open-label risperidone therapy was added to their existing regimens of mood-stabilizing treatments. Other antipsychotic drugs were not allowed., Results: Ninety-five patients completed the 6-week trial. At week 6, the mean +/- SD dose of risperidone was 4.7+/-2.5 mg/day. The mean scores on the assessment scales at baseline and week 6 (unless otherwise stated) were as follows: YMRS, 22.7 and 4.7, an improvement of 18.0 points (p < .0001); PANSS (at baseline and week 4), 74.1 and 54.2, an improvement of 19.9 points (p < .0001); HAM-D, 14.0 and 7.4, an improvement of 6.6 points (p < .0001); CGI (at baseline and week 4), 2.6 and 1.7, an improvement of 0.9 points (p < .0001). At week 4, most patients had shown improvement in symptom severity, and 9.3% were completely symptom-free. There were no statistically significant differences between baseline and week 4 in the severity of extrapyramidal symptoms as measured by the UKU. Risperidone was well tolerated; side effects were few and generally mild., Conclusion: The results to date with risperidone indicate that it may have both antipsychotic and mood-stabilizing properties. Despite the limitations of the open-label design, the results indicate that risperidone is a safe and effective therapy in combination with mood-stabilizers for the treatment of patients with manic, hypomanic, and depressive symptoms of mixed episodes in schizoaffective disorder, bipolar type.

Background: Noncompliance with medication is a very common feature among bipolar patients. Rates of poor compliance may reach 64% for bipolar disorders, and noncompliance is the most frequent cause of recurrence. Knowledge of the clinical factors associated with noncompliance would enhance clinical management and the design of strategies to achieve a better outcome for bipolar patients. Although most patients withdraw from medication during maintenance treatment, compliance studies in euthymic bipolar samples are scarce., Method: Compliance treatment and its clinical correlates were assessed at the end of 2-year follow-up in 200 patients meeting Research Diagnostic Criteria for bipolar I or bipolar II disorder by means of compliance-focused interviews, measurements of plasma concentrations of mood stabilizers, and 2 structured interviews: the Schedule for Affective Disorders and Schizophrenia and the Structured Clinical Interview for DSM-III-R Axis II disorders. Well-compliant patients and poorly compliant patients were compared with respect to several clinical and treatment variables., Results: The rate of mildly and poorly compliant patients was close to 40%. Comorbidity with personality disorders was strongly associated with poor compliance. Poorly compliant patients had a higher number of previous hospitalizations, but reported fewer previous episodes. The type of treatment was not associated with compliance., Conclusion: Clinical factors, especially comorbidity with personality disorders, are more relevant for treatment compliance than other issues such as the nature of pharmacologic treatment. Compliant patients may have a better outcome in terms of number of hospitalizations, but not necessarily with respect to the number of episodes. Bipolar patients, especially those with personality disorders, should be monitored for treatment compliance.