Mauricio Tohen

Textbook in psychiatric epidemiology.

Contributors.Preface.PART I: STUDY DESIGNS AND METHODS.Chapter 1. Introduction to Epidemiologic Research Methods (J. Fleming and C.-C. Hsieh).Chapter 2. Analysis of Categorized Data: Use of the Odds ratio as a Measure of Association (S. Hillis and R. Woolson).Chapter 3. Methods in Psychiatric Genetics (S. Faraone, et al.).Chapter 4. Reliability (P. Shrout).Chapter 5. Validity: Definitions and Applications to Psychiatric Research (J. Goldstein and J. Simpson).Chapter 6. Mental Health Services Research (J. Burke, Jr.).Chapter 7. The Pharmacoepidemiology of Psychiatric Medications (P. Wang, et al.).Chapter 8. Peering into the Future of Psychiatric Epidemiology (E. Susser, et al.).PART II: ASSESSMENT.Chapter 9. Studying the Natural History of Psychopathology (W. Eaton).Chapter 10. The Developmental Edpidemiology of Psychiatric Disorder (M. Cannon, et al.).Chapter 11. Birth and Development of Psychiatric Interviews (L. Robins).Chapter 12. Symptom Scales and Diagnostic Schedules in Adult Psychiatry (J. Murphy).Chapter 13. DSM-IV and Psychiatric Epidemiology (M. First).Chapter 14. The National Comorbidity Survey (R. Kessler and E. Walters).PART III: EPIDEMIOLOGY OF MAJOR PSYCHIATRIC DISORDERS.Chapter 15. Epidemiology of Psychosis with Special Reference to Schizophrenia (E. Bromet, et al.).Chapter 16. Epidemiology of Depressive and Anxiety Disorders (E. Horwath, et al.).Chapeter 17. Epidemiology of Bipolar Disorder (M. Tohen and J. Angst).Chapter 18. The Epidemiology of First-Onset Mania (T. Lloyd and P. Jones).Chapter 19. Epidemiology of Alcohol Use, Abuse, and Dependence (N. Day and G. Homish).Chapter 20. Epidemiology of Drug Dependence (J. Anthony, with J. Helzer).Chapter 21. Personality Disorders: Epidemiological Findings, Methods and Concepts (M. Lyons and B. Jerskey).PART IV: EPIDEMIOLOGY OF SPECIAL POPULATIONS.Chapter 22. Epidemiology and Geriatric Psychiatry (C. Hybels and D. Blazer).Chapter 23. The Epidemiology of Child and Adolescent Mental Disorder (S. Buka, et al.).Chapter 24. Epidemiology of Mood and Anxiety Disorders in Children and Adolescents (K. Merikangas and S. Avenevoli).Index.

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.

The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders.

OBJECTIVES Via an international panel of experts, this paper attempts to document, review, interpret, and propose operational definitions used to describe the course of bipolar disorders for worldwide use, and to disseminate consensus opinion, supported by the existing literature, in order to better predict course and treatment outcomes. METHODS Under the auspices of the International Society for Bipolar Disorders, a task force was convened to examine, report, discuss, and integrate findings from the scientific literature related to observational and clinical trial studies in order to reach consensus and propose terminology describing course and outcome in bipolar disorders. RESULTS Consensus opinion was reached regarding the definition of nine terms (response, remission, recovery, relapse, recurrence, subsyndromal states, predominant polarity, switch, and functional outcome) commonly used to describe course and outcomes in bipolar disorders. Further studies are needed to validate the proposed definitions. CONCLUSION Determination and dissemination of a consensus nomenclature serve as the first step toward producing a validated and standardized system to define course and outcome in bipolar disorders in order to identify predictors of outcome and effects of treatment. The task force acknowledges that there is limited validity to the proposed terms, as for the most part they represent a consensus opinion. These definitions need to be validated in existing databases and in future studies, and the primary goals of the task force are to stimulate research on the validity of proposed concepts and further standardize the technical nomenclature.

Structural brain abnormalities in first-episode mania.

Using magnetic resonance imaging (MRI), we studied brain morphometric differences between patients with first-episode mania (n = 17) and normal control subjects (n = 16). Patients were admitted for their first psychiatric hospitalization and met DSM-III-R criteria for bipolar disorder, manic or mixed. Diagnoses were made using the Structured Clinical Interview for DSM-III-R. Patients and control subjects were matched for age, gender, height, past history of substance abuse, and handedness, although control subjects had attained higher levels of education. MRI inversion recovery coronal scans were used for measurements. Volumetric measurements were obtained for cerebral hemispheres, lateral and third ventricles, caudate, thalamus, and cingulate gyrus. Patients with first-episode mania demonstrated significantly larger third-ventricular volumes, possibly increased lateral ventricular volumes, and differences in gray/white matter distribution compared with normal control subjects. The possible pathophysiological meaning of these findings is discussed.

A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania.

There are no rapid-acting intramuscular formulations of atypical antipsychotics available for quickly calming an agitated patient with bipolar disorder. In this study, 201 agitated patients with bipolar mania were randomly assigned to receive one to three injections of the atypical antipsychotic olanzapine (10 mg, first two injections; 5 mg, third injection), the benzodiazepine lorazepam (2 mg, first two injections; 1 mg, third injection), or placebo (placebo, first two injections; olanzapine, 10 mg, third injection) within a 24-hour period. Agitation was measured at baseline, every 30 minutes for the first 2 hours, and at 24 hours after the first injection using the Positive and Negative Syndrome Scale–Excited Component subscale and two additional agitation scales. At 2 hours after the first injection, patients treated with olanzapine showed a significantly greater reduction in scores on all agitation scales compared with patients treated with either placebo or lorazepam. At 24 hours after the first injection, olanzapine remained statistically superior to placebo in reducing agitation in patients with acute mania, whereas patients treated with lorazepam were not significantly different from those treated with placebo or olanzapine. Furthermore, no significant differences among the three treatment groups were observed in safety measures, including treatment-emergent extrapyramidal symptoms, the incidence of acute dystonia, or QTc interval changes. These findings suggest that intramuscular olanzapine is a safe and effective treatment for reducing acute agitation in patients with bipolar mania.

A prospective open-label treatment trial of olanzapine monotherapy in children and adolescents with bipolar disorder

OBJECTIVE The goal of this study was to assess the effectiveness and tolerability of olanzapine in the treatment of acute mania in children and adolescents. METHODS This was an 8-week, open-label, prospective study of olanzapine monotherapy (dose range 2.5-20 mg/day) involving 23 bipolar youths (manic, mixed, or hypomanic; 5-14 years old). Weekly assessments were made using the Young Mania Rating Scale (YMRS), Clinical Global Impressions Severity Scale (CGI-S), Brief Psychiatric Rating Scale, and Childrens Depression Rating Scale. Adverse events were assessed through self-reports, vital sign and weight monitoring, laboratory analytes, and extrapyramidal symptom rating scales (Barnes Akathisia Scale, Simpson-Angus Scale, and Abnormal Involuntary Movement Scale). RESULTS Twenty-two of the 23 youths (96%) completed the study. Olanzapine treatment was associated with significant improvement in mean YMRS score (-19.0 +/- 9.2, p < 0.001). Using predefined criteria for improvement of > or = 30% decline in the YMRS and a CGI-S Mania score of < or = 3 at endpoint, the overall response rate was 61%. Overall, olanzapine was well tolerated, and extrapyramidal symptom measures were not significantly different from baseline. Body weight increased significantly over the study (5.0 +/- 2.3 kg, p < 0.001). CONCLUSIONS Open-label olanzapine treatment was efficacious and well tolerated in the treatment of acute mania in youths with bipolar disorder. Future placebo-controlled, double-blind studies are warranted.

Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome

BACKGROUND The prodromal phase of schizophrenic disorders has been described prospectively. The present study aimed to determine the short-term efficacy and safety of olanzapine treatment of prodromal symptoms compared with placebo. METHODS This was a double-blind, randomized, parallel-groups, placebo-controlled trial with fixed-flexible dosing conducted at four sites. Sixty patients met prodromal diagnostic criteria, including attenuated psychotic symptoms, as determined by structured interviews. Olanzapine 5-15 mg daily or placebo was prescribed for 8 weeks. RESULTS In the mixed-effects, repeated-measures analysis, the treatment x time interaction for the change from baseline on the Scale of Prodromal Symptoms total score was statistically significant, and post hoc analyses revealed that the olanzapine-placebo difference reached p<.10 by week 6 and p<.05 at week 8. Ratings of extrapyramidal symptoms remained low in each group and were not significantly different. Olanzapine patients gained 9.9 lb versus.7 lb for placebo patients (p<.001). CONCLUSIONS This short-term analysis suggests olanzapine is associated with significantly greater symptomatic improvement but significantly greater weight gain than is placebo in prodromal patients. Extrapyramidal symptoms with olanzapine were minimal and similar to those with placebo. Future research over the longer term with more patients will be needed before recommendations can be made regarding routine treatment.

FUNCTIONAL IMPAIRMENT AND COGNITION IN BIPOLAR DISORDER

Bipolar disorder is a common, chronic and severe mental disorder, affecting approximately 2% of the adult population. Bipolar disorder causes substantial psychosocial morbidity that frequently affects the patients marriage, children, occupation, and other aspects of the patients life. Few studies have examined the functional impairment in patients with affective illness. Earlier outcome studies of mania reported favorable long-term outcomes. However, modern outcome studies have found that a majority of bipolar patients evidence high rates of functional impairment. These low reports of functional recovery rates are particularly surprising. The basis for such limited functional recovery is not entirely clear. Factors associated with functional dysfunction include presence of inter-episode symptoms, neuroleptic treatment, lower social economic class, and lower premorbid function. Cognitive dysfunction, a symptom domain of schizophrenia, has been identified as an important measure of outcome in the treatment of schizophrenia. Recently, there has been some suggestion that there may be impaired neuropsychological performance in euthymic patients with recurring mood disorders. Whether impaired neuropsychological performance in associated with the functional impairment in bipolar patients who have achieved syndromal recovery is an intriguing question. The literature on functional impairment and cognition in bipolar disorder is reviewed.

First episode schizophrenia-related psychosis and substance use disorders: acute response to olanzapine and haloperidol.

BACKGROUND Co-occurring substance use disorders, mostly involving alcohol, cannabis or cocaine, occur commonly in patients with schizophrenia and are associated with increased morbidity and mortality. Available but limited data suggest that substance use disorders (especially cannabis use disorders) may also be common in first-episode patients and appear linked to a poor outcome in these patients. Strategies to curtail substance use form an important dimension of the treatment program for both first-episode and chronic patients. We report on rates of co-occurring substance use disorders in patients within their first episode of schizophrenia-related psychosis from a multicenter, international treatment trial of olanzapine vs. haloperidol. METHODS The study involved 262 patients (of 263 who were randomized and who returned for a post-randomization evaluation) within their first episode of psychosis (schizophrenia, schizoaffective disorder or schizophreniform disorder) recruited from 14 academic medical centers in North America and Western Europe. Patients with a history of substance dependence within 1 month prior to entry were excluded. RESULTS Of this sample, 97 (37%) had a lifetime diagnosis of substance use disorder (SUD); of these 74 (28% of the total) had a lifetime cannabis use disorder (CUD) and 54 (21%) had a lifetime diagnosis of alcohol use disorder (AUD). Patients with SUD were more likely to be men. Those with CUD had a lower age of onset than those without. Patients with SUD had more positive symptoms and fewer negative symptoms than those without SUD, and they had a longer duration of untreated psychosis. The 12-week response data indicated that 27% of patients with SUD were responders compared to 35% of those without SUD. Patients with AUD were less likely to respond to olanzapine than those without AUD. DISCUSSION These data suggest that first-episode patients are quite likely to have comorbid substance use disorders, and that the presence of these disorders may negatively influence response to antipsychotic medications, both typical and atypical antipsychotics, over the first 12 weeks of treatment.

Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode.

BACKGROUND Many patients recovering from a first psychotic episode will discontinue medication against medical advice, even before a 1-year treatment course is completed. Factors associated with treatment adherence in patients with chronic schizophrenia include beliefs about severity of illness and need for treatment, treatment with typical versus atypical antipsychotic and medication side effects. METHOD In this 2-year prospective study of 254 patients recovering from a first episode of schizophrenia, schizophreniform, or schizoaffective disorder we examined the relationship between antipsychotic medication non-adherence and patient beliefs about: need for treatment, antipsychotic medication benefits, and negative aspects of antipsychotic medication treatment. We also examined the relationship between medication non-adherence and treatment with either haloperidol or olanzapine, and objective measures of symptom response and side effects. RESULTS The likelihood of becoming medication non-adherent for 1 week or longer was greater in subjects whose belief in need for treatment was less (HR=1.75, 95% CI 1.16, 2.65, p=0.0077) or who believed medications were of low benefit (HR=2.88, 95 CI 1.79-4.65, p<0.0001). Subjects randomized to haloperidol were more likely to become medication non-adherent for >or=1 week than subjects randomized to olanzapine (HR-1.51, 95% CI 1.01, 2.27, p=0.045). CONCLUSION Beliefs about need for treatment and the benefits of antipsychotic medication may be intervention targets to improve likelihood of long-term medication adherence in patients recovering from a first episode of schizophrenia, schizoaffective, or schizophreniform disorder.