Gustavo H. Vázquez

The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders

OBJECTIVE The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. METHOD An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. RESULTS There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. CONCLUSIONS Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

Mania associated with antidepressant treatment: comprehensive meta-analytic review

Tondo L, Vázquez G, Baldessarini RJ. Mania associated with antidepressant treatment: comprehensive meta‐analytic review.

Staging systems in bipolar disorder: an International Society for Bipolar Disorders Task Force Report.

We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined.

Predominant recurrence polarity among 928 adult international bipolar I disorder patients

Baldessarini RJ, Undurraga J, Vázquez GH, Tondo L, Salvatore P, Ha K, Khalsa H‐MK, Lepri B, Ha TH, Chang JS, Tohen M, Vieta E. Predominant recurrence polarity among 928 adult international bipolar I disorder patients.

Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: A review

OBJECTIVES Compare reported rates of mood-shifts from major depression to mania/hypomania/mixed-states during antidepressant (AD)-treatment and rates of diagnostic change from major depressive disorder (MDD) to bipolar disorder (BPD). METHODS Searching computerized literature databases, followed by summary analyses. RESULTS In 51 reports of patients diagnosed with MDD and treated with an AD, the overall risk of mood-switching was 8.18% (7837/95,786) within 2.39 ± 2.99 years of treatment, or 3.42 (95% CI: 3.34-3.50) %/year. Risk was 2.6 (CI: 2.5-2.8) times greater with/without AD-treatment by meta-analysis of 10 controlled trials. Risk increased with time up to 24 months of treatment, with no secular change (1968-2012). Incidence rates were 4.5 (CI: 4.1-4.8)-times greater among juveniles than adults (5.62/1.26 %/year; p<0.0001). In 12 studies the overall rate of new BPD-diagnoses was 3.29% (1928/56,754) within 5.38 years (0.61 [0.58-0.64] %/year), or 5.6-times lower (3.42/0.61) than annualized rates of mood-switching. CONCLUSIONS AD-treatment was associated with new mania-like responses in 8.18% of patients diagnosed with unipolar MDD. Contributions to mood-switching due to unrecognized BPD versus mood-elevating pharmacological effects, as well as quantitative associations between switching and later diagnosis of BPD not associated with AD-treatment remain uncertain. LIMITATIONS Rates and definitions of mood-switching with ADs varied greatly, exposure-times rarely were precisely defined, and there was little information on predictive associations between mood-switches and BPD-diagnosis.

Age at onset versus family history and clinical outcomes in 1,665 international bipolar-I disorder patients

Early onset in bipolar disorder (BPD) has been associated with greater familial risk and unfavorable clinical outcomes. We pooled data from seven international centers to analyze the relationships of family history and symptomatic as well as functional measures of adult morbidity to onset age, or onset in childhood (age <12), adolescence (12-18), or adulthood (19-55 years). In 1,665 adult, DSM-IV BPD-I patients, onset was 5% in childhood, 28% in adolescence, and 53% at peak ages 15-25. Adolescent and adult onset did not differ by symptomatic morbidity (episodes/year, percentage of months ill, co-morbidity, hospitalization, suicide attempts) or family history. Indications of favorable adult functional outcomes (employment, living independently, marriage and children, and a composite measure including education) ranked, by onset: adult > adolescent > child. Onset in childhood versus adolescence had more episodes/year and more psychiatric co-morbidity. Family history was most prevalent with childhood onset, similar over onset ages 12-40 years, and fell sharply thereafter. Multivariate modeling sustained the impression that family history and poor functional, but not symptomatic, outcomes were associated with younger, especially childhood onset. Early onset was more related to poor functional outcomes than greater symptomatic morbidity, with least favorable outcomes and greater family history with childhood onset.

Stigma and functioning in patients with bipolar disorder

OBJECTIVE The aim of this study was to investigate the impact of self-rated stigma and functioning in patients with bipolar disorder in Latin-America. METHODS Two-hundred and forty-one participants with bipolar disorder were recruited from three Latin American countries (Argentina, Brazil, and Colombia). Functional impairment was assessed with the Functioning Assessment Short Test (FAST) and experiences with and impact of perceived stigma was evaluated using the Inventory of Stigmatizing Experiences (ISE). RESULTS Higher scores of self-perceived stigma were correlated with lower scores of functioning. After multiple regression analysis, being on disability benefit, current mood symptoms and functioning were associated with self-perceived stigma. CONCLUSIONS This is the first study to demonstrate an association between stigma and poor functioning in bipolar disorder. Possible implications of such findings for practitioners are discussed. LIMITATIONS The main limitation of this study is that the Inventory of Stigmatizing Experiences has not yet been validated in a population of bipolar patients in our countries. The sample size and heterogeneous clinical subjects from different countries and cultures limit the generalization of the present findings.

Functional impairment in bipolar II disorder: Is it as disabling as bipolar I?

INTRODUCTION It is well established that patients with bipolar disorder experience functional impairment even in remission. Nevertheless, bipolar II disorder remains understudied because most investigations to date include only bipolar I patients or just a small sample of bipolar II patients, without explicitly comparing both subtypes of disorder. The main objective of the current report is to evaluate overall and multiple domains of functioning, specifically in bipolar II disorder compared to patients with bipolar I disorder and healthy subjects. METHODS 233 subjects from 3 groups were compared: bipolar I patients (n=106), bipolar II patients (n=66) and healthy controls (n=61). Bipolar patients meeting criteria of remission were recruited at the Hospital Clinic of Barcelona and at different study sites in Argentina. All participants were assessed with 17-item Hamilton Depression Rating Scale (HAM-D), Young Mania Rating Scale (YMRS) and the Functioning Assessment Short Test (FAST). Clinical and sociodemographic data were also recorded. RESULTS Both subgroups of patients, bipolar I and bipolar II, showed lower overall functioning (p<0.001) and in each domain of the FAST scale (all, p<0.001) when compared to the healthy control group. Tukey post hoc test revealed that bipolar II patients scored worse in the cognitive domain compared to bipolar I patients. However, after controlling for potential confounding variables, this difference disappeared and only older age (p<0.005) and HAM-D scores (p<0.001) remained significant. CONCLUSIONS Our results suggest that bipolar II patients are as disabled as bipolar I patients. This may be explained, in part, because bipolar II patients experience greater lifetime residual depressive symptoms than the bipolar I subgroup, which may have particular impact on cognitive domains of functioning.

Predominant polarity and temperament in bipolar and unipolar affective disorders

INTRODUCTION Recently, the concept of predominant polarity (two-thirds of episodes belonging to a single pole of the illness) has been introduced to further characterise subtypes of bipolar disorders. This concept has been proven to have diagnostic and therapeutic implications, but little is known on the underlying psychopathology and temperaments. With this study, we aimed to further validate the concept and explore its relationships with temperament. METHODS This study enrolled 143 patients with bipolar or unipolar disorder. We analysed predominant polarity in the sample of bipolar I patients (N=124), focussing on those who showed a clear predominance for one or the other polarity, and distinguishing manic/hypomanic (MP) from depressive polarity (DP), and a unipolar major depression (UP) group (N=19),. We also assessed temperament by means of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A). RESULTS Over 55% of the bipolar I sample fulfilled predominant polarity criteria, with two-thirds of those meeting criteria for MP and one third for DP. MP and DP were similar in scoring higher than UP on the hyperthymic/cyclothymic scales of the TEMPS-A; the UP group scored higher on the anxious/depressive scales. DISCUSSION Our results show that both bipolar I MP and DP subgroups are temperamentally similar and different from UP. Depression in DP bipolar I patients should be viewed as the overlap of depression on a hyperthymic/cyclothymic temperament. These findings confirm the value of the predominant polarity concept as well as the importance of temperaments to separate bipolar from unipolar disorders.

Treatments for Acute Bipolar Depression: Meta- analyses of Placebo-controlled, Monotherapy Trials of Anticonvulsants, Lithium and Antipsychotics

BACKGROUND Optimal treatments for bipolar depression, and the relative value of specific drugs for that purpose, remain uncertain, including agents other than antidepressants. METHODS We searched for reports of placebo-controlled, monotherapy trials of mood-stabilizing anticonvulsants, second-generation antipsychotics, or lithium for acute major depressive episodes in patients diagnosed with type I or II bipolar disorder and applied random-effects meta-analysis to evaluate their efficacy, comparing outcomes based on standardized mean drug-placebo differences (SMD) in improvement, relative response rates (RR), and number-needed-to-treat (NNT). RESULTS We identified 24 trials of 10 treatments (lasting 7.5 weeks, with ≥ 50 collaborating sites/trial) that met eligibility criteria: lamotrigine (5 trials), quetiapine (5), valproate (4), 2 each for aripiprazole, olanzapine, ziprasidone, and 1 each for carbamazepine, lithium, lurasidone, and olanzapine-fluoxetine. Overall, pooled drug-over-placebo responder-rate superiority (RR) was moderate (29% [CI: 19-40%]), and NNT was 8.2 (CI: 6.4-11). By SMD, apparent efficacy ranked: olanzapine + fluoxetine ≥ valproate > quetiapine > lurasidone > olanzapine, aripiprazole, and carbamazepine; ziprasidone was ineffective, and lithium remains inadequately studied. Notably, drugs were superior to placebo in only 11/24 trials (5/5 with quetiapine, 2/4 with valproate), and only lamotrigine, quetiapine and valproate had > 2 trials. Treatment-associated mania-like reactions were uncommon (drugs: 3.7%; placebo: 4.7%). DISCUSSION Controlled trials of non-antidepressant treatments for bipolar depression remain scarce, but findings with olanzapine-fluoxetine, lurasidone, quetiapine, and perhaps carbamazepine and valproate were encouraging; lithium requires adequate testing.