Showing papers in "Archives of General Psychiatry in 1997"

A molecular and cellular theory of depression

Abstract: Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.

Lifetime Co-occurrence of DSM-III-R Alcohol Abuse and Dependence With Other Psychiatric Disorders in the National Comorbidity Survey

Abstract: Objective: To study patterns of co-occurrence of lifetimeDSM-III-Ralcohol disorders in a household sample. Methods: Data came from the National Comorbidity Survey (NCS), a nationally representative household survey. Diagnoses were based on a modified version of the Composite International Diagnostic Interview. Results: Respondents with lifetimeNCS/DSM-III-Ralcohol abuse or dependence had a high probability of carrying at least 1 other lifetimeNCS/DSM-III-Rdiagnosis. Retrospective reports have suggested that most lifetime co-occurring alcohol disorders begin at a later age than at least 1 other NCS/DSM-III-Rdisorder. Earlier disorders are generally stronger predictors of alcohol dependence than alcohol abuse and stronger among women than men. Lifetime co-occurrence is positively, but weakly, associated with the persistence of alcohol abuse among men and of alcohol dependence among both men and women. Conclusions: Caution is needed in interpreting the results due to the fact that diagnoses were made by nonclinicians and results are based on retrospective reports of the age at onset. Within the context of these limitations, though, these results show that alcohol abuse and dependence are often associated with other lifetimeDSM-III-Rdisorders and suggest that, at least in recent cohorts, the alcohol use disorders are usually temporally secondary. Prospective data and data based on clinically confirmed diagnoses are needed to verify these findings.

'Vascular depression' hypothesis.

Abstract: We propose that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. The "vascular depression" hypothesis is supported by the comorbidity of depression, vascular disease, and vascular risk factors and the association of ischemic lesions to distinctive behavioral symptoms. Disruption of prefrontal systems or their modulating pathways by single lesions or by an accumulation of lesions exceeding a threshold are hypothesized to be central mechanisms in vascular depression. The vascular depression concept can generate studies of clinical and heuristic value. Drugs used for the prevention and treatment of cerebrovascular disease may be shown to reduce the risk for vascular depression or improve its outcomes. The choice of antidepressants in vascular depression may depend on their effect on neurologic recovery from ischemic lesions. Research can clarify the pathways to vascular depression by focusing on the site of the lesion, the resultant brain dysfunction, the presentation of depression and time of onset, and the contribution of nonbiological factors.

Coming to Terms With the Terms of Risk

Abstract: Terms such as risk, risk factors, and especially the term cause are inconsistently and imprecisely used, fostering scientific miscommunication and misleading research and policy. Clarifying such terms is the essential first step. We define risk and a risk factor (protective factor) and their potency, set out the conceptual basis of the methods by which risk factors are identified and potency demonstrated, and propose criteria for establishing the status of a risk factor as a fixed or variable marker or a causal risk factor. All definitions are based on the state of scientific knowledge (empirical documentation), rather than on hypotheses, speculations, or beliefs. We discuss common approaches and pitfalls and give a psychiatric research example. Imprecise reports can impede the search for understanding the cause and course of any disease and also may be a basis of inadequate clinical or policy decision-making. The issues in risk research are much too important to tolerate less than precise terminology or the less than rigorous research reporting that results from imprecise and inconsistent terminology.

A Double-blind, Randomized, Placebo-Controlled Trial of Fluoxetine in Children and Adolescents With Depression

Abstract: Background: Depression is a major cause of morbidity and mortality in children and adolescents. To date, randomized, controlled, double-blind trials of antidepressants (largely tricyclic agents) have yet to reveal that any antidepressant is more effective than placebo. This article is of a randomized, double-blind, placebo-controlled trial of fluoxetine in children and adolescents with depression. Method: Ninety-six child and adolescent outpatients (aged 7-17 years) with nonpsychotic major depressive disorder were randomized (stratified for age and sex) to 20 mg of fluoxetine or placebo and seen weekly for 8 consecutive weeks. Randomization was preceded by 3 evaluation visits that included structured diagnostic interviews during 2 weeks, followed 1 week later by a 1-week, single-blind placebo run-in. Primary outcome measurements were the global improvement of the Clinical Global Impressions scale and the Children's Depression Rating Scale—Revised, a measure of the severity depressive symptoms. Results: Of the 96 patients, 48 were randomized to fluoxetine treatment and 48 to placebo. Using the intent to treat sample, 27 (56%) of those receiving fluoxetine and 16 (33%) receiving placebo were rated "much" or "very much" improved on the Clinical Global Impressions scale at study exit (ϰ2=5.1,df=1,P=.02). Significant differences were also noted in weekly ratings of the Children's Depression Rating Scale—Revised after 5 weeks of treatment (using last observation carried forward). Equivalent response rates were found for patients aged 12 years and younger (n=48) and those aged 13 years and older (n=48). However, complete symptom remission (Children's Depression Rating Scale—Revised ≤28) occurred in only 31% of the fluoxetine-treated patients and 23% of the placebo patients. Conclusion: Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients with severe, persistent depression. Complete remission of symptoms was rare.

Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia.

Abstract: Background: Impaired Wisconsin Card Sorting Test (WCST) performance has been one critical piece of evidence suggesting frontal lobe dysfunction in schizophrenia However, the specific cognitive processes underlying impaired performance have not been identified Impaired WCST performance in schizophrenia might in part reflect a fundamental working memory deficit Method: We examined the performance of 30 normal subjects and 36 patients with schizophrenia on a neuropsychological battery including a novel measure of working memory—letter-number (LN) span Results: Patients with schizophrenia were impaired on LN span performance, which was also highly correlated with WCST performance (r=074) Between-group WCST differences were eliminated when we covaried LN span Regression analyses suggested that LN span performance predicted the WCST category achieved score, whereas measures of set shifting, verbal fluency, and attention were predictive of perseveration Conclusion: Working memory may be a critical determinant of one aspect of WCST performance in schizophrenia

Risk Factors for Bulimia Nervosa: A Community-Based Case-Control Study

Abstract: Background: Many apparently disparate risk factors have been implicated as causes of eating disorders. This study was designed to test the hypothesis that 2 broad classes of risk factors exist for bulimia nervosa: those that increase the risk for development of a psychiatric disorder in general and those that increase the risk of dieting. It was predicted that the latter are especially common among persons with bulimia nervosa. Methods: A case-control design was used involving 2 integrated comparisons. First, 102 subjects with bulimia nervosa were compared with 204 healthy control subjects without an eating disorder. Second, the same 102 subjects with bulimia nervosa were compared with 102 subjects with other psychiatric disorders. To reduce sampling bias, the subjects were recruited directly from the community. A broad range of putative risk factors was assessed. The subjects with bulimia nervosa and the healthy control subjects differed in their rates of exposure to most of the putative risk factors. Far fewer differences were evident between the subjects with bulimia nervosa and the control subjects with other psychiatric disorders, although exposure to factors that were likely to increase the risk of dieting and to negative self-evaluation and certain parental problems (including alcohol use disorder) were substantially more common among those with bulimia nervosa. The findings support the hypothesis that bulimia nervosa is the result of exposure to general risk factors for psychiatric disorder and risk factors for dieting. An unexpected finding was the particularly high rates of premorbid negative self-evaluation and certain parental problems among those with bulimia nervosa. Results: The subjects with bulimia nervosa and the healthy control subjects differed in their rates of exposure to most of the putative risk factors. Far fewer differences were evident between the subjectswith bulimia nervosa and the control subjects with other psychiatric disorders, although exposure to factors that were likely to increase the risk of dieting and to negative self-evaluation and certain parental problems (including alcohol use disorder) were substantially more common among those with bulimia nervosa. Conclusions: The findings support the hypothesis that bulimia nervosa is the result of exposure to general risk factors for psychiatric disorder and risk factors for dieting. An unexpected finding was the particularly high rates of premorbid negative self-evaluation and certain parental problems among those with bulimia nervosa.

Psychiatric and Substance Use Comorbidity Among Treatment-Seeking Opioid Abusers

Abstract: Background: Major studies of psychiatric comorbidity in opioid abusers reported rates of comorbidity that far exceeded general population estimates. These studies were published more than a decade ago and reported on few women and few substance use diagnoses. Methods: Psychiatric and substance use comorbidity was assessed in 716 opioid abusers seeking methadone maintenance. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition diagnostic assessment was conducted 1 month after admission. Rates of psychiatric and substance use disorder were compared by gender, and associations were assessed between psychiatric comorbidity and dimensional indexes of substance use severity, psychosocial impairment, and personality traits. Results: Psychiatric comorbidity was documented in 47% of the sample (47% women and 48% men). Antisocial personality disorder (25.1%) and major depression (15.8%) were the most common diagnoses. Patients had at least 2 substance use diagnoses, most often opioid and cocaine dependence. Demographics, substance use history, and personality variables discriminated between patients with vs without comorbidity. Psychiatric comorbidity also was associated with a more severe substance use disorder. Conclusions: Psychiatric comorbidity, especially personality and mood disorder, was common in men and women. The positive associations between psychiatric comorbidity and severity of substance use and other psychosocial problems were most consistent among those with antisocial personality.

A clinical psychotherapy trial for adolescent depression comparing cognitive, family, and supportive therapy.

Abstract: Background: Previous studies in nonclinical samples have shown psychosocial treatments to be efficacious in the treatment of adolescent depression, but few psychotherapy treatment studies have been conducted in clinically referred, depressed adolescents. Methods: One hundred seven adolescent patients with DSM-III-R major depressive disorder (MDD) were randomly assigned to 1 of 3 treatments: individual cognitive behavior therapy, systemic behavior family therapy (SBFT), or individual nondirective supportive therapy (NST). Treatments were 12 to 16 sessions provided in as many weeks. Intent-to-treat analyses were conducted using all follow-up data. Results: Of the 107 patients enrolled in the study, 78 (72.9%) completed the study, 4 (3.7%) never initiated treatment, 10 (9.3%) had exclusionary criteria that were undetected at entry, 8 (7.5%) dropped out, and 7 (6.5%) were removed for clinical reasons. Cognitive behavior therapy showed a lower rate of MDD at the end of treatment compared with NST (17.1% vs 42.4%; P =.02), and resulted in a higher rate of remission (64.7%, defined as absence of MDD and at least 3 consecutive Beck Depression Inventory scores P =.03) or NST (39.4%; P =.04). Cognitive behavior therapy resulted in more rapid relief in interviewer-rated (vs both treatments, P =.03) and self-reported depression (vs SBFT, P =.02). All 3 treatments showed significant and similar reductions in suicidality and functional impairment. Parents' views of the credibility of cognitive behavior therapy improved compared with parents' views of both SBFT ( P =.01) and NST ( P =.05). Conclusion: Cognitive behavior therapy is more efficacious than SBFT or NST for adolescent MDD in clinical settings, resulting in more rapid and complete treatment response.

Sex differences in posttraumatic stress disorder

Abstract: Background: Epidemiologic surveys in the general population documented a higher rate of posttraumatic stress disorder (PTSD) in women than in men. To date, the finding has received little scientific attention. This study examines the extent to which sex differences in PTSD might be explained by previously identified risk factors and whether the sex difference in PTSD varied by age at exposure to traumatic events. Methods: The NIMH-DIS (NIMH Diagnostic Interview Schedule, Version III Revised) was used to measure DSM-IIIR disorders in a random sample of 1007 young adults. Cox proportional hazards models were used to estimate changes in the hazards ratio for PTSD associated with sex when potential risk factors were included. Results: Lifetime prevalence of exposure to traumatic events and number of traumatic events did not vary by sex. The prevalence of PTSD was higher for women than for men exposed to traumatic events (hazards ratio, 2.3; 95% confidence interval, 1.5-3.6). Preexisting anxiety disorders or major depressive disorders played a part in the observed sex difference in PTSD. Family history of anxiety disorder and early separation from parents, although significant risk factors for PTSD in subjects of both sexes, were unrelated to the sex difference in PTSD. The sex difference in PTSD was markedly greater if exposure occurred in childhood than later on. Conclusions: Posttraumatic stress disorder is more likely to develop in females than in males after exposure to a traumatic event. Susceptibility to PTSD in females might be greater in childhood than after age 15 years. Explanations of the sex difference might involve characteristics of individuals and of the traumatic experiences.

Offspring of Depressed Parents: 10 Years Later

Abstract: Background: There have been numerous studies that have shown that offspring of depressed parents are at a high risk for major depressive disorder (MDD) and impairment. None have followed up the offspring into adulthood to obtain more precise estimates of risk. Method: One hundred eighty-two offspring from 91 families, in which 1 or more parents had MDD (high risk) or in which neither parent was depressed (low risk), were blindly reassessed in the third follow-up, using a structured diagnostic instrument 10 years after their initial identification. Results: Compared with the offspring for whom neither parent was depressed, the offspring of depressed parents had increased rates of MDD, particularly before puberty, and phobias (both at approximately a 3-fold risk), panic disorder, alcohol dependence (at a 5-fold risk), and greater social impairment. The peak age at onset for MDD in both high- and low-risk offspring ranged from 15 to 20 years. The peak age at onset for anxiety disorder was considerably earlier, especially in female offspring in the high-risk group. The onset of alcohol dependence in the offspring in the high-risk group peaked in adolescence and then after the age of 25 years. The depressed offspring of depressed parents, compared with nondepressed parents, had more serious and impairing depressions during the follow-up period but were less likely to go for treatment. Conclusions: The offspring of depressed parents are a high-risk group for onset of anxiety disorder and MDD in childhood, MDD in adolescence, and alcohol dependence in adolescence and early adulthood. The findings support the potential value of early detection in the offspring of depressed parents.

The prevalence of DSM-III-R diagnoses in a national sample of Dutch adolescents.

Abstract: Background: We estimated the 6-month prevalence of psychiatric disorders among Dutch adolescents, using standardized, internationally available, and replicable assessment procedures, and assessed sex differences and comorbidity of diagnoses. Methods: In phase 1, the parent, self-report, and teacher versions of the Child Behavior Checklist screened a sample representative of 13- to 18-year-olds from the Dutch general population. In phase 2, the parent (P) and child (C) versions of the Diagnostic Interview Schedule for Children (DISC) provided DSM-III-R diagnoses for a selected subsample of 780 subjects. Results: The prevalence of any disorder was 21.5% for the DISC-C and 21.8% for the DISC-P. There was little overlap between subjects identified as having a disorder by the DISC-P and the DISC-C; only 4% met the criteria for any disorder on both. The most common disorders were simple phobia, social phobia, and conduct disorder. The most frequent comorbid diagnoses were anxiety and mood disorders. Conclusions: Although prevalences of more than 21% for DISC-C—and DISC-P—derived diagnoses seem high, many adolescents with DSM-III-R diagnoses functioned quite well. The prevalence of any DSMIII-R diagnosis based on the DISC-C or DISC-P, in combination with the criterion for a definite case, was 7.9%.

Psychiatric Sequelae of Posttraumatic Stress Disorder in Women

Abstract: Background: The risk for first-onset major depression, anxiety, and substance use disorders associated with prior posttraumatic stress disorder (PTSD) was estimated in a sample of women. Methods: The National Institute of Mental Health Diagnostic Interview Schedule, revised according to DSMIII-R , was used to measure lifetime psychiatric disorders in a stratified random sample of 801 mothers of children, who participated in a study of cognitive and psychiatric outcomes by level of birth weight. Cox proportional hazards models with time-dependent covariates were used to calculate the hazards ratios of first onset of other disorders following PTSD. Results: The lifetime prevalence of traumatic events was 40% and of PTSD, 13.8%. Posttraumatic stress disorder signaled increased risks for first-onset major depression (hazards ratio, 2.1) and alcohol use disorder (hazards ratio, 3.0). The risk for major depression following PTSD was of the same magnitude as the risk for major depression following other anxiety disorders. Women with preexisting anxiety and PTSD had significantly increased risk for first-onset major depression. Additional analysis showed that preexisting major depression increased women's vulnerability to the PTSD-inducing effects of traumatic events and risk for exposure to traumatic events. Conclusions: Posttraumatic stress disorder influences the risk for first-onset major depression and alcohol use disorder. The causal explanation of these temporally secondary disorders is unclear and might involve the effect of PTSD or underlying vulnerabilities exposed by the traumatic experience.

Fluoxetine and Impulsive Aggressive Behavior in Personality-Disordered Subjects

Abstract: Background: Evidence of an inverse relationship between central serotonergic (serotonin [5-hydroxytryptamine]) system function and impulsive aggressive behavior has been accumulating for more than 2 decades. If so, pharmacological enhancement of serotonin activity should be expected to reduce impulsive aggressive behavior in subjects in whom this behavior is prominent. Methods: A double-blind, placebo-controlled trial of the selective serotonin-uptake inhibitor fluoxetine hydrochloride was conducted in 40 nonmajor-depressed, nonbipolar or schizophrenic, DSM-III-R personality—disordered individuals with current histories of impulsive aggressive behavior and irritability. Measures included the Overt Aggression Scale—Modified for Outpatients, Clinical Global Impression Rating of Improvement, and several secondary measures of aggression, depression, and anxiety. Results: Fluoxetine, but not placebo, treatment resulted in a sustained reduction in scores on the lrritability and Aggression subscales of the Overt Aggression Scale—Modified for Outpatients that was first apparent during months 2 and 3 of treatment, respectively. Fluoxetine was superior to placebo in the proportion of "responders" on the Clinical Global Impression Rating of Improvement: first at the end of month 1, and then finally demonstrating a sustained drug-placebo difference from the end of month 2 through the end of month 3 of treatment. These results were not influenced by secondary measures of depression, anxiety, or alcohol use. Conclusion: Fluoxetine treatment has an antiaggressive effect on impulsive aggressive individuals with DSM-III-R personality disorder.

Family and Individual Therapy in Anorexia Nervosa: A 5-Year Follow-up

Abstract: Background: There is evidence that specific psychological treatments are effective in patients with eating disorders. Our goal was to determine by means of a controlled trial whether psychological treatments, previously found to be effective in anorexia nervosa, gave rise to enduring benefits. Methods: A 5-year follow-up was conducted on Patients who had participated in a previous trial of family therapy for anorexia and bulimia nervosa. Family therapy or individual supportive therapy had been administered to 80 outpatients for 1 year beginning on discharge from hospital after weight restoration. The 80 patients had been subdivided into 4 prognostically homogeneous groups of which 2 turned out to be the most important: patients with early onset and short history of anorexia nervosa, and patients with late-onset anorexia nervosa. At the 5-year follow-up, the efficacy of the outpatient therapies was again assessed by the maintenance of weight, and the categories of general outcome and dimensions of clinical functioning defined by the Morgan-Russell scales. Results: Significant improvements were found in the group of 80 patients as a whole, mainly attributable to the natural outcome of anorexia nervosa, and most evident in the early onset and short history group, as expected. Within 2 of the prognostic groups, significant benefits attributable to the previous psychological treatments were still evident, favoring family therapy for patients with early onset and short history of anorexia nervosa and favoring individual supportive therapy for patients with late-onset anorexia nervosa. Conclusions: Much of the improvements found at a 5year follow-up can be attributed to the natural outcome of the illness. Nevertheless, it was still possible to detect long-term benefits of psychological therapies completed 5 years previously.

Quetiapine in Patients With Schizophrenia: A High- and Low-Dose Double-blind Comparison With Placebo

Abstract: Background: Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypical dibenzothiazepine antipsychotic with a greater affinity for 5-hydroxytryptamine2(5-HT2) receptors than for D2dopamine receptors; its efficacy in patients with schizophrenia was shown in early phase 2 trials (maximum dose, 750 mg/d). Methods: In this multicenter, double-blind, placebo-controlled trial, 286 patients hospitalized with chronic or subchronic schizophrenia (DSM-III-R) were randomized to 6 weeks of treatment with high-dose quetiapine fumarate (>750 mg/d), n=96; low-dose quetiapine fumarate (>250 mg/d), n=94; or placebo, n=96. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Severity of Illness item scores were the primary efficacy variables. Secondary efficacy variables included the BPRS positive-symptom cluster score, the Modified Scale for the Assessment of Negative Symptoms summary score (United States only), and the total score from the negative scale of the Positive and Negative Syndrome Scale (Europe only). Scores were analyzed using an analysis of covariance for change from baseline at end point with last observations carried forward. The model included baseline score (covariate), center, and treatment. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale and the Barnes Akathisia Scale; abnormal involuntary movements were assessed using the Abnormal Involuntary Movement Scale. Frequency distributions of grouped change-from-baseline scores were analyzed using χ2tests. Results: Of 280 patients in whom the efficacy of quetiapine was evaluated, 159 (42% of those receiving high-dose treatment; 57%, low-dose treatment; and 59%, placebo) withdrew before trial completion, primarily because of treatment failure. Significant (P Conclusions: Quetiapine is an effective antipsychotic with a favorable safety profile. The optimum dose is probably greater than 250 mg/d.

The clinical course of unipolar major depressive disorders

Abstract: A FUNDAMENTAL paradigmatic shift is occurring in the understanding of unipolar major depressive disorders (MDD) among the general public, by many public health experts, and by the practicing psychiatric community. Most people in our society no longer view depression as a mysterious sickness of spirit or emotional weakness, but rather as a disease of the brain and an important health problem. 1 International public health experts acknowledge the high prevalence of unipolar MDD 2 combined with the pervasive human misery and impairment associated with it, and have identified this disease in 1990 as the fourth-ranked cause of disability and premature death worldwide. 3 In parallel, the treatment of unipolar MDD has evolved from incarceration, exorcism, and prayer to classic psychoanalysis, and now in the modern era to treatment with empirically proven, effective antidepressant medications and depression-specific brief psychotherapies. Meta-analyses of 6 standardized treatment studies by Thase et al 4 have

Natural history of diagnostic interview schedule/DSM-IV major depression: The Baltimore Epidemiologic Catchment Area follow-up

Abstract: Background: Natural history can be characterized by incidence, recurrence, and duration of episodes. Research on the incidence of major depression is rare; studies of recurrence and duration are limited to clinical samples. Methods: The Baltimore, Md, site of the Epidemiologic Catchment Area Program followed up its 1981 baseline cohort of 3481 respondents with an additional assessment in 1993 to 1996. Interviews were obtained from 1920 respondents (73% of the survivors). The Diagnostic Interview Schedule and the same survey procedures as in 1981 were used, augmented with a Life Chart Interview for dating the onset and duration of syndromes. Results: There were 71 new cases of Diagnostic Interview Schedule/DSM-IVmajor depression and 23 698 person-years of exposure, generating an estimated incidence of 3.0 per 1000 per year. Incidence peaked while subjects were in their 30s, with a smaller peak when they were in their 50s. Prodromal symptoms often occurred many years before the full criteria for diagnosis were met. Women were at higher risk for becoming new cases but had neither higher risk for recurrence nor longer episodes than men. Episodes of depression lasted for 12 weeks. The duration of an episode, and time to an episodefree year, was longer in the first episode than in recurrent episodes. Conclusions: The incidence estimated in this study is consistent with that found in the few other similar studies performed. The bimodality of onset suggests the value of further exploring the heterogeneity of depression via its natural history. Reported differences in prevalence between men and women seem to be due to differences in incidence, not chronicity.

Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations.

Abstract: Background: Few reliable correlates of treatment response in depression have emerged despite nearly 40 years of research. We examined the correlates of recovery in a "mega-analysis," or meta-analysis of original data, of 595 patients with major depressive disorder enrolled in 6 standardized treatment protocols. Methods: All patients (mean age, 44 years; 31% male and 69% female) met criteria for nonbipolar, nonpsychotic primary major depressive disorder and were treated for 16 weeks with either cognitive behavior therapy or interpersonal psychotherapy alone (psychotherapy alone; n=243) or interpersonal psychotherapy plus antidepressant pharmacotherapy (combined therapy; n=352). The impact of treatment type, severity, study, and other covariates on recovery rates or time to recovery were examined by means of χ 2 , log-rank tests, the Cox proportional hazards model, and sensitivity analyses. Results: Whereas combined therapy was not significantly more effective than psychotherapy alone in milder depressions, a highly significant advantage was observed in more severe recurrent depressions. Poorer outcomes were also observed in women and older patients, although these effects were dependent on inclusion of particular studies. Conclusions: Mega-analysis is a powerful method for comparing the efficacy of treatments and examining correlates of response. Using this method, we found new evidence in support of the widespread clinical impression that combined therapy is superior to psychotherapy alone for treatment of more severe, recurrent depressions.

The Cross-national Epidemiology of Panic Disorder

Abstract: Background: Epidemiological data on panic disorder from community studies from 10 countries around the world are presented to determine the consistency of findings across diverse cultures. Method: Data from independently conducted community surveys from 10 countries (the United States, Canada, Puerto Rico, France, West Germany, Italy, Lebanon, Taiwan, Korea, and New Zealand), using the Diagnostic Interview Schedule and DSM-III criteria and including over 40 000 subjects, were analyzed with appropriate standardization for age and sex differences among subjects from different countries. Results: The lifetime prevalence rates for panic disorder ranged from 1.4 per 100 in Edmonton, Alberta, to 2.9 per 100 in Florence, Italy, with the exception of that in Taiwan, 0.4 per 100, where rates for most psychiatric disorders are low. Mean age at first onset was usually in early to middle adulthood. The rates were higher in female than male subjects in all countries. Panic disorder was associated with an increased risk of agoraphobia and major depression in all countries. Conclusions: Panic disorder is relatively consistent, with a few exceptions, in rates and patterns across different countries. It is unclear why the rates of panic and other psychiatric disorders are lower in Taiwan.

Naltrexone and Alcohol Dependence: Role of Subject Compliance

Abstract: Background: Two previous double-blind, placebo-controlled studies demonstrated that naltrexone (50 mg/d) reduces alcohol drinking in alcohol-dependent subjects. In both studies, treatment compliance was excellent. However, a robust treatment effect size for naltrexone relative to placebo has been shown for compliant subjects but not for subjects who missed research visits. The goal of this study was to determine the effectiveness of naltrexone in subjects who received psychosocial treatment in a more naturalistic setting with respect to the role of treatment attendance and medication compliance. Methods: Ninety-seven alcohol-dependent subjects were randomly assigned to receive either naltrexone (n=48) or matching placebo (n=49) for 12 weeks. All subjects received individual counseling (twice per week for the first month followed by once per week). Results: Overall, naltrexone showed only modest effects in reducing alcohol drinking for the 12 weeks of treatment. However, naltrexone treatment efficacy improved across a variety of outcome measures for subjects who completed treatment and were highly compliant with taking medication. Conclusions: Naltrexone is clinically effective relative to placebo in individuals who comply with the treatment protocol and take medication. The modest treatment effects in the entire sample suggest that the clinical efficacy of naltrexone could be improved by enhancing treatment compliance.

Visual imagery and perception in posttraumatic stress disorder. A positron emission tomographic investigation

Abstract: Background: Relative regional cerebral blood flow (rCBF) changes were measured in Vietnam combat veterans with and without posttraumatic stress disorder (PTSD) during exposure to combat-related stimuli. Methods: Positron emission tomography was used to measure rCBF in 7 combat veterans with PTSD (PTSD group) and 7 healthy combat veterans (control group) who viewed and generated visual mental images of neutral, negative, and combat-related pictures. Results: Unlike control subjects, subjects with PTSD had increased rCBF in ventral anterior cingulate gyrus and right amygdala when generating mental images of combatrelated pictures; when viewing combat pictures, subjects with PTSD showed decreased rCBF in Broca's area. Conclusions: Results suggest that ventral anterior cingulate gyrus and right amygdala play a role in the response of combat veterans with PTSD to mental images of combat-related scenes. Reexperiencing phenomena of PTSD, which often involve emotional visual mental imagery, may be likewise associated with increased rCBF in these regions.

Depression During Mania: Treatment Response to Lithium or Divalproex

Abstract: Background: Little information exists from controlled studies about clinical characteristics that predict treatment response in mania. The presence of depressive symptoms during manic episodes may be associated with poor response to psychopharmacological treatments. This is an investigation of the relation between depressive symptoms and treatment response in acute manic episodes. Methods and Design: In a parallel-group, doubleblind study, 179 patients hospitalized for acute manic episodes were randomized to receive divalproex sodium, lithium carbonate, or placebo (ratio, 2:1:2). The study was carried out at 9 academic medical centers. Patients had comprehensive evaluations of behavior and symptoms before and during 3 weeks of treatment. The primary outcome measure, change in mania factor scores derived from the Schedule for Affective Disorders and Schizophrenia: Change Version, was compared in pa- tients with and without depressive symptoms at baseline according to nurse- or physician-rated scales. Results: Depressive symptoms were associated with poor antimanic response to lithium and with better response to divalproex. This was not due to differences in overall severity of illness, substance abuse, gender, age, or history. Conclusions: These data suggest that even a modest level of pretreatment depression-related symptoms is a robust predictor of lithium nonresponse, and is associated with better response to divalproex. Although their overall efficacy in acute mania is similar, lithium and divalproex may be most effective in clinically and biologically distinct groups of patients.

Behavior of Boys in Kindergarten and the Onset of Substance Use During Adolescence

Abstract: Background: The purpose of this study was to assess the usefulness of personality dimensions measured at ages 6 and 10 years in predicting early onset of cigarette smoking, alcohol abuse, and other drug use in boys. In addition, the stability of the prediction between the measurements at ages 6 and 10 years was investigated. Methods: Data from a large longitudinal study of boys were used to assess the relation between childhood personality and the onset of substance use from 10 to 15 years of age. Childhood personalities were assessed by teachers' ratings of behaviors. Self-reports of smoking cigarettes, getting drunk, and using other drugs provided the measurement of substance use. Discrete-time survival analysis was used for the statistical analyses. Results: High novelty-seeking and low harm avoidance significantly predict early onset of substance use (eg, cigarettes, alcohol, and other drugs), but reward dependence was unrelated to any of the outcomes studied. The results also indicated that either set of predictors (ie, the personality dimensions measured at ages 6 and 10 years) could be used to predict onset of cigarette smoking, getting drunk, and other drug use, because the power of prediction was similar between the measurements at ages 6 and 10 years. Conclusions: High novelty-seeking and low harm avoidance lead to early onset of substance use in boys. The stability of the prediction between ages 6 and 10 years suggests that the kindergarten assessments may be used for preventive efforts at school entry instead of waiting until early adolescence.

Complex interaction of the sleep-wake cycle and circadian phase modulates mood in healthy subjects.

Abstract: Background: Several studies of healthy volunteers have revealed that subjective mood may vary with the duration of prior wakefulness and with the time of day. However, in these studies, the effects of extended wakefulness and circadian phase remained confounded, and the interaction of these 2 processes could not be assessed quantitatively. Methods: In the present study, a total of 24 healthy young subjects (16 men, 8 women) lived on a 30-hour sleep-wake schedule for 19 to 23 days or on a 28-hour sleep-wake schedule for 33 to 36 days; both schedules induced desynchrony between the subjects' sleep-wake cycle and their endogenous circadian pacemaker. Subjective mood was assessed by 2 types of visual analog scales, which were administered twice every 2 hours and every 20 minutes, respectively, during all scheduled wake fulness episodes. A circadian phase and an interval elapsed since awakening were attributed to each data point, and circadian and wake-dependent fluctuations of mood were assessed. Results: A significant variation of mood with circadian phase was observed, but no reliable main effect of the duration of prior wakefulness was found. A statistically significant interaction of circadian and wake-dependent fluctuations was evident; when the analysis was restricted to specific circadian phases, mood improved, deteriorated, or remained stable with the duration of prior wakefulness. Conclusions: These results indicate that, in healthy young subjects, subjective mood is influenced by a complex and nonadditive interaction of circadian phase and duration of prior wakefulness. The nature of this interaction is such that moderate changes in the timing of the sleep-wake cycle may have profound effects on subsequent mood.

Multisomatoform Disorder: An Alternative to Undifferentiated Somatoform Disorder for the Somatizing Patient in Primary Care

Abstract: Background: For clinical or research use in primary care, theDSM-IVdiagnostic criteria for somatization disorder are too restrictive, while the criteria for undifferentiated somatoform disorder are overly inclusive. In this article, we examine the validity of multisomatoform disorder, defined as 3 or more medically unexplained, currently bothersome physical symptoms plus a long (≥2 years) history of somatization. Methods: Data from the Primary Care Evaluation of Mental Disorders Study of 1000 patients from 4 primary care sites were analyzed. The outcomes assessed were 6 domains of health-related quality of life, using the 20-item Short-Form General Health Survey; selfreported disability days and health care use; satisfaction with care; and physician-rated difficulty of the encounter. Results: Multisomatoform disorder was diagnosed in 82 (8.2%) of the 1000 patients who were enrolled in the Primary Care Evaluation of Mental Disorders Study. Compared with mood and anxiety disorders, multisomatoform disorder was associated with comparable impairment in health-related quality of life, more self-reported disability days and clinic visits, and greater clinician-perceived patient difficulty. Conclusions: Multisomatoform disorder may be a valid diagnosis and potentially more useful than the DSM-IV diagnosis of undifferentiated somatoform disorder. Also, because multisomatoform disorder has a large and independent effect on impairment, its diagnosis should not be precluded simply because of a coexisting mood or anxiety disorder.

Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial.

Abstract: Background: The selective serotonergic medication fluoxetine has demonstrated efficacy in the treatment of major depression and has suggested efficacy in the treatment of alcoholism. However, no completed trials with any selective serotonergic medication have been reported in patients who display both major depression and alcoholism, despite previous observations that both depression and alcoholism are associated with low serotonergic functioning. Methods: Fifty-one patients diagnosed as having comorbid major depressive disorder and alcohol dependence were randomized to receive fluoxetine (n=25) or placebo (n=26) in a 12-week, double-blind, parallel-group trial. Weekly ratings of depression and alcohol consumption were obtained throughout the 12-week course of the study. Results: The improvement in depressive symptoms during the medication trial was significantly greater in the fluoxetine group than in the placebo group. Total alcohol consumption during the trial was significantly lower in the fluoxetine group than in the placebo group. Conclusions: Fluoxetine is effective in reducing the depressive symptoms and the alcohol consumption of patients with comorbid major depressive disorder and alcohol dependence. It is unknown whether these results generalize to the treatment of less depressed and less suicidal alcoholics.

Reduction of Synaptophysin Immunoreactivity in the Prefrontal Cortex of Subjects With Schizophrenia: Regional and Diagnostic Specificity

Abstract: Background: Multiple lines of evidence indicate that the prefrontal cortex is a site of dysfunction in schizophrenia. However, the apparent absence of gross structural abnormalities in this area suggests that the pathophysiological characteristics of schizophrenia may involve more subtle disturbances in prefrontal cortical circuitry, such as alterations in synaptic connectivity and transmission. In this study, immunoreactivity for synaptophysin, an integral membrane protein of small synaptic vesicles, was used to assess the integrity of cortical synaptic circuitry in schizophrenia. Methods: Using immunocytochemical techniques and adjusted optical density measurements, we examined synaptophysin immunoreactivity in prefrontal cortical areas 9 and 46 and in area 17. (the primary visual cortex) from 10 pairs of case subjects with schizophrenia and control subjects matched on a pairwise basis for age, sex, race, and postmortem interval, and in 5 matched pairs of nonschizophrenic psychiatric case subjects and normal control subjects. Results: Compared with levels found in matched control subjects, synaptophysin immunoreactivity in areas 46 and 9 was significantly decreased (P Conclusions: Additional studies are required to determine if the decrease in levels of synaptophysin immunoreactivity is caused by a decrease in the number or size of presynaptic terminals, a decrease in the number of synaptic vesicles per terminal, or a decrease in the expression of synaptophysin. However, all of these potential explanations are consistent with a disturbance in synaptic transmission in the prefrontal cortex of patients with schizophrenia.

Maternal Smoking During Pregnancy and the Risk of Conduct Disorder in Boys

Abstract: Background: Previous animal and human studies have indicated that prenatal exposure to nicotine is associated with adverse reproductive outcomes, including altered neural structure and functioning, cognitive deficits, and behavior problems in the offspring. Our study extends previous research on humans by controlling a broad range of correlates of maternal smoking during pregnancy to determine if smoking is associated with behavior problems in the offspring severe enough to qualify for DSM-III-R diagnoses. Method: Subjects were 177 clinic-referred boys, ages 7 to 12 years at the time of the first assessment, who underwent longitudinal assessment for 6 years using annual structured diagnostic interviews. Correlates of maternal smoking during pregnancy and previously identified demographic, parental, perinatal, and family risk factors for the disruptive behavior disorders were controlled in logistic regression analyses. Results: Mothers who smoked more than half a pack of cigarettes daily during pregnancy were significantly more likely to have a child with conduct disorder (odds ratio, 4.4; P =.001) than mothers who did not smoke during pregnancy. This association was statistically significant when controlling for socioeconomic status, maternal age, parental antisocial personality, substance abuse during pregnancy, and maladaptive parenting. Conclusions: Maternal smoking during pregnancy appears to be a robust independent risk factor for conduct disorder in male offspring. Maternal smoking during pregnancy may have direct adverse effects on the developing fetus or be a marker for a heretofore unmeasured characteristic of mothers that is of etiologic significance for conduct disorder.

Hypercortisolism Associated With Social Subordinance or Social Isolation Among Wild Baboons

Abstract: Background: The phenomena of basal hypercortisolism and of dexamethasone resistance have long intrigued biological psychiatrists, and much is still unknown as to the causes and consequences of such adrenocortical hyperactivity in various neuropsychiatric disorders. We have analyzed basal cortisol concentrations and adrenocortical responsiveness to dexamethasone in a population of wild baboons living in a national park in Kenya. We tested whether social subordinance in a primate is associated with dexamethasone resistance. Furthermore, we examined whether individual differences in adrenocortical measurements were predicted by the extent of social affiliation in these animals. Methods: Seventy yellow baboons ( Papio cynocephalus ) were anesthetized and injected with 5 mg of dexamethasone; the cortisol response was monitored for 6 hours. The animals were of both sexes in a range of ages and had known ranks in the dominance hierarchies within their troops. Extensive behavioral data were available for a subset of 12 adult males who were anesthetized under circumstances that also allowed for the determination of basal cortisol concentrations. Results: The socially subordinate baboons were less responsive to dexamethasone than were the dominant ones; as one manifestation of this, postdexamethasone cortisol values were more than 3 times higher in the dozen lowest-ranking animals compared with the dozen highest. In addition, socially isolated males had elevated basal cortisol concentrations and showed a trend toward relative dexamethasone resistance. Conclusions: Our findings indicate that social status and degree of social affilitation can influence adrenocortical profiles; specifically, social subordinance or social isolation were associated in our study with hypercortisolism or feedback resistance.