Recovery from psychotic illness: a 15- and 25-year international follow-up study.

BACKGROUND: Poorly defined cohorts and weak study designs have hampered cross-cultural comparisons of course and outcome in schizophrenia. AIMS: To describe long-term outcome in 18 diverse treated incidence and prevalence cohorts. To compare mortality, 15- and 25-year illness trajectory and the predictive strength of selected baseline and short-term course variables. METHODS: Historic prospective study. Standardised assessments of course and outcome. RESULTS: About 75% traced. About 50% of surviving cases had favourable outcomes, but there was marked heterogeneity across geographic centres. In regression models, early (2-year) course patterns were the strongest predictor of 15-year outcome, but recovery varied by location; 16% of early unremitting cases achieved late-phase recovery. CONCLUSIONS: A significant proportion of treated incident cases of schizophrenia achieve favourable long-term outcome. Sociocultural conditions appear to modify long-term course. Early intervention programmes focused on social as well as pharmacological treatments may realise longer-term gains.

Statistical cost-effectiveness analysis of two treatments based on net health benefits.

Statistical methods for cost-effectiveness analysis (CEA) for two treatments that mimic the deterministic optimal rules of CEA are presented. In these rules the objective is to determine the treatment with the maximal effectiveness whose unit cost is less than an amount, lambda, that a decision-maker is willing to pay (WTP). This is accomplished by identifying the treatment with the largest positive net health benefit (NHB), which is a function of lambda, while controlling the familywise error rate both when the WTP value is given and when it is unspecified. Fieller's theorem is used to determine a region of WTP values where the NHBs of the treatments are not distinguishable. For each lambda outside of the confidence region, the larger treatment is identified. A newly developed one-tailed analogue of Fieller's theorem is used to determine the WTP values where a treatment's NHB is positive. The situation in which both treatments are experimental is distinguished from the case where one of the treatments is usual care. The one-tailed confidence region is used in the latter case to obtain the lambda values where the NHBs are not different, and determining the region of positivity of the NHBs may be unnecessary. An example is presented in which the cost-effectiveness of two antipsychotic treatments is evaluated.

The prevalence and correlates of untreated serious mental illness.

OBJECTIVE: To identify the number of people in the United States with untreated serious mental illness (SMI) and the reasons for their lack of treatment. DATA SOURCE/STUDY DESIGN: The National Comorbidity Survey; cross-sectional, nationally representative household survey. DATA COLLECTION: An operationalization of the SMI definition set forth in the Alcohol, Drug Abuse, and Mental Health Administration Reorganization Act identified individuals with SMI in the 12 months prior to the interview. The presence of SMI then was related to the use of mental health services in the past 12 months. PRINCIPAL FINDINGS: Of the 6.2 percent of respondents who had SMI in the year prior to interview, fewer than 40 percent received stable treatment. Young adults and those living in nonrural areas were more likely to have unmet needs for treatment. The majority of those who received no treatment felt that they did not have an emotional problem requiring treatment. Among those who did recognize this need, 52 percent reported situational barriers, 46 percent reported financial barriers, and 45 percent reported perceived lack of effectiveness as reasons for not seeking treatment. The most commonly reported reason both for failing to seek treatment (72 percent) and for treatment dropout (58 percent) was wanting to solve the problem on their own. CONCLUSIONS: Although changes in the financing of services are important, they are unlikely by themselves to eradicate unmet need for treatment of SMI. Efforts to increase both self-recognition of need for treatment and the patient centeredness of care also are needed.

Assessing the onset of relief of a treatment for migraine.

It is common for clinical trials designed to compare treatments for migraine to incorporate a component for estimating onset. Our objective is to describe a stopwatch method for collecting data on time to meaningful relief and a conceptual framework for describing and analysing the results. The survival distribution of onset is modelled in two parts: the probability that onset does not occur, and the survival distribution conditional on its occurrence. Using data from a clinical trial comparing an active treatment and placebo, we illustrate the method and find that the distributions of onset among those with onset do not differ, but the probabilities that onset occurs are substantially different. We illustrate how the model can be used to help determine how long patients without onset should wait before further intervention, how patients interpret the phrase meaningful relief, and how baseline clinical characteristics affect the onset.

Power and sample size in cost-effectiveness analysis.

For resource allocation under a constrained budget, optimal decision rules for mutually exclusive programs require that the treatment with the highest incremental cost-effectiveness ratio (ICER) below a willingness-to-pay (WTP) criterion be funded. This is equivalent to determining the treatment with the smallest net health cost. The designer of a cost-effectiveness study needs to select a sample size so that the power to reject the null hypothesis, the equality of the net health costs of two treatments, is high. A recently published formula derived under normal distribution theory overstates sample-size requirements. Using net health costs, the authors present simple methods for power analysis based on conventional normal and on nonparametric statistical theory.

Ratio-based and net benefit-based approaches to health care resource allocation: proofs of optimality and equivalence.

Both incremental cost-effectiveness ratios and net benefits have been proposed as summary measures for use in cost-effectiveness analyses. We present a unifying proof of the optimality and equivalence of ICER- and net benefit-based approaches to the health resource allocation problem, including both 'fixed budget' and 'fixed price' decision rules. If internally consistent willingness-to-pay values are used, ratio- and net benefit-based decision rules identify the same optimal allocation. Because they have identical resource allocation implications, use of one or other of the two approaches must be based on other criteria, such as their behaviour under conditions of uncertainty.

The usefulness of average cost-effective ratios.

We demonstrate that average cost-effectiveness ratios (CERs) play an important role in the evaluation of the cost-effectiveness of treatments. Criticisms of the usefulness of CERs derive mostly from the context of resource allocation under a constrained budget in which some decisions are based on incremental CERs. However, we show that in many cases, these decision rules are equivalent to decision rules on CERs. This follows for mutually exclusive treatments first, because a treatment is eliminated by extended dominance if and only if there is a mixed treatment with a smaller CER, where the mixing parameter lies in a certain interval. Second, after elimination of treatments by dominance and by extended dominance, resources can be allocated in order of increasing CERs. Moreover, the CER is a parameter that characterizes clinical and economical properties of a treatment independent of its comparators.

Estimating the size of a population from a single sample: methodology and practical issues.

In contrast to classical capture recapture methods, the single-sample method of Laska, Meisner, and Siegel (1988) (LMS) enables estimation of the size of a population, N*, on the basis of a single survey. For example, it may be desired to estimate the unduplicated number of individuals served by a mental health center during the last year on the basis of a 1-week sample. The time since each of the sampled individuals last engaged in the activity that defines the population is ascertained. The LMS estimator of N* and its unbiasedness property are motivated in a simple way, and an improved LMS estimator is introduced if additional information is available. An empirical assessment of the procedure is made using mental health service data for which the true population size is known. The performance of the extended LMS estimator is a substantial improvement over the standard LMS estimator.

Classification of the effectiveness of combination treatments.

According to FDA regulations, a combination drug is not efficacious unless each component contributes to the claimed effects. For a univariate endpoint, this implies that the combination at specific doses must be superior to each of its components at the same doses. More demanding is the property of synergy, in which the effect of the combination must be superior to the effect expected based on those of its components. If it is equal to those effects, it is additive, and if it is inferior, it is antagonistic. We give regions in the combination dose plane where these concepts are well defined. If the effect of the combination is greater than the greatest effect achievable by any of its components it is therapeutically synergistic. A combination can be antagonistic, yet its components can still contribute to the claimed effects. If it is additive, synergistic or therapeutically synergistic, its components must contribute to the claimed effects. We relate these concepts and provide designs and sequential procedures for determining whether a combination is therapeutically synergistic, synergistic, additive, antagonistic and contributing or antagonistic and non-contributing.

Seguimiento a largo plazo de la esquizofrenia en 16 países: descripción del estudio internacional de la esquizofrenia desarrollado por la Organización Mundial de la Salud / Long term follow-up of schizophrenia in 16 country

un hallazgo inesperado del Estudio Internacional Piloto de la Esquizofrenia, iniciado por la Organización Mundial de la Salud (OMS) en 1967, fue que los pacientes pertenecientes a países fuera de Europa y de los estados Unidos tienen un curso de enfermedad más favorable a corto y mediano plazo que aquellos observados en países desarrollados. desde entonces, la OMS, ha intensificado sus programas de investigación en esquizofrenia y ha iniciado un grupo de estudios internacionales que han confirmado estos hallazgos iniciales y explorado las razones posibles para tales diferencias en el curso y pronóstico de la esquizofrenia. Aun cuando tales trabajos han brindado importantes hallazgos y han generado hipótesis pertinentes adicionales, no explican las diferencias en pronóstico. El presente trabajo describe una nueva iniciativa en la cual aproximadamente 2500 individuos pertenecientes a estudios multicentricos previos de esquizofrenia de la OMS, son seguidos por el 15 a 25 años posteriores a su evaluación inicial. Tomaron parte en esta investigación diecinueve centros de investigación en 16 paise. Se describe la Metodología de la investigación

History of violent behaviour and schizophrenia in different cultures. Analyses based on the WHO study on Determinants of Outcome of Severe Mental Disorders.

BACKGROUND: Information on patterns and correlates of the violent behaviour of individuals with schizophrenia is largely limited to populations in developed countries. Data from a World Health Organization epidemiological study of schizophrenia and related disorders, the Determinants of Outcome of Severe Mental Disorders (DOSMD), presented an opportunity to study patterns of violence across multinational settings. METHOD: Centres in 10 countries participated in the DOSMD study. An incidence sample of 1017 patients with schizophrenia who had their first-in-lifetime contact with a helping agency as a result of their psychotic symptoms was obtained. Data were available on their history of violent behaviour, substance use, and demographics. RESULTS: The occurrence rate of assault in the entire cohort was 20.6 per hundred, but the rate was three times higher in the developing countries (31.5 per hundred) than in developed countries (10.5 per hundred). History of assault was associated with positive symptoms, such as excitement and auditory hallucinations, and with serious alcohol problems. CONCLUSIONS: The cultural context and the specific characteristics of the disease in individuals with schizophrenia may interactively affect rates of violent behaviour.

Statistical inference for cost-effectiveness ratios.

Methods for statistical inference for cost-effectiveness (C/E) ratios for individual treatment and for incremental cost-effectiveness (delta C/ delta E) ratios when two treatments are compared are presented. In a lemma, we relate the relative magnitude of two C/E ratios to the delta C/ delta E ratio. We describe a statistical procedure to test for dominance, or admissibility, that can be used to eliminate an inferior treatment. The one-sided Bonferroni's confidence interval procedure is generalized to the two-sided case. The method requires only that two confidence intervals be available, one for cost and one for effectiveness. We describe Fieller-based confidence intervals and show them to be shorter than Bonferroni intervals. When distribution assumptions hold and variance and covariance estimates are available, Fieller intervals are preferable. However, Bonferroni intervals can be applied in more diverse situations and are easier to calculate. A simple Bonferroni based technique, and a likelihood ratio statistic given by Siegel, Laska and Meisner, for testing the null hypothesis that the C/E ratios of two treatments are equal is presented. The approaches are applied to the data from a phase II clinical trial of a new treatment for sepsis considered previously by others.

Statistical methods for cost-effectiveness analyses.

A statistical framework is presented for examining cost and effect data on competing interventions obtained from an RCT or from an observational study. Parameters of the join distribution of costs and effects or a regression function linking costs and effects are used to define cost-effectiveness (c-e) measures. Several new c-e measures are proposed that utilize the linkage between costs and effects on the patient level. These measures reflect perspectives that are different from those of the commonly used measures, such as the ratio of expected cost to expected effect, and they can lead to different relative rankings of the interventions. The cost-effectiveness of interventions are assessed statistically in a two stage procedure that first eliminates clearly inferior interventions. Members of the remaining admissible set are then rank ordered according to a c-e preference measure. Statistical techniques, particularly in the multivariate normal case, are given for several commonly used c-e measures. These techniques provide methods for obtaining confidence intervals, for testing the hypothesis of admissibility and for the equality of interventions, and for ranking interventions. The ideas are illustrated for a hypothetical clinical trial of antipsychotic agents for community-based persons with mental illness.

Long-term follow-up of schizophrenia in 16 countries. A description of the International Study of Schizophrenia conducted by the World Health Organization.

An unexpected finding of the International Pilot Study of Schizophrenia, launched by the World Health Organization (WHO) in 1967, was that patients in countries outside Europe and the United States have a more favourable short- and medium-term course of the disease than those seen in developed countries. Since then, WHO has intensified its schizophrenia research programme and has initiated a set of international studies that have confirmed these initial findings and explored possible reasons for such differences in the course and outcome of schizophrenia. While such work has provided important findings and has generated additional pertinent hypotheses, it did not explain the differences in outcome. The present paper describes a new initiative in which approximately 2500 subjects involved in previous WHO multicentre schizophrenia studies are being followed up for between 15 and 25 years after initial examination. Nineteen research centres in 16 countries are taking part in this work. The research methodology is described.

Estimating population size when duplicates are present.

Each of K mental health programmes reports the number of patients served in a year. The sum of these numbers, y, is an overcount because some patients are seen in more than one programme. Health care planners need to know the unduplicated number served by the mental health system. Thus, there is an unknown number, M, of distinct individuals who appear on one or more of K lists; some appear on multiple lists and the duplicates are not readily identifiable. Let X be the number of lists on which a randomly selected individual appears. When E(X) is known, y/E(X) is the natural estimator of M. We assume that we know the number of programmes, Xi, used by the ith individual in a random sample of recipients of service. Here, the intuitive estimator, Y/X has desirable statistical properties. We give confidence interval estimators for M. We apply the method to estimate the number of individuals served in 1991 by the mental health programmes in New York State.

Blunted change in cerebral glucose utilization after haloperidol treatment in schizophrenic patients with prominent negative symptoms.

OBJECTIVE: The purpose of this report was to determine 1) the effects of chronic haloperidol treatment on cerebral metabolism in schizophrenic patients, 2) the relation between negative symptoms and haloperidol-induced regional changes in cerebral glucose utilization, and 3) the relation between metabolic change and clinical antipsychotic effect. METHOD: Cerebral glucose utilization, as determined by position emission tomography (PET), was studied in 18 male schizophrenic subjects before and after chronic treatment with haloperidol at a standardized plasma level. RESULTS: Overall, haloperidol caused a widespread decrease in absolute cerebral glucose metabolism. The cerebral metabolic response to haloperidol was blunted in patients with high pretreatment negative symptom scores. CONCLUSIONS: Taken together with the results from a previously reported PET study of the effects of an acute amphetamine challenge (in which 14 of the current subjects participated), these data suggest that the negative symptom complex is associated with diminished cerebral response to change in dopaminergic activity. This deficit cannot be solely accounted for by structural differences.

Placebo washout in trials of antipsychotic drugs.

For antipsychotic phase 3 clinical trials, we compare the relative merits of a placebo washout period with an alternate design strategy using a low-dose antipsychotic treatment. Evaluations are made with respect to the achievement of specific clinical trial design goals including the effect on power for detecting between-treatment and within-treatment pre-post differences. The relative merits of these two designs are discussed separately for those patients who enter the initial leadin period after withdrawal from previous antipsychotic medication and for those not on medication immediately before that period.

Mortality and temporal course of probable Alzheimer's disease: a 5-year prospective study.

Alzheimer's disease (AD) is associated with an increased mortality in comparison with aged control populations. The relationship between the clinical and the temporal course of AD has not been well studied over significant intervals. Community-residing patients with probable AD (N = 103, 42 men, mean age = 70.2 +/- 8.0 years) were studied at baseline on demographic and clinical variables, including measures of global deterioration (Global Deterioration Scale; GDS), mental status and cognition (e.g., Mini-Mental State Examination; MMSE), and functional impairment (Functional Assessment Staging; FAST). Baseline characteristics included a GDS range of Stage 4, 5, or 6 (38.8%, 39.8%, and 21.4%, respectively) and a mean MMSE score of 15.4 +/- 5.6. The mean follow-up interval was 4.6 +/- 1.4 years. Follow-ups were done blind to baseline measures and when necessary were conducted in residential and nursing home settings. Of locatable subjects (n = 95, 92%), 30 (31.6%) were decreased. Survivors (n = 65) had a mean GDS stage of 6.2 +/- 0.9 and a mean MMSE score of 5.1 +/- 6.9; 51% had MMSE scores of 0. Increased age and male gender, but not baseline clinical dementia variables, increased the risk of death (ps < .01). Change in clinical variables correlated significantly with time elapsed (r = .32, p < .05, for MMSE change, to r = .48, p < .001, for GDS change). Significant variance in temporal change (i.e., time elapsed) was accounted for by change in two of the five clinical measures studied (i.e., GDS and FAST; multiple r = .53). The results support previous estimates of mean duration of the GDS and FAST stages. For subjects with probable AD followed over approximately 5 years, clinical variables changed significantly over time in survivors. However, the majority of temporal variance in the course of AD remains unexplained.

Characterizing onset in psychopharmacological clinical trials.

In addition to describing treatment efficacy in terms of changes in rating scale scores, the distributions of time to occurrence of major clinical events such as onset and response are clinically important information. Issues in the design, conduct and analysis of clinical trials in which the time to onset of effect or time to response is to be characterized are discussed. A criterion must be defined to signal that the clinical event has occurred. Onset properties are given in terms of (1) the probability of obtaining onset and (2) for patients who obtain onset, the distribution of time to onset. A statistical model and methods to estimate parameters and compare onset times of treatments are described. A simple formula that can be used to aid in clinical decision making as to when to alter treatment if onset has not yet occurred is presented.

Acute d-amphetamine challenge in schizophrenia: effects on cerebral glucose utilization and clinical symptomatology.

The effects of d-amphetamine (0.5 mg/kg orally) on regional cerebral glucose utilization were measured with positron emission tomography (PET) in 17 schizophrenics (along with a placebo-control group of an additional six schizophrenic patients). The acute d-amphetamine challenge tended to decrease glucose utilization throughout much of the brain, with a regional effect that was statistically significant in the left temporal cortex. There was no apparent relationship between the effects of amphetamine-induced changes in regional cerebral metabolism and psychotic symptom exacerbation. An exploratory analysis suggested that features characteristic of Crow's type II syndrome were significant predictors of cerebral hyporesponsivity to stimulant challenge, however.