Dopaminergic agents in the treatment of bipolar depression: a systematic review and meta-analysis.

OBJECTIVE: To systematically examine the effects of dopaminergic agents (modafinil, armodafinil, pramipexole, methylphenidate, and amphetamines) on bipolar depression outcomes. METHODS: Meta-analysis of randomized controlled trials was performed to assess the efficacy and safety of treatment with dopaminergic agents in bipolar depression. In a secondary analysis, findings from both randomized controlled trials and high-quality observational studies were pooled by means of meta-analytic procedures to explore dopaminergic treatment-related new mania. RESULTS: Nine studies (1716 patients) were included in our meta-analysis of randomized controlled trials. Treatment with dopaminergic agents for bipolar depression was associated with an increase in both response (1671 individuals, RR 1.25, 95% CI 1.05 to 1.50) and remission rates (1671 individuals, RR 1.40, 95% CI 1.14, 1.71). There was no evidence of an increased risk of mood switch associated with this treatment (1646 individuals, RR 0.96, 95% CI 0.49, 1.89). Our secondary analysis (1231 individuals) yielded a cumulative incidence of mood switch of 3% (95% CI 1.0, 5.0) during a mean follow-up period of 7.5 months. CONCLUSIONS: Preliminary findings suggest that dopaminergic agents may represent a useful alternative for the treatment of bipolar depression, with no evidence for a related increase in the risk of mood destabilization during short-term follow-up.

Mood instability and functional recovery in bipolar disorders.

OBJECTIVE: The aim of this study was to identify psychopathological factors associated with long-term functional outcome in euthymic bipolar disorder patients and to test new measures of mood instability and symptoms intensity. METHOD: Fifty-five patients with more than 12 months of follow-up were included. In addition to traditional clinical variables, the time spent ill was documented using a modified life-charting technique based on NIHM life-charting method. New measures, Mood Instability Factor, and Mood Intensity Factor were defined and assessed. Functioning Assessment Short Test (FAST) was used to assess disability. RESULTS: The follow-up period was 3.00 ± 1.51 years. Weeks with subsyndromal depressive symptoms (ß = 0.133, t = 2.556, P = 0.014), weeks with mild manic symptoms (ß = 1.441, t = 3.10, P = 0.003), and the Mood Instability Factor (ß = 0.105, t = 3.593, P = 0.001) contributed to approximately 46% of the FAST total score variance. CONCLUSION: New methodologies including subsyndromal symptoms and mood instability parameters might contribute to understand the worse long-term functional outcome that affects a considerable percentage of BD patients even after episode remission. Concerns about therapeutic approaches are discussed.

Social cognition in euthymic bipolar disorder: systematic review and meta-analytic approach.

OBJECTIVE: Deficits in social cognition have been reported in euthymic subjects with bipolar disorder (BD). However, some studies have failed to find differences favoring controls. As most investigations have been conducted with small samples, they have not had sufficient power to detect statistically significant differences. Furthermore, studies communicating positive results have scarcely attempted to estimate effect sizes for patient-control differences. The aim of this study was to summarize the findings of reports on social cognition in patients with euthymic BD and to combine their data to identify possible deficits and quantify their magnitude. METHOD: Systematic literature review and meta-analysis. RESULTS: Impairments of moderate magnitude (0.5 < d < 0.8) were noted across mentalizing skills, whereas small but significant effect sizes (d < 0.5) were observed for facial emotion recognition. No patient-control differences were found for decision-making. CONCLUSION: Meta-analytic findings provide evidence for emotion processing and theory of mind deficits in remitted bipolar patients. However, it is not yet clear whether these areas of impairment are related to neurocognitive dysfunctions or to medication effects. The results are discussed with regard to targets for future neuropsychological research on BDs.

Decision making in euthymic bipolar I and bipolar II disorders.

BACKGROUND: The main aim of this study was to compare a large population of patients with bipolar disorder (BD) types I and II strictly defined as euthymic with healthy controls on measures of decision making. An additional aim was to compare performance on a decision-making task between patients with and without a history of suicide attempt. METHOD: Eighty-five euthymic patients with BD-I or BD-II and 34 healthy controls were included. All subjects completed tests to assess verbal memory, attention and executive functions, and a decision-making paradigm (the Iowa Gambling Task, IGT). RESULTS: Both groups of patients had worse performance than healthy controls on measures of verbal memory, attention and executive function. No significant differences were found between BD-I, BD-II and healthy controls on measures of decision making. By contrast, patients with a history of suicide attempt had lower performance in the IGT than patients without a history of suicide attempt. CONCLUSIONS: Patients with euthymic BD-I and BD-II had intact decision-making abilities, suggesting that this does not represent a reliable trait marker of the disorder. In addition, our results provide further evidence of an association between impairments in decision making and vulnerability to suicidal behavior.

Characterization of Mood Instability through Bipolar Disorders: A cluster-analytic approach using weekly prospective life-chart methodology.

BackgroundThe aim of this study was to characterize mood instability (MI) in Bipolar Disorder (BD) and to investigate potential differences between subtype I and II. MethodsLife-charts from weekly mood ratings of 90 patients were used to compute: weeks spent with symptoms, number of episodes, and MI. Regression analyses were conducted to assess the relationship between BD subtype and MI adjusting by all potential confounding factors. Hierarchical cluster analysis was performed to determine the appropriate number of clusters that described the data and to assign subjects to a specific cluster based on their MI. We then compared clusters on clinical and psychosocial outcomes. ResultsMedian follow-up was 5 years (IQR: 3.6-7.9). Patients spent 15.2%, 5%, and 3% of follow-up with depressive, manic, and mixed symptoms, respectively. BD type II presented higher MI (ß = 1.83, 95% CI: 0.66-3.00) and subsydromal symptoms than BD type I patients. No differences in functioning or recurrences were found between subtypes. Differences in MI between the two clusters mimicked those between type I and II but enhanced (ß = 3.86, 95%CI -4.72, -2.66). High MI (n = 43) patients presented poorer functioning and higher recurrences compared to Low MI patients (n = 43). ConclusionBD type II presented higher MI and subsyndromal symptoms than BD type I patients. However, these differences did not translate into clinically relevant outcomes. A classification based on MI may provide useful clinical insights.

Subjective response to antipsychotics in bipolar disorders: A review of a neglected area.

BACKGROUND: The term "subjective response to antipsychotic" (SRA) refers to changes in the subjective state experienced due to antipsychotic (AP) exposition that is independent of the therapeutic or physical side effects of these drugs. This dimension of analysis has been extensively explored in schizophrenic disorders, finding that negative SRA is an early and independent predictor of compliance as well as a successful pathway to construct current theoretical frameworks of these disorders. There is an increasing use of AP in bipolar disorders' treatment (BD) but no reviews on the topic have been published to date in this population. The aim of this work is to review published data of SRA in BD patients and to discuss their clinical and theoretical implications. METHODS: An extensive search in online databases was performed. Reports were reviewed and included if they described SRA in BD or included instruments aimed to assess it. Reports of cognitive, sexual, motor autonomic side effects were excluded. Findings were summarized in a narrative fashion. RESULTS: Nine reports fulfilled the inclusion criteria and were included in the revision, reporting data from 1282 BD patients. Among these, three were prospective studies and three explored relations between SRA and treatment compliance. CONCLUSIONS: There is an asymmetry between the increase in the use of antipsychotics in BD and the lack of data regarding the SRA. Phenomenologically, SRA in BD is similar to that found in schizophrenic subjects. Some of these symptoms may be misdiagnosed as depressive symptoms. The existing data show that SRA has a strong correlation with treatment compliance as well as a promising way to develop theoretical paradigms for these disorders.

A longitudinal mirror-image assessment of morbidity in bipolar disorder.

BACKGROUND: Evidence about the clinical course of bipolar disorder is inconsistent and limited. The aim of this study was to assess changes in morbidity in patients with bipolar disorder along a mean follow-up period of 80months. METHODS: Based on a mirror-image design, the follow-up period of each patient was divided into two halves. Then, three measures of morbidity - number of affective episodes, time spent ill, and cycle length - were recorded and compared between each half of the follow-up period. RESULTS: On average, there was a trend to a smaller amount of time spent with subclinical symptomatology during the second half of the follow-up period. In contrast, there were no differences in terms of number of episodes, time spent with clinical symptoms, or cycle length between the first and second half of the follow-up period. A subgroup analysis identified 21.9% of patients with consistent data of a worsening during follow-up. CONCLUSIONS: The results suggest that, on average, there is stability or slight improvement of clinical morbidity over the course of BD. Then, worsening of the clinical course may be a feature of a subgroup of patients rather than an inherent characteristic of the disorder. These subgroups or patient profiles could represent an opportunity for further studies to assess clinical, pathophysiologic, and therapeutic features associated with them.

Are major depression and bipolar disorder neuropsychologically distinct? A meta-analysis of comparative studies.

BACKGROUND: Neuropsychological deficits are present in both major depression and bipolar disorder. So far, however, reports directly comparing these mood disorders with regard to cognitive outcomes have been scant and yielded inconsistent results. This work aims to combine the findings of comparative studies of cognition in major depression and bipolar disorder in order to explore whether these neuropsychiatric conditions present with distinct cognitive features. METHODS: The main online databases were extensively searched to retrieve reports assessing neurocognitive functioning in two groups of mood disorder patients, one with major depressive disorder and another with bipolar disorder, both in the same phase of illness. Between-group effect sizes for cognitive variables were obtained from selected studies and pooled by means of meta-analytic procedures. RESULTS: During euthymia, a significant overall effect size (Hedges'g=0.64, P<0.001) favoring major depressive disorder was found for verbal memory as assessed with list learning tests, whereas no significant between-group differences were found for the remaining variables analyzed. During depressive episodes, similar cognitive outcomes were observed between groups. CONCLUSION: At present, it is not possible to postulate specific neuropsychological profiles for major depression and bipolar disorder in light of available evidence. It remains to be ascertained whether the differences found for verbal memory constitute an expression of distinct underlying mechanisms or whether they are best explained by sample characteristics or differential exposure to variables with a negative impact on cognition.

Complementary and alternative medicines usage in bipolar patients from Argentina and Colombia: associations with satisfaction and adherence to treatment.

BACKGROUND: The use of Complementary and Alternative Medicines (CAM) has been reported by around half the patients undergoing medical treatment for chronic conditions. CAM use could be higher in people affected by bipolar disorders (BD). Some questions about CAM use in BD have not been investigated enough. We report here the results of an anonymous survey on CAM-use conducted among BD outpatients of two centers located in Argentina and Colombia. METHODS: an anonymous self-survey was administrated to bipolar euthymic outpatients treated at each center. The survey included a self-report measure of adherence to psychiatric treatment and a modified version of CGI to asses satisfaction with the current treatment. RESULTS: 200 patients completed the survey. Although samples differ in socio-economic profile, they do not differ in their reported CAM-usage (more than 40%). CAM-usage did not modify the adherence or satisfaction with the psychiatric treatment reported level. Thirty eight percent of those who were still resorting to CAM failed to inform it to their clinician. CAM-usage was rated as "useful" or "very useful" by 52% of patients. LIMITS: adherence to current medical treatment and satisfaction with current treatment were investigated by a self-reported instrument. DISCUSSION: the prevalence of CAM usage found is similar to that of other studies. CAM usage seems to be ubiquitous, which takes to posit that a subgroup of patients may be in need of treatment with greater magical-religious components. Half of these patients were reluctant to disclose CAM use. Clinicians may need to consider coexistence between "traditional" treatments and CAM for these patients.

Dopamine sudden depletion as a model for mixed depression.

Up to date research on Bipolar Disorders' phenomenology is in keeping with early descriptions made by E. Kraëpelin regarding the overlap in clinical presentation of both manic and depressive symptoms, namely, mixed states. The latter constitute a highly prevalent and characteristic clinical presentation of Bipolar Disorders' and entail therapeutic difficulties, prognostic implications and increased suicidal risk. Notwithstanding, mixed states', more specifically mixed depression, have been underestimated and bypassed to the point where currently neither diagnostic criteria nor specific therapeutic recommendations are provided. In addition to the lack of agreement on nosography and diagnostic criteria, mixed depression is usually excluded from Bipolar Disorders' neurobiological models. Furthermore, renewed interest in the role of dopamine in Bipolar Disorders' physiopathology has left aside hypothesis that may account for the aforementioned clinical presentation. Interestingly enough, other syndromes arising from sudden dopamine depletion such as neuroleptic dysphoria or withdrawal syndromes from dopaminergic drugs, bear remarkable clinical similarities with mixed depression. These syndromes have been subject of further research and may thus provide a model for mixed states' physiopathology. Indeed, this article accounts for clinical similarities between mixed depression, neuroleptic induced dysphoria, and other behavioural syndromes arising from sudden dopamine depletion. After reviewing neurochemical basis of such syndromes we present, to the best of our knowledge, the first neurobiological hypothesis for mixed depression. Specifically, such hypothesis regards over activation symptoms as auto regulatory attempts to compensate for sudden dopaminergic depletion. This hypothesis provides with a beginning step for the neglected problem of mixed depression, a non-antithetic link between the dopaminergic hypothesis for both manic and depressive symptoms, a plausible explanation regarding inter individual variability to mixed depression susceptibility, and suggests new approaches for the development of novel treatments in which dopamine dysregulation should be targeted.