A.M.A. Nivoli

New treatment guidelines for acute bipolar mania: A critical review

A number of treatment guidelines for bipolar disorder have been published and updated in the last few years. They are aimed at providing a synthesis of the best available scientific knowledge, and their application to every-day work should be helpful to clinicians. The aim of this report is to critically review recent guidelines focusing on the treatment of manic/hypomanic and mixed episodes. Guidelines are quite heterogeneous in methodology and conclusions, but they all agree that the treatment of manic/hypomanic and mixed episodes should generally be initiated with a medication such as lithium (Li), valproate (VPA) or atypical antipsychotics (AAP), including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone as monotherapy. All guidelines agree on stopping ongoing antidepressant medication during mania. Combination therapy including Li or VPA with an AAP is suggested usually as second-line choice, sometimes as first-choice treatment for severe mania. Carbamazepine is mostly suggested as second line and not recommended in combination. Other antiepileptic drugs are not recommended for the treatment of mania, although lamotrigine may be maintained if it was prescribed previously for the prevention of depressive episodes. Main sources of discrepancies among guidelines include benefit-risk ratio issues (how much priority is given to efficacy over safety and tolerability), starting with combination versus monotherapy, and how to deal with treatments which are more experience-based than evidence-based (i.e.: electroconvulsive therapy).

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.

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.

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.

Lithium: Still a Cornerstone in the Long-Term Treatment in Bipolar Disorder?

Background: Scientific literature considers lithium a key treatment for the acute and long-term management of bipolar disorder (BD). Despite its worldwide clinical use, the effectiveness of lithium has been questioned. The aim of this work is to critically review the available data on randomized controlled trials (RCTs) concerning long-term lithium treatment. Methods: A systematic search for long-term treatment RCTs with at least 6 months of follow-up was performed. Six RCTs enrolling 1,561 bipolar I and II patients of adult and pediatric age, randomizing 534 to lithium, were identified. All studies are controlled trials sponsored by industry, investigating new treatments for BD, with lithium as an active comparator, and therefore not specifically designed to study lithium efficacy or safety. Results: Results from earliest studies suggest a high effectiveness of lithium against both mania and depression, while more recent studies highlight lithium as more effective than placebo in mania and hypomania, without significant evidence in depression. Lithium does not achieve significant differences in efficacy when compared with divalproex; it seems less effective than lamotrigine in preventing depression and less effective than olanzapine in manic and mixed episodes. Conclusions: Despite a number of methodological issues (enriched designs, unbalanced samples, potential inclusion of lithium nonresponders in some studies), lithium appears to have a clear antimanic prophylactic activity and some efficacy in the prevention of depression. Lithium should still have a major role in the long-term treatment of BD.

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.

What we know and what we don't know about the treatment of schizoaffective disorder

Schizoaffective disorder (SAD) is a chronic, severe and disabling illness consisting on the concurrent presentation of symptoms of schizophrenia and affective disorders (depression and/or mania). Evidence for the treatment of SAD mostly derives from studies based on mixed samples (i.e. schizophrenic and schizoaffective patients) or on extrapolations from studies on schizophrenia or bipolar disorder. The objective of the present review is to systematically consider and summarize the best evidence-based approaches to the treatment of SAD and extensively point out the gap between treatment research and clinical practice of this disorder. The complex problem of controlling the pleomorphic presentation of SADs syndromic construct is reflected in the lack of evidence on key topics, including: diagnostic consistency, pharmacological approaches (mood stabilizers, antidepressants, both in acute and maintenance treatment as well as their possible combination), and the adjunctive role of psychosocial and biophysical interventions. Finally, treatment strategies for SAD, both unipolar and bipolar type, are proposed.

Factors associated with initial treatment response with antidepressants in bipolar disorder.

INTRODUCTION Controversy in antidepressant (AD) use in bipolar depression relies in its potential induction of mood switches and ineffectiveness. Responders to acute AD add-on treatment maintain response with continued treatment, whilst partial/non-responders fail to reach remission despite continuation treatment. We aimed to identify response predictors to acute AD addition in bipolar depression in order to optimize treatment choice in bipolar depression and avoid unnecessary AD exposure of people unlikely to respond. METHODS Two hundred and twenty-one DSM-IV-TR depressed bipolar - type I and II - patients were treated with AD on an observational study. AD response was defined as an at least 50% drop from baseline of their HDRS17 score after 8weeks of treatment. One hundred and thirty-eight patients (138, 62.4%) fulfilled response criteria (RI) whilst 83 patients (37.6%) did not (NRI). In all cases AD therapy was on top of previously prescribed stabilizers and/or atypical antipsychotics. RESULTS RI patients were more likely to have had previous response to ADs, whereas NRI had a higher number of previous mood switches with ADs during past depressive episodes. Psychotic symptoms were more frequent amongst RI, whilst lifetime history of atypical depression was more frequent amongst NRI. NRI had more total, depressive, and hypomanic, but not manic or mixed, episodes in the past than RI. Analyzed through a logistic regression, higher previous response to ADs and lower rate of past hypomanic episodes in RI were the variables explaining intergroups (RI vs. NRI) differences. DISCUSSION Taking into account the proper caution in the use of Ads in bipolar disorder, there is a subgroup of bipolar patients who might benefit from adjunctive Ads. Looking at specific clinical factors during the course of the illness could help physicians in deciding whether to use an antidepressant in a bipolar depressed patient already treated with mood stabilizers.

Psychotic versus non-psychotic bipolar II disorder

INTRODUCTION Psychotic symptoms in bipolar II disorder, allowed by definition only during a depressive episode, are present in a range between 3% and 45%. Little is known regarding the impact of psychotic symptoms on the clinical course of bipolar II patients. Findings from previous reports are controversial and focused specifically on bipolar I disorder. The aim of this study was to ascertain the clinical characteristics of individuals with bipolar II disorder with and without lifetime history of psychotic symptoms. METHODS The sample consisted of 164 DSM-IV Bipolar II patients consecutively recruited from the Barcelona Bipolar Disorder Program. Patients were divided in Bipolar II patients with (N=32) and without (N=132) lifetime history of psychotic symptoms. Clinical and sociodemographic features were compared. RESULTS Thirty-two out of 164 patients with bipolar II disorder had a history of psychosis during depression (19.5%). Bipolar II patients with a history of psychotic symptoms showed a higher number of hospitalizations than patients without such a history (p<0.001). They were also older but were less likely to have a family history of bipolar illness and any mental disorder than non-psychotic bipolar II patients. Melancholic and catatonic features were significantly more frequent in psychotic bipolar II patients (p<0.001). CONCLUSIONS Our findings confirm that the presence of psychotic symptoms in bipolar II disorder is not rare. Psychotic bipolar II disorder may be a different phenotype from non-psychotic bipolar disorder.

Bipolar disorder in the elderly: a cohort study comparing older and younger patients.

The purpose of this study was to analyze differences in clinical and socio‐demographic characteristics between older and younger bipolar outpatients paying special attention to depressive symptoms in a large, naturalistic cohort.