Giulio Perugi

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.

Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study.

CONTEXT Major depressive disorder, the most common psychiatric illness, is often chronic and a major cause of disability. Many patients with major depressive episodes who have an underlying but unrecognized bipolar disorder receive pharmacologic treatment with ineffective regimens that do not include mood stabilizers. OBJECTIVE To determine the frequency of bipolar disorder symptoms in patients seeking treatment for a major depressive episode. DESIGN Multicenter, multinational, transcultural, cross-sectional, diagnostic study. The study arose from the initiative Bipolar Disorders: Improving Diagnosis, Guidance and Education (BRIDGE). SETTING Community and hospital psychiatry departments. PATIENTS Participants included 5635 adults with an ongoing major depressive episode. MAIN OUTCOME MEASURES The frequency of bipolar disorder was determined by applying both DSM-IV-TR criteria and previously described bipolarity specifier criteria. Variables associated with bipolarity were assessed using logistic regression. RESULTS A total of 903 patients fulfilled DSM-IV-TR criteria for bipolar disorder (16.0%; 95% confidence interval, 15.1%-17.0%), whereas 2647 (47.0%; 95% confidence interval, 45.7%-48.3%) met the bipolarity specifier criteria. Using both definitions, significant associations (odds ratio > 2; P < .001) with bipolarity were observed for family history of mania/hypomania and multiple past mood episodes. The bipolarity specifier additionally identified significant associations for manic/hypomanic states during antidepressant therapy, current mixed mood symptoms, and comorbid substance use disorder. CONCLUSIONS The bipolar-specifier criteria in comparison with DSM-IV-TR criteria were valid and identified an additional 31% of patients with major depressive episodes who scored positive on the bipolarity criteria. Family history, illness course, and clinical status, in addition to DSM-IV-TR criteria, may provide useful information for physicians when assessing evidence of bipolarity in patients with major depressive episodes. Such an assessment is recommended before deciding on treatment.

Polarity of the first episode, clinical characteristics, and course of manic depressive illness: A systematic retrospective investigation of 320 bipolar I patients

In 320 patients with established bipolar I disorder, we examined the past course on the basis of polarity at onset (depressive, mixed, and manic). Despite the obvious limitations of retrospective methodology, information on course parameters in a large sample of affective disorders is most practically obtained by such methodology. We believe that our systematic interview of patients and their relatives--as well as the systematic study of their records--minimized potential biases. Depressive onsets were the most common, accounting for 50%, followed by mixed and manic onsets in about equal proportion. In general, the polarity of episodes over time reflected polarity at onset. Those with depressive onset had significantly higher levels of rapid cycling, as well as suicide attempts, but were significantly less likely to develop psychotic symptoms. Mixed onsets, too, had high rates of suicide attempts, but differed from depressive onsets in having significantly more chronicity yet negligible rates of rapid cycling at follow-up evaluation. Because cases with depressive onset had received significantly higher rates of psychopharmacologic treatment, our data are compatible with the hypothesis that antidepressants may play a role in the induction of rapid cycling. Overall, our data support the existence of distinct longitudinal patterns within bipolar I disorder, which in turn appear correlated with the polarity at onset. In particular, rapid cycling and mixed states emerge as distinct psychopathologic processes.

Psychopathology, Temperament, and Past Course in Primary Major Depressions. 1. Review of Evidence for a Bipolar Spectrum

In reviewing recent findings on affective conditions in the interface of unipolar and bipolar disorders, we find evidence favoring a partial return to Kraepelins broad concept of manic-depressive illness, which included many recurrent depressives and temperamental variants. This review addresses methodologic, clinical, and familial considerations in the definition and characterization of a proposed spectrum of bipolar disorders which subsumes episodic and chronic forms. Episodic bipolar disorders are subclassified into bipolar schizoaffective, and bipolar I and II, and bipolar III or pseudo-unipolar forms. Chronic bipolar disorders could be either intermittent or persistent, and are subclassified into chronic mania, protracted mixed states, and rapid-cycling forms, as well as the classical temperaments (cyclothymic, hyperthymic, irritable and dysthymic).

Depressive comorbidity of panic, social phobic, and obsessive–compulsive disorders re-examined: is there a bipolar ii connection?

Utilizing the DSM-III-R schema, we have investigated lifetime comorbidity between panic disorder with or without agoraphobia (PD), social phobia (SP) and obsessive-compulsive disorder (OCD) on the one hand, and mood disorder on the other. Compared with PD, the results for SP and OCD showed significantly higher numbers of comorbid anxiety and mood disorders. In addition, SP and OCD were significantly more likely to cooccur with each other than with PD. The complexity of these comorbid patterns is underscored by the finding of significantly higher numbers of anxiety disorders in those with lifetime comorbidity with bipolar (especially bipolar II) disorder. We conclude that the comorbidity between anxiety and mood disorders - conventionally conceived as the relationship between anxiety and unipolar depressive states -- might very well extend into the domain of bipolar spectrum disorders in a subset of these disorders. Among the latter, the spontaneous or antidepressant-induced switches into brief disinhibited (hypomanic) behavior can be conceptualized to lie on a dimensional continuum with the temperamental inhibition (or constraint) underlying the anxiety disorders under discussion. These findings and theoretical considerations have important therapeutic implications.

Psychopathology, Temperament, and Past Course in Primary Major Depressions. 2. Toward a Redefinition of Bipolarity with a New Semistructured Interview for Depression

We report on the utility of a new instrument to identify subtypes of major depressive episodes with special reference to pseudo-unipolar conditions. By incorporating reliable measures of depressive and hyperthymic temperamental characteristics in subtype definitions, we achieve the sharpest possible demarcation between unipolar and bipolar disorders. The new procedures also reveal that 1 out of 3 primary depressives in a consecutive series of 405 patients belong to the bipolar spectrum. Furthermore, among bipolars, bipolar II disorder (redefined as major depressions with hypomania or hyperthymic temperament) represents the most common variant. We discuss the nosologic, therapeutic, methodologic and theoretical implications of these considerations on the unipolar-bipolar dichotomy. Given that major depression emerges as the final common clinical expression of a heterogeneous group of disorders, it underscores the importance of focusing on temperament and course of illness in subclassification efforts such as attempted here.

QTc Interval Prolongation in Patients on Long-Term Methadone Maintenance Therapy

Objective: The aim of the present study was to assess the incidence of abnormal QTc interval values in a population of subjects on a long-term methadone maintenance treatment, as a single therapy, and with methadone dosages ranging between 10 and 600 mg/daily (mean ± SD = 87 ± 76). Method: Basal ECG recordings were carried out in 83 former heroin addicts on long-term successful methadone maintenance therapy for at least 6 months, while no other known QT-prolonging agent was being administered. Results: Eighty-three percent of the subjects had a more prolonged QT interval than the reference values for persons of the same sex and age. Only 2 patients displayed a QTc interval of >500 ms. No correlation emerged between QTc values and methadone dosages. Conclusion: Patients on long-term methadone maintenance treatment show longer than expected QTc interval values. This data, associated with the finding that methadone is a rather potent inhibitor of HERG potassium channels and that it may induce torsade de pointes in predisposed subjects, supports the recommendation that patients entering methadone treatment (MT) are screened for cardiac risk factors. ECG might be considered in ongoing MT patients especially before starting QT-prolonging medications.

Gender-related differences in body dysmorphic disorder (Dysmorphophobia)

Body Dysmorphic Disorder (BDD), which consists of pathological preoccupations with defects in different body parts, has been systematically studied only in the last decade. We hypothesized that gender would differentially influence the localization of the preoccupations as well as the extent and type of comorbidity with other psychiatric disorders. With the use of a specially constructed semistructured interview, we evaluated 58 consecutive outpatients with DSM-III-R BDD (women = 41.4%, men = 58.6%). Women had significantly more preoccupations with breast and legs, checking in the mirror and camouflaging, as well as lifetime comorbidity with panic, generalized anxiety, and bulimia. Men had significantly higher preoccupations with genitals, height, excessive body hair, as well as higher lifetime comorbidity with bipolar disorder. Although BDD is almost never found without comorbidity, it does appear to be an autonomous syndrome, and gender tends to influence the nature and extent of this comorbidity.

ANXIOUS–BIPOLAR COMORBIDITY: Diagnostic and Treatment Challenges

This article describes multiple anxiety comorbidity in the setting of unstable bipolar syndromes, associated with alcohol and substance abuse. Also described are panic attacks during mania, social phobia followed by hypomania as well as bipolar disorder manifesting as episodic obsessive-compulsive disorder. The use of psychotropic combinations is necessary because of the syndromic complexity and the contrasting effects of pharmacologic treatments. The identification of differential patterns of comorbidity may provide important information in distinguishing more homogeneous clinical subtypes of affective disorders from the genetic, temperamental, and therapeutic point of view. The pattern of complex relationships among these disorders requires better-designed prospective observations. This is also true for putative temperamental (e.g. cyclothymia, interpersonal sensitivity) and personality (e.g. histrionic and borderline) factors, which might play a predisposing role in several clinically comorbid syndromes.

Prevalence of psychiatric disorders in thyroid diseased patients.

Several studies have underlined the high prevalence of psychiatric symptoms and disorders in thyroid diseases. The aim of this study was to evaluate the prevalence of psychiatric disorders in 93 inpatients affected by different thyroid diseases during their lifetimes, by means of a standardized instrument, i.e., the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-III-Revised, Upjohn Version (SCID-UP-R). The results showed higher rates of panic disorder, simple phobia, obsessive-compulsive disorder, major depressive disorder, bipolar disorder and cyclothymia in thyroid patients than in the general population. These findings would suggest that the co-occurrence of psychiatric and thyroid diseases may be the result of common biochemical abnormalities.