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A study to investigate the effect of human immunodeficiency virus (HIV) status on the course of neurological impairment, conducted by the HIV Center at Columbia University, followed a cohort of HIV positive and negative gay men for 5 years and assessed the presence or absence of neurological impairment every 6 months. Almost half of the subjects dropped out before the end of the study for reasons that might have been related to the missing neurological data. We propose likelihood-based methods for analysing such binary longitudinal data under informative and noninformative drop-out. A transition model is assumed for the binary response, and several models for the drop-out processes are considered which are functions of the response variable (neurological impairment). The likelihood ratio test is used to compare models with informative and noninformative drop-out mechanisms. Using simulations, we investigate the percentage bias and mean-squared error (MSE) of the parameter estimates in the transition model under various assumptions for the drop-out. We find evidence for informative drop-out in the study, and we illustrate that the bias and MSE for the parameters of the transition model are not directly related to the observed drop-out or missing data rates. The effect of HIV status on the neurological impairment is found to be statistically significant under each of the models considered for the drop-out, although the regression coefficient may be biased in certain cases. The presence and relative magnitude of the bias depend on factors such as the probability of drop-out conditional on the presence of neurological impairment and the prevalence of neurological impairment in the population under study. [ABSTRACT FROM AUTHOR]

Objective: Cigarette smoking is associated with a higher risk for suicide and attempted suicide, but psychopathological or biological explanations for this association have not been explored. Lower serotonin function and impulsive/aggressive traits are associated with suicidal acts, including completed suicide. The authors hypothesized that the relationship that may exist between cigarette smoking and suicidal behavior may be associated with lower serotonin function and the presence of impulsive/aggressive traits., Method: Study subjects were 347 patients with a psychiatric disorder (175 with depression, 127 with schizophrenia, and 45 with other disorders). Fifty-three percent of the subjects (N=184) had a lifetime history of suicide attempt, and 47% (N=163) had never attempted suicide. Smoking behavior, lifetime suicidal behavior, and psychopathology were assessed. Serotonin function was assessed in a subgroup of patients with depression (N=162) by using a fenfluramine challenge test and/or measurement of CSF levels of 5-hydroxyindoleacetic acid., Results: Among all patients, smokers were more likely to have made a suicide attempt (adjusted odds ratio=2.60, 95% confidence interval=1.60-4.23) and had higher suicidal ideation and lifetime aggression scores, compared with nonsmokers. An inverse relationship was observed between amount of cigarette smoking and both indices of serotonin function., Conclusions: The association between cigarette smoking and the presence and severity of suicidal behavior across major psychiatric disorders may be related to lower brain serotonin function in smokers with depression. Further investigation is required to replicate these findings, to measure serotonin function in patients with disorders other than depression, and to test potential therapeutic effects of serotonin-enhancing treatments on both smoking behavior and suicide risk.

We applied a mixed effects model to investigate between- and within-study variation in improvement rates of 180 schizophrenia outcome studies. The between-study variation was explained by the fixed study characteristics and an additional random study effect. Both rate difference and logit models were used. For a binary proportion outcome p(i) with sample size n(i) in the ith study, (circumflexp(i)(1-circumflexp(i))n)(-1) is the usual estimate of the within-study variance sigma(i)(2) in the logit model, where circumflexpi) is the sample mean of the binary outcome for subjects in study i. This estimate can be highly correlated with logit(circumflexp(i)). We used (macronp(i)(1-macronp)n(i))(-1) as an alternative estimate of sigma(i)(2), where macronp is the weighted mean of circumflexp(i)'s. We estimated regression coefficients (beta) of the fixed effects and the variance (tau(2)) of the random study effect using a quasi-likelihood estimating equations approach. Using the schizophrenia meta-analysis data, we demonstrated how the choice of the estimate of sigma(2)(i) affects the resulting estimates of beta and tau(2). We also conducted a simulation study to evaluate the performance of the two estimates of sigma(2)(i) in different conditions, where the conditions vary by number of studies and study size. Using the schizophrenia meta-analysis data, the estimates of beta and tau(2) were quite different when different estimates of sigma(2)(i) were used in the logit model. The simulation study showed that the estimates of beta and tau(2) were less biased, and the 95 per cent CI coverage was closer to 95 per cent when the estimate of sigma(2)(i) was (macronp(1-macronp)n(i))(-1) rather than (circumflexp(i)(1-circumflexp)n(i))(-1). Finally, we showed that a simple regression analysis is not appropriate unless tau(2) is much larger than sigma(2)(i), or a robust variance is used., (Copyright 2001 John Wiley & Sons, Ltd.)

In studying decline among cognitively impaired people, a prevalent cohort study design is commonly used to account for entry into the study at different levels of impairment. The data set typically consists of many short series of repeated measurements collected over time. However, the time origin, such as time of disease/impairment onset, is often uncertain. In order to model non-linear decline patterns in functional test scores and associated risk factors with such data, we propose two approaches as alternatives to Liu et al. One approach models change over adjacent visits with varying time intervals. The second models the change since baseline using a random effect for heterogeneity of change. We used these two approaches to examine the decline in cognitive test scores among special care unit (SCU) and non-SCU residents at the New York sites of the National Institute on Aging (NIA) collaborative studies of special dementia care. The analyses suggest that, controlling for several covariates, SCU residents experienced more rapid cognitive decline than did non-SCU residents. The relative advantages and disadvantages of the two models are discussed., (Copyright 2000 John Wiley & Sons, Ltd.)

This article extends the acute outcome findings from a study comparing psychological and pharmacological interventions for bulimia nervosa (B.T. Walsh et al., 1997) by examining 3 additional domains: predictive factors, therapeutic alliance, and time course of change. One hundred twenty women were randomized to cognitive-behavioral therapy (CBT), supportive psychotherapy (SPT) plus antidepressant medication or a placebo, or a medication-alone condition. Results indicate that high baseline frequencies of binge eating and vomiting, as well as a positive history of substance abuse or dependence, are negative prognostic indicators. Although a greater overall therapeutic alliance may increase the likelihood of remission, symptom change over the course of treatment may have as much of an impact on patient ratings of alliance as the reverse. CBT was significantly more rapid than SPT in reducing binge eating and vomiting frequencies.

Objective: Risk factors for suicide attempts have rarely been studied comprehensively in more than one psychiatric disorder, preventing estimation of the relative importance and the generalizability of different putative risk factors across psychiatric diagnoses. The authors conducted a study of suicide attempts in patients with mood disorders, psychoses, and other diagnoses. Their goal was to determine the generalizability and relative importance of risk factors for suicidal acts across diagnostic boundaries and to develop a hypothetical, explanatory, and predictive model of suicidal behavior that can subsequently be tested in a prospective study., Method: Following admission to a university psychiatric hospital, 347 consecutive patients who were 14-72 years old (51% were male and 68% were Caucasian) were recruited for study. Structured clinical interviews generated axis I and axis II diagnoses. Lifetime suicidal acts, traits of aggression and impulsivity, objective and subjective severity of acute psychopathology, developmental and family history, and past substance abuse or alcoholism were assessed., Results: Objective severity of current depression or psychosis did not distinguish the 184 patients who had attempted suicide from those who had never attempted suicide. However, higher scores on subjective depression, higher scores on suicidal ideation, and fewer reasons for living were reported by suicide attempters. Rates of lifetime aggression and impulsivity were also greater in attempters. Comorbid borderline personality disorder, smoking, past substance use disorder or alcoholism, family history of suicidal acts, head injury, and childhood abuse history were more frequent in suicide attempters., Conclusions: The authors propose a stress-diathesis model in which the risk for suicidal acts is determined not merely by a psychiatric illness (the stressor) but also by a diathesis. This diathesis may be reflected in tendencies to experience more suicidal ideation and to be more impulsive and, therefore, more likely to act on suicidal feelings. Prospective studies are proposed to test this model.

Although electroconvulsive therapy (ECT) is believed to have a rapid onset of antidepressant activity, there has been limited investigation in this area. This study contrasted alternative statistical methods for testing treatment group differences in the rapidity of clinical response to ECT. Patients with major depression were randomly assigned to receive right unilateral or bilateral ECT and low or high electrical dosage relative to seizure threshold. The 24-item Hamilton Rating Scale for Depression (HRSD) was administered by blinded clinical raters twice weekly (non-treatment days). We evaluated four alternative statistical strategies. Two methods considered time to improvement as a dependent variable: (a) time (treatment number) to reach various cutoffs for percentage decrease in HRSD from baseline; and (b) survival analysis using the same cutoffs for percentage decreases as endpoints. Two methods considered time to improvement as an independent variable: (c) the slope of linear regression of HRSD scores against treatment number; and (d) a random regression model using the HRSD scores as repeated measures. The statistical methods differed in whether or not omnibus group differences were observed, the criterion level of improvement associated with group differences, and the results of pairwise comparisons establishing specific therapeutic advantages. Survival analysis generally displayed the greatest sensitivity in detecting treatment group differences.

Objective: Two treatments for bulimia nervosa have emerged as having established efficacy: cognitive-behavioral therapy and antidepressant medication. This study sought to address 1) how the efficacy of a psychodynamically oriented supportive psychotherapy compared to that of cognitive-behavioral therapy; 2) whether a two-stage medication intervention, in which a second antidepressant (fluoxetine) was employed if the first (desipramine) was either ineffective or poorly tolerated, added to the benefit of psychological treatment; and 3) if the combination of medication and psychological treatment was superior to a course of medication alone., Method: A total of 120 women with bulimia nervosa participated in a randomized, placebo-controlled trial., Results: Cognitive-behavioral therapy was superior to supportive psychotherapy in reducing behavioral symptoms of bulimia nervosa (binge eating and vomiting). Patients receiving medication in combination with psychological treatment experienced greater improvement in binge eating and depression than did patients receiving placebo and psychological treatment. In addition, cognitive-behavioral therapy plus medication was superior to medication alone, but supportive psychotherapy plus medication was not., Conclusions: At present, cognitive-behavioral therapy is the psychological treatment of choice for bulimia nervosa. A two-stage medication intervention using fluoxetine adds modestly to the benefit of psychological treatment.

Objective: This study was undertaken to test the feasibility of using functional magnetic resonance imaging (MRI) to examine changes in cortical activation in response to verbal tasks in two brain regions., Method: Twelve schizophrenic patients and 11 comparison subjects underwent functional MRI of the frontal and temporal lobes. Stimulus sequences were divided into five 30-second segments by using a task-activation paradigm that alternated between resting and stimulated states. Functional images were collected every 30 seconds by using a gradient echo pulse sequence., Results: Schizophrenic subjects demonstrated significantly less left frontal activation and greater left temporal activation than comparison subjects during a word fluency task., Conclusions: These preliminary data suggest that functional MRI has the sensitivity to detect differences in activation between comparison subjects and schizophrenic patients during higher cortical functions. These findings are in agreement with PET studies that reported reduced left frontal activation during challenge paradigms for the schizophrenic patients.

Objective: This study evaluated the feasibility and impact of gradually reducing relatively high doses of fluphenazine decanoate by one-half for chronically impaired, poor inner-city patients with schizophrenia., Method: Forty-three patients currently receiving an average of 23 mg (0.3 mg/kg) of fluphenazine decanoate every 2 weeks were divided alternately into a group to remain at current doses (control group) and a group to undergo stepwise 50% dose reduction over 5 months under double-blind conditions. Clinical status and side effects were assessed quarterly for a year. Relapse was determined clinically and by changes in psychopathology ratings., Results: Eighty-six percent (N = 37) of the patients (control group, N = 17; reduced-dose group, N = 20) completed the study. The groups did not differ at baseline in demographic or clinical variables or neuroleptic dose. In the reduced-dose group, doses were lowered to an average of 11.5 mg every 2 weeks. The two groups did not differ throughout the year in number of relapses, and hospitalization rates fell similarly in both (overall, by about 67%). Clinical measures changed little. Extrapyramidal symptoms worsened in the control group but improved slightly in the reduced-dose group. Tardive dyskinesia worsened in both groups, but less in the reduced-dose group., Conclusions: Maintenance neuroleptic doses much lower than the conventional ones can be achieved safely in schizophrenic patients by gradual reduction, without clinical worsening and perhaps with fewer extrapyramidal symptoms and less tardive dyskinesia. The two-thirds lower hospitalization rate, with substantial financial savings, apparently was due to nonspecific effects of research intervention.

Objective: This study was undertaken to assess the twentieth-century literature on outcome in schizophrenia for historical trends that might be associated with changes in diagnostic and therapeutic practice and to test the hypothesis that both improved biological treatment and changes in diagnostic criteria have influenced outcome., Method: Meta-analysis of the international literature on outcome in schizophrenia or dementia praecox from 1895 to 1992 identified 821 studies; 320 of these, with 51,800 subjects in 368 cohorts, met the inclusion criteria for the study., Results: Only 40.2% of patients were considered improved after follow-ups averaging 5.6 years (range = 1-40). Outcome was significantly better when patients were diagnosed according to systems with broad criteria (46.5% were improved) or undefined criteria (41.0% were improved) rather than narrow criteria (27.3% were improved). The proportion of patients who improved increased significantly after mid-century (for 1956-1985 versus 1895-1955, 48.5% versus 35.4%), probably reflecting improved treatment as well as a broadened concept of schizophrenia. However, in the past decade, the average rate of favorable outcome has declined to 36.4%, perhaps reflecting the re-emergence of narrow diagnostic concepts., Conclusions: Overall, less than half of patients diagnosed with schizophrenia have shown substantial clinical improvement after follow-up averaging nearly 6 years. Despite considerable gains in improvement rates after mid-century, there has been a decline since the 1970s. These historical changes probably reflect improved treatment, shifts in diagnostic criteria, and selection bias related to changes in health care.

The Personality Diagnostic Questionnaire-Revised (PDQ-R) was sent to first-degree relatives of major psychotic patients for identification of DSM-III-R personality disorders (PDs). Responses to the PDQ-R were interpreted both literally and empirically, and compared with the Structured Interview for DSM-III PDs (SIDP) as the standard. For literal interpretation, symptoms reported were counted directly for case identification using fixed DSM-III-R thresholds. The empirical approach adjusted the threshold for case identification to maximize concordance with the SIDP. Comparison of the two methods showed that using empirically determined thresholds in some scales gives better concordance with the SIDP. For the dependent and histrionic PD scales, the improvements were statistically significant. The area under the receiver operating characteristic (ROC) curve was computed for each PDQ-R scale to summarize its discriminatory capability across all thresholds. Areas under the ROC curve indicated that the schizoid, schizotypal, borderline, dependent, passive-aggressive, and histrionic PD scales in the PDQ-R have better discriminatory qualities than other PDQ-R scales.

Longitudinal studies have a prominent role in psychiatric research; however, statistical methods for analyzing these data are rarely commensurate with the effort involved in their acquisition. Frequently the majority of data are discarded and a simple end-point analysis is performed. In other cases, so called repeated-measures analysis of variance procedures are used with little regard to their restrictive and often unrealistic assumptions and the effect of missing data on the statistical properties of their estimates. We explored the unique features of longitudinal psychiatric data from both statistical and conceptual perspectives. We used a family of statistical models termed random regression models that provide a more realistic approach to analysis of longitudinal psychiatric data. Random regression models provide solutions to commonly observed problems of missing data, serial correlation, time-varying covariates, and irregular measurement occasions, and they accommodate systematic person-specific deviations from the average time trend. Properties of these models were compared with traditional approaches at a conceptual level. The approach was then illustrated in a new analysis of the National Institute of Mental Health Treatment of Depression Collaborative Research Program dataset, which investigated two forms of psychotherapy, pharmacotherapy with clinical management, and a placebo with clinical management control. Results indicated that both person-specific effects and serial correlation play major roles in the longitudinal psychiatric response process. Ignoring either of these effects produces misleading estimates of uncertainty that form the basis of statistical tests of hypotheses.

Two hundred twenty-four first-degree relatives of patients with psychotic disorders were administered the Structured Interview for DSM-III Personality Disorders (SIDP) and completed a self-report instrument to assess dimensions of the five-factor model of personality. All of the DSM-III personality disorders were related to one or more dimensions of the five personality factors; however, the correlations were generally low. It seems that the five personality factors describe important features of DSM-III personality disorders, but are not sufficient to completely explain their characteristics. Future use of the five-factor model in conjunction with personality disorder diagnoses may provide useful information for clinical work and research purposes.

The atypical neuroleptic clozapine has an unusual profile of clinical effects and a distinctive spectrum of pharmacological actions. Plasma measures of catecholamines and their metabolites have been used in the past to study the action of typical neuroleptics. We obtained longitudinal assessments of plasma measures of dopamine (pDA), norepinephrine (pNE), and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG), in eight treatment-resistant or treatment-intolerant schizophrenic patients who were treated with clozapine for 12 weeks following a prolonged drug-washout period. Our findings from the study of these eight patients suggest the following: Plasma levels of HVA and possibly NE derived from the neuroleptic-free baseline period may predict response to clozapine; plasma levels of HVA and MHPG decrease during the initial weeks of treatment in responders but not in nonresponders; and plasma levels of DA and NE increase in both responders and nonresponders to clozapine.

Mothers whose children had been sexually abused reported experiencing serious psychological symptoms following disclosure of the abuse. Over a one-year period, their emotional status improved. Strong relationships between mothers' reports of their own and their children's symptoms were accompanied by persistent discrepancies between maternal and direct assessments of the children's emotional states. Findings suggest that addressing maternal distress is important to the study and treatment of child sexual abuse.

A novel, simple approach to retrospective assessment of "blindability" was applied to data on outpatients in a controlled, double-blind clinical comparison of a putative antidepressant, etoperidone, and placebo. A "blind" evaluator proved capable of discriminating between the active drug and placebo on the basis of reported side effects alone, raising questions about the true blindness of the study.

Eye tracking and brain morphology assessed by magnetic resonance imaging were examined in 48 patients in their first episode of schizophrenia and in 15 normal controls. Schizophrenic patients showed higher rates of eye tracking dysfunction and more abnormal brain morphology involving the lateral ventricles, medial temporal lobe (MTL) structures and the frontal-parietal cortex than controls. Enlargement of the lateral ventricles and global rating of abnormal brain morphology were significantly more prevalent in male schizophrenics than female schizophrenics. These findings indicate that abnormalities in a variety of brain regions are present in some schizophrenics during the period shortly after the first hospitalization and could not be a function of treatment or chronic illness. We found no relation between abnormal eye tracking and any single feature of abnormal brain morphology. However, normal eye tracking was significantly associated with MTL abnormalities in schizophrenics, reflecting an inverse association between quality of eye tracking and degree of abnormality in MTL structures. These results suggest that abnormal eye tracking is not mediated by the same processes that lead to structural brain anomalies in schizophrenia.

Although sleep disturbance is a prominent feature of mania, its polysomnographic (PSG) features have received little study. To investigate more systematically the PSG characteristics of sleep in mania, all-night PSG evaluations were performed for two to four consecutive nights in 19 young manic patients (age range, 18 to 36 years), 19 age-matched patients with major depression, and 19 age-matched normal control subjects. Manic and depressed patients displayed nearly identical profiles of PSG abnormalities compared with normal control subjects, including disturbed sleep continuity, increased percentage of stage 1 sleep, shortened rapid eye movement latency, and increased rapid eye movement density. These results are similar to those reported in previous studies of major depression, and they are consistent with the possibility that the sleep disturbance in mania and major depression is caused by the same mechanism.

This paper presents an analysis of categorical variables subject to non-response. We incorporate the incomplete data into the analysis by modelling the distribution of the variables of interest and the non-response mechanism. We discuss issues of model selection and interpretation and the effect of discarding incomplete observations. In addition, we describe how to perform all of the computations with standard statistical software. We discuss the problem of incomplete categorical data within the context of a study of the effect of lead exposure on learning difficulties in children. In this study, many of the children are not observed on some of the variables of interest. It is particularly important in this study to incorporate the incomplete data, since there is evidence that non-response is related to the variables of interest. We reach different conclusions when we incorporate the incomplete data into the analysis than we reach when we discard the incomplete data. We also examine the sensitivity of our conclusions to the choice of a model for the non-response mechanism.

Pretreatment 24 hr urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and the Depression-type (D-type) scores (derived from a multivariate discriminant function equation based on levels of urinary catecholamines and metabolites) were examined as possible predictors of antidepressant responses to either imipramine or alprazolam. In the case of imipramine, the responders had significantly lower pretreatment urinary MHPG levels (p = 0.002) and D-type scores (p less than 0.001) than did nonresponders. In contrast, responders to the antidepressant effects of alprazolam had significantly higher pretreatment urinary MHPG levels (p less than 0.05) and D-type scores (p = 0.02) than did nonresponders. For each antidepressant treatment, D-type scores appeared to provide a better separation of responders from nonresponders than did urinary MHPG levels. For each drug, the effect size for the difference in mean log-transformed D-type scores between responders and nonresponders was greater than the effect size for the difference in mean log-transformed MHPG levels. The difference between the effect sizes was statistically significant for imipramine (p = 0.02) and tended toward significance for alprazolam using two-tailed tests. These results suggest that the D-type equation, which was initially derived to separate bipolar manic-depressive depressions from other subgroups of depressive disorders, can also be used to predict differential responses to certain antidepressant drugs in patients with unipolar depressions.

Smooth pursuit eye movements (SPEMs) of 11 bipolar manic patients were impaired during lithium treatment, which, however, improved their clinical condition. SPEM impairment was evident in a general qualitative degradation of eye tracking integrity, in a tendency for gain to be lowered, and in an increase in the number of saccadic events. Individual differences in the nature and magnitude of effects of lithium on eye movements were noteworthy.

In a cohort of 170 middle and upper-middle class children participating in a prospective study of child development and low-level lead exposure, higher blood lead levels at age 24 months were associated with lower scores at age 57 months on the McCarthy Scales of Children's Abilities. The mean blood lead level at age 24 months was 6.8 micrograms/dL (SD = 6.3; 75th, 90th, and 99th percentiles: 8.8, 13.7, 23.6, respectively) and for all but 1 child was less than 25 micrograms/dL, the current definition of an "elevated" level. After adjustment for confounding, scores on the General Cognitive Index decreased approximately 3 points (SE = 1.4) for each natural log unit increase in 24-month blood lead level. The inverse association between lead level and performance was especially prominent for visual-spatial and visual-motor integration skills. Higher prenatal exposures were not associated with lower scores at 57 months except in the subgroup of children with "high" concurrent blood lead levels (ie, greater than or equal to 10 micrograms/dL). The concentration of lead in the dentine of shed deciduous teeth was not significantly associated with children's performance after adjustment for confounding.

A 4-year follow-up of 75 patients was conducted to investigate outcome after recovery from an episode of mania. Predictors of an unfavorable outcome included poor occupational status prior to index episode, history of previous episodes, history of alcoholism, psychotic features and symptoms of depression during the index manic episode, male gender, and interepisode affective symptoms at 6 months' follow-up. The mortality risk during the follow-up period was 4%. The identification of specific risk factors depended on the definition of outcome and the length of follow-up.