Marc Valentí

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.

Efficacy of modern antipsychotics in placebo-controlled trials in bipolar depression: a meta-analysis

Randomized, controlled trials have demonstrated efficacy for second-generation antipsychotics in the treatment of acute mania in bipolar disorder. Despite depression being considered the hallmark of bipolar disorder, there are no published systematic reviews or meta-analyses to evaluate the efficacy of modern atypical antipsychotics in bipolar depression. We systematically reviewed published or registered randomized, double-blind, placebo-controlled trials (RCTs) of modern antipsychotics in adult bipolar I and/or II depressive patients (DSM-IV criteria). Efficacy outcomes were assessed based on changes in the Montgomery-Asberg Depression Rating Scale (MADRS) during an 8-wk period. Data were combined through meta-analysis using risk ratio as an effect size with a 95% confidence interval (95% CI) and with a level of statistical significance of 5% (p<0.05). We identified five RCTs; four involved antipsychotic monotherapy and one addressed both monotherapy and combination with an antidepressant. The two quetiapine trials analysed the safety and efficacy of two doses: 300 and 600 mg/d. The only olanzapine trial assessed olanzapine monotherapy within a range of 5-20 mg/d and olanzapine-fluoxetine combination within a range of 5-20 mg/d and 6-12 mg/d, respectively. The two aripiprazole placebo-controlled trials assessed doses of 5-30 mg/d. Quetiapine and olanzapine trials (3/5, 60%) demonstrated superiority over placebo (p<0.001). Only 2/5 (40%) (both aripiprazole trials) failed in the primary efficacy measure after the first 6 wk. Some modern antipsychotics (quetiapine and olanzapine) have demonstrated efficacy in bipolar depressive patients from week 1 onwards. Rapid onset of action seems to be a common feature of atypical antipsychotics in bipolar depression.

Gender differences in a cohort study of 604 bipolar patients: The role of predominant polarity

BACKGROUND Some clinical differences between gender regarding the course and outcome of bipolar disorders have already been described and some others remain still controversial. AIMS To explore gender differences regarding clinical and socio-demographic characteristics amongst bipolar patients with particular attention to predominant polarity and depressive symptoms. METHOD Data were collected from DSM-IV type I and II bipolar patients (n=604), resulting from the systematic follow-up of the Bipolar Disorders Program, Hospital Clinic of Barcelona, over an average follow-up of 10 years. Socio-demographic and clinical variables were collected in order to detect gender-related differences. RESULTS Bipolar women are more likely than men to show a predominance of depressive polarity as well as a depressive onset whilst men would be more likely to suffer from comorbid substance use disorders. Women significantly have a higher lifetime prevalence of psychotic depression and a higher prevalence of axis II comorbid disorders. Bipolar women are also more likely to have a family history of suicide and a lifetime history of attempted suicide. Suicide attempts are more often violent amongst bipolar men. In a backward logistic regression model, two variables were responsible for most gender-related clinical differences: type of predominant polarity - more likely to be depressive amongst women - (B=-0.794, p=0.027, Exp(B)=0.452; CI= 0.223-0.915), alcohol abuse (B=-1.095, p=0.000, Exp(B)=2990; CI= 1.817-4.919) and cocaine abuse (B=0.784, p=0.033, Exp(B)=2.189; CI= 1.066-4.496) - more prevalent amongst men. CONCLUSION The main characteristic featuring bipolar women is depression, both at illness onset and as a predominant polarity all along the illness course. This may have important diagnostic and therapeutic implications.

Treatment of bipolar disorder: a complex treatment for a multi-faceted disorder.

BackgroundManic-depression or bipolar disorder (BD) is a multi-faceted illness with an inevitably complex treatment.MethodsThis article summarizes the current status of our knowledge and practice of its treatment.ResultsIt is widely accepted that lithium is moderately useful during all phases of bipolar illness and it might possess a specific effectiveness on suicidal prevention. Both first and second generation antipsychotics are widely used and the FDA has approved olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole for the treatment of acute mania. These could also be useful in the treatment of bipolar depression, but only limited data exists so far to support the use of quetiapine monotherapy or the olanzapine-fluoxetine combination. Some, but not all, anticonvulsants possess a broad spectrum of effectiveness, including mixed dysphoric and rapid-cycling forms. Lamotrigine may be effective in the treatment of depression but not mania. Antidepressant use is controversial. Guidelines suggest their cautious use in combination with an antimanic agent, because they are supposed to induce switching to mania or hypomania, mixed episodes and rapid cycling.ConclusionThe first-line psychosocial intervention in BD is psychoeducation, followed by cognitive-behavioral therapy. Other treatment options include Electroconvulsive therapy and transcranial magnetic stimulation. There is a gap between the evidence base, which comes mostly from monotherapy trials, and clinical practice, where complex treatment regimens are the rule.

Suicidal Risk Factors in Bipolar I and II Disorder Patients

BACKGROUND Suicidal risks may be similar in bipolar I and II disorders, but predictive risk factors are not well established for each disorder type or across cultures. METHOD Accordingly, we compared selected demographic and clinical factors for long-term association with nonlethal suicidal acts or ideation in 290 DSM-IV bipolar I (n = 204) and II (n = 86) disorder patients followed for a mean of 9.3 years at the University of Barcelona, using preliminary bivariate comparisons followed by multivariate logistic regression modeling. RESULTS Rates of suicidal ideation (41.5%) and acts (19.7%) were similarly prevalent with bipolar I and II disorders and somewhat more common among women. Factors significantly and independently associated with suicidal acts were determined by multivariate modeling and ranked in order of their strength of association: suicidal ideation, more mixed episodes, Axis II comorbidity, female sex, more antidepressant trials, rapid cycling, predominant lifetime depression, having been hospitalized, older onset, and longer delay of diagnosis. Suicidal ideation was associated with suicidal acts, more antidepressant trials, predominant depressions, more mixed-episodes/year, depressive first-lifetime episodes, electroconvulsive therapy use, delay of bipolar disorder diagnosis, unemployment, melancholic features, Axis II disorders, rapid cycling, and more depressions per year. Risk factors selectively associated with suicidal risk, overall, included more mixed-states per year and melancholic features, whereas hospitalization, unemployment, and predominantly depressive recurrences were more characteristic of diagnostic subtypes. CONCLUSIONS Suicidal risk-factors found to be independent of bipolar disorder diagnostic subtype included mixed-states, melancholic depressive features, and more antidepressant trials.

Pharmacological Management of Bipolar Depression: Acute Treatment, Maintenance, and Prophylaxis

Although the most distinctive clinical feature of bipolar disorder is the pathologically elevated mood, it does not usually constitute the prevalent mood state of bipolar illness. The majority of patients with bipolar disorder spend much more time in depressive episodes, including subsyndromal depressive symptoms, and bipolar depression accounts for the largest part of the morbidity and mortality of the illness. The pharmacological treatment of bipolar depression mostly consists of combinations of at least two drugs, including mood stabilizers (lithium and anticonvulsants), atypical antipsychotics, and antidepressants. Antidepressants are the most frequently prescribed drugs, but recommendations from evidence-based guidelines are not conclusive and do not overtly support their use. Among antidepressants, best evidence exists for fluoxetine, but in combination with olanzapine. Although some guidelines recommend the use of selective serotonin reuptake inhibitors or bupropion in combination with antimanic agents as first-choice treatment, others do not, based on the available evidence. Among anticonvulsants, the use of lamotrigine is overall recommended as a first-line choice, but acute monotherapy studies have failed. Valproate is generally mentioned as a second-line treatment. Lithium monotherapy is also suggested by most guidelines as a first-line treatment, but its efficacy in acute use is not totally clear. Amongst atypical antipsychotics, quetiapine, in monotherapy or as adjunctive treatment, is recommended by most guidelines as a first-line choice. Olanzapine monotherapy is also suggested by some guidelines and is approved in Japan. Armodafinil, pramipexole, ketamine, and lurasidone are recent proposals. Long-term treatment in bipolar disorder is strongly recommended, but guidelines do not recommend the use of antidepressants as a maintenance treatment. Lithium, lamotrigine, valproate, olanzapine, quetiapine, and aripiprazole are the recommended first-line maintenance options.

Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients.

Valentí M, Pacchiarotti I, Rosa AR, Bonnín CM, Popovic D, Nivoli AMA, Murru A, Grande Í, Colom F, Vieta E. Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients.
Bipolar Disord 2011: 13: 145–154.

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.

Risk factors for antidepressant-related switch to mania.

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.

Differential outcome of bipolar patients receiving antidepressant monotherapy versus combination with an antimanic drug

INTRODUCTION Despite antidepressants are widely used in treating bipolar depression, there is much debate about their utility and their potential dangers, involving mood switches and suicidality. Our hypothesis was that the pattern of initial antidepressant prescription, i.e., alone (AM) or in combination with stabilizers (AC) might impact the long-term outcome of patients with bipolar disorder (BP). We aimed to test this hypothesis and to identify outcome measures that could be predicted by initial AM or AC treatment in patients with BP. METHODS We included 95 patients with DSM-IV BP from a pool of 138 patients following a BP program. Patients were rated for initial AM vs. AC treatment when they were first seen in primary care and subdivided into two groups accordingly. Differences in their clinical course were sought investigating course both retrospectively and prospectively (mean follow-up 10 years). Primary outcome measures comprised suicidality and switch rate. RESULTS There were significantly more patients who switched in the AM group than in the AC group. The number of suicide attempts was higher in the AM group. Significance was retained after performing logistic regression. LIMITATIONS Sample size was small and severe BP patients might be overrepresented in this sample. DISCUSSION Initial AM treatment of patients subsequently diagnosed as BP may entrain a course characterized by higher proneness to switch and suicidal behaviour. Accurate initial diagnosis of bipolar depression should prompt combined treatment with antimanic drugs.