Estimated yield of early detection of prodromal or first episode patients by screening first degree relatives of schizophrenic patients.

Screening a population of relatives of current schizophrenic patients could be an efficient means to accrue a sample of early first episode or prodromal patients for a prediction study or an intervention study. The risk of new onset schizophrenia cases in any one year in a population of relatives depends on the number of schizophrenic probands and three additional factors: (1) the age of onset distribution for schizophrenia; (2) the lifetime risk of the at-risk group of relatives selected; and (3) the number of at-risk relatives per proband and their age distribution. Estimates are made for each of these parameters, and calculations are presented. The base model suggests that screening all siblings and children of patients with schizophrenia would yield approximately 19 new cases of schizophrenia per year per 10,000 relatives screened. The results of the calculation are relatively insensitive to reasonable variation of most model parameter estimates. The yield of new cases obtained by screening relatives of current patients appears to be low if the purpose is to recruit a sample for an early intervention study over a relatively short period of time.

Use of the Medication Event Monitoring System to estimate medication compliance in patients with schizophrenia.

OBJECTIVE: To determine the feasibility of using the Medication Event Monitoring System (MEMS) to estimate medication compliance in patients with schizophrenia or schizoaffective disorder. SUBJECTS AND SETTING: Fourteen of 35 consecutive patients admitted to a psychiatric inpatient hospital with schizophrenia or schizoaffective disorder who met eligibility requirements and gave informed consent. INTERVENTION: After random assignment to either risperidone or typical antipsychotic treatment, medication upon discharge from hospital was dispensed in a bottle with a MEMS cap which recorded the number of bottle openings and the date and time of each opening. The first 6 patients were asked to return monthly for data downloading. The next 8 were asked to return weekly during the first month and every 2 weeks thereafter; they were also paid $5 for returning each bottle. OUTCOME MEASURES: MEMS data collected over a 6-month period and hospital readmission data. RESULTS: Patient medication compliance data were collected from 10 (71%) of 14 patients during the first month, from 7 (58%) of 12 (2 patients dropped out) during the second and from 5 (45%) of 11 (a third patient dropped out) during months 3-6. Mean compliance rates were 63% for the first month and ranged from 56% to 45% over the next 5. First-month compliance rates were significantly lower for those who were subsequently readmitted to hospital (n = 7) than for those who were not (p < 0.01). CONCLUSIONS: Electronic monitoring devices can be used to estimate compliance with medication regimens in patients with severe schizophrenic disorders, but there are methodological improvements that can be made to increase data recovery and compliance, and these are discussed.

Neuroleptic use in the treatment of Post-Traumatic Stress Disorder.

BACKGROUND: There have been few studies of the use of neuroleptics in the treatment of Post-Traumatic Stress Disorder (PTSD). This study uses data from two large outcome studies to: (1) examine demographic and treatment characteristics associated with neuroleptic prescription in the treatment of PTSD, and (2) compare the outcomes of neuroleptic-treated patients with those not receiving neuroleptics. METHODS: A secondary analysis of an observational outcome study of 831 inpatients and 554 outpatients (all males) receiving treatment at the VA for combat-related PTSD was performed. Patients were classified as having either received neuroleptics during the following year or not. Sociodemographic characteristics, treatment and medication history and detailed information about PTSD symptoms were obtained at baseline and 12 months. First, the two groups were compared with respect to the demographic and clinical variables. We then conducted a series of separate paired t-tests to determine whether there was significant improvement from baseline to follow up in each group and a series of analyses of covariance that compared outcomes in the two groups, adjusting for baseline differences. RESULTS: Approximately 9% of inpatients and 10% of outpatients were treated with neuroleptics. Patients who received neuroleptics had both more psychiatric and more social impairment. They also demonstrated more severe PTSD (especially intrusive symptoms) despite having similar combat exposure. Outcomes after one year for the group treated with neuroleptics were not significantly different from the group not treated with neuroleptics. CONCLUSIONS: Neuroleptic use in the treatment of PTSD is targeted at more seriously ill patients and was not associated with substantial improvement.

Impact of clozapine on completed suicide.

OBJECTIVE: Clozapine has been found to be superior to typical neuroleptics in ameliorating the symptoms of refractory schizophrenia. This study evaluated clozapine's effect on the rate of death due to suicide. METHOD: All patients over a 4-year period who initiated treatment with clozapine while hospitalized within the Department of Veterans Affairs (VA) system (N=1,415) were matched with a schizophrenic control group (N=2,830) by propensity scoring-a widely accepted statistical method that has been used relatively little in psychiatric research. Centralized VA databases and a national death registry were used to identify all deaths within the two groups, along with listed causes, for the 3 years after discharge. RESULTS: Veterans exposed to clozapine while inpatients were significantly less likely to die during the follow-up period than those in the control group, but this was entirely attributable to the much lower rate of death due to respiratory disorders in the clozapine group. There were no significant differences in rates of suicide or accidental death. CONCLUSIONS: These results fail to support the hypothesis that clozapine treatment is associated with significantly fewer deaths due to suicide.

Consistency of atypical antipsychotic superiority to placebo in recent clinical trials.

BACKGROUND: The use of control placebos in clinical trials of new antipsychotic medications is increasingly under examination. The active controlled equivalence study could offer a potential alternative design. First, however, it must be clear that any proposed standard control agent has been consistently superior to placebo in previous studies. METHODS: Through a Freedom of Information Act request, we identified nine placebo-controlled trials of risperidone, olanzapine, or quetiapine. RESULTS: Meta-analysis indicated that the pooled estimate of the true population effect size +/- SE was 0.46 +/- 0.06 for categorical response rates and >0.53 +/- 0.07 for the continuous Brief Psychiatric Rating Scale change score outcome measure. If the desired detectable effect size is set very conservatively at a 95% confidence lower bound for the estimate of true effect size, statistical power for random samples of 80 per group drawn from a population of subjects similar to that of the nine meta-analyzed studies is.67 for categorical response rates and >.82 for the continuous measure, based on one-sided alpha =.05. CONCLUSIONS: These data suggest substantial confidence that a therapeutic dose of an atypical antipsychotic will be statistically superior to placebo in an adequately sized randomized trial, when reporting a continuous measure as the principal outcome.

Impact of clozapine prescription on inpatient resource utilization.

Although clozapine has been demonstrated to be clinically superior to typical neuroleptics in refractory schizophrenia, it is also more expensive. It had been hoped that the increased costs associated with its use would be offset by decreases in the utilization of other expensive resources, especially inpatient care. All patients who had clozapine initiated during an inpatient hospitalization within the VA for schizophrenia over a 4-year period (N = 1415) were matched with a comparison group (N = 2,830) on key service utilization variables and other possible confounding demographic and clinical variables using propensity scoring-an accepted statistical method, although still relatively little used in psychiatry. By using centralized VA databases, subsequent inpatient resource utilization for the 3 years after index discharge was examined. Veterans exposed to clozapine while inpatients recorded 33 (36%) more inpatient days in the subsequent 3 years after discharge than the comparison group (124 +/- 190 days vs. 91 +/- 181 days, p = .0002). When all patients exposed to clozapine were divided according to whether they had received 1 year of clozapine treatment after discharge, those that received less than 1 year's treatment recorded significantly more inpatient days than either those maintained on clozapine or controls. These results suggest that in actual practice clozapine treatment may cost substantially more than treatment with conventional neuroleptics.

Benzodiazepine use in posttraumatic stress disorder among veterans with substance abuse.

Veterans with posttraumatic stress disorder (PTSD) and substance abuse may abuse benzodiazepines and develop violent dyscontrol when using them. A total of 370 veterans were compared by substance abuse diagnosis (50%), benzodiazepine use (36%), and their interaction on 1-year outcomes after inpatient discharge. Substance abusers were less likely to be prescribed benzodiazepines (26% vs. 45%). No outcome showed a differential worsening by substance abuse or benzodiazepines, although some baseline differences were noted. Outpatient health care utilization was lower in benzodiazepine users (47 vs. 33 visits). Among PTSD patients with comorbid substance abuse, benzodiazepine treatment was not associated with adverse effects on outcome, but it may reduce health care utilization.

Characteristics of participants and nonparticipants in medication trials for treatment of schizophrenia.

OBJECTIVE: The study compared the characteristics of patients who participated in efficacy trials of medications for treatment of schizophrenia with those of the other patients in the clinical population from which the trial participants had been selected. METHODS: Study participants from ten trials of treatment efficacy conducted at a community mental health center in the early and mid-1990s were compared with nonparticipants using data on demographic and diagnostic characteristics and service utilization from the center's administrative database. Six of the trials selected patients with schizophrenia and no concurrent substance use disorder, and four selected patients with dual diagnoses of schizophrenia and a substance use disorder. RESULTS: Compared with nonparticipants, participants in both types of trial were about six to eight years younger, were two to four times less likely to have ever married, and used more services. Participants in trials that selected patients with no substance use disorder were more likely to be high school graduates and were four times more likely to work full time, compared with nonparticipants. Participants in trials that selected patients with dual diagnoses were likely to be minorities and less likely to have medical comorbidities, compared with nonparticipants. CONCLUSIONS: Participants in treatment efficacy trials differed substantially from nonparticipants. Some characteristics of the trial participants, including reduced likelihood of ever having been married and male gender, have been associated with poorer treatment outcomes in earlier studies. Other characteristics, such as younger age and greater likelihood of having graduated from high school and of working full time, have been associated with better outcomes.

Word and tone working memory deficits in schizophrenia.

BACKGROUND: Verbal memory deficits have been reported in many studies of patients with schizophrenia. We evaluated the specificity of these deficits by comparing patients and control subjects on several verbal and nonverbal auditory memory tests. METHODS: Performance of stable, medicated outpatients with DSM-III-R diagnoses of schizophrenia (N = 38) was compared with that of healthy subjects (N = 39) on a word list immediate recall task, tone delayed discrimination tasks, and word and tone serial position tasks. Before memory testing, patients were divided into 2 groups based on their ability to perform normally on a screening test requiring pitch discrimination and sustained attention. RESULTS: The nonverbal tests were more difficult for control subjects than the verbal tests. Despite this, patients who performed normally on the screening test of perception and attention performed normally on both nonverbal tests but had highly significant deficits on both verbal tests (P<.001 and P = .02). Patients who performed poorly on the screening test had highly significant performance deficits on all the memory tests. CONCLUSIONS: One subgroup of patients with schizophrenia has a selective deficit in verbal memory despite normal motivation, attention, and general perceptual function. Another group has deficits in multiple aspects of cognitive function suggestive of failure in early stages of information processing.

Naltrexone augmentation of neuroleptics in schizophrenia.

This study was conducted to determine whether the addition of naltrexone to ongoing neuroleptic treatment would facilitate the reduction in positive or negative symptoms in patients with schizophrenia. Twenty-one patients meeting DSM-III criteria for schizophrenia were enrolled; all patients had been stabilized for at least 2 weeks on their dosage of neuroleptic medicine before entering the study. Patients were randomized to receive either placebo or naltrexone 200 mg/day for 3 weeks in addition to their neuroleptic. Patients randomized initially into the placebo arm were crossed over to receive naltrexone in a single-blind fashion for 3 additional weeks. All patients were rated weekly with the Brief Psychiatric Rating Scale (BPRS). Fifteen patients received placebo and six received naltrexone in the first 3 weeks. No significant effects of naltrexone on total BPRS scores or BPRS subscale scores were observed. Patients who received naltrexone on a single-blind basis at the end of the placebo-controlled trial demonstrated a transient exacerbation in negative symptoms as reflected by the total BPRS score and the BPRS Withdrawal-Retardation subscale score. Repeated-measures analysis of variance (ANOVA) on the BPRS total score of the subsequent treatment with naltrexone showed a trend for a significance in the drug by time effect. Repeated-measures ANOVA on the BPRS Withdrawal-Retardation subscale of the subsequent treatment with naltrexone showed a significant drug by time effect. The current data failed to indicate a clinical benefit when naltrexone was added to the neuroleptic regimen. Other potential applications of naltrexone in schizophrenia are addressed.

Normal neurocognitive performance after extended practice in patients with schizophrenia.

This study evaluated new methods for improving the performance of patients with schizophrenia on specific neurocognitive tasks. Patients (n = 22) practiced sustained perceptual, memory and motor tasks 5 times/week for 10 weeks. Tasks were initially easy enough for patients to do well, but were made gradually more difficult over the 10 weeks. Patients received base pay and performance-based monetary supplements. No coaching or ongoing instruction was provided, and performance gains were assumed to depend upon implicit learning. High functioning healthy controls (n = 5) were given the same tasks at difficulty levels comparable to those achieved by patients after 10 weeks of practice. After 10 weeks of practice, 16 of the 22 patients performed as well or better than the best control on the perceptual and memory tasks, and 11 patients performed within the range of control subjects on the motor task. Half of the patients retested 6 months after training maintained supranormal performance, while the others showed marked performance declines. Patients with schizophrenia appear to have greater potential for neurocognitive improvement, and potentially for employment, than generally appreciated.

Chronic neuroleptic exposure in bipolar outpatients.

BACKGROUND: Although the chronic use of neuroleptic medications is generally discouraged in patients with bipolar disorder, data on the actual extent of this practice are relatively scarce. METHOD: All bipolar patients receiving treatment at the Connecticut Mental Health Center on September 1, 1994, were identified through a computerized administrative database; the medical record was then examined. Patients were included in the study if (1) the last two recorded diagnoses in the chart were concordant for bipolar disorder and (2) the patient had not been hospitalized in the past year. RESULTS: Of 49 patients meeting review criteria, 33 (67%) met criteria for chronic neuroleptic exposure. The mean +/- SD continuous neuroleptic dosage for these 33 outpatients was 416 +/- 527 mg/day chlorpromazine (CPZ) equivalents. The dosage distribution was skewed, with 17 (52%) receiving < or = 200 mg/day CPZ [corrected] equivalents. CONCLUSION: Chronic neuroleptic administration occurred frequently in our sample of nonhospitalized bipolar outpatients.

Effects of clozapine on smoking in chronic schizophrenic outpatients.

BACKGROUND: The effects of clozapine administration on smoking were examined in chronic schizophrenic outpatients. METHOD: Twenty-nine of 30 schizophrenic outpatients enrolled in a university-affiliated Community Mental Health Center clozapine clinic were retrospectively surveyed by semistructured questionnaire regarding smoking before and after clozapine administration. RESULTS: Smokers comprised 62% (N = 18) of patients, and within this group, there was a significant decrease in reported daily cigarette use during clozapine treatment compared with level of use when patients had been treated with typical neuroleptics (1.67 +/- 1.13 vs. 1.26 +/- 0.72 packs/day, p = .025). CONCLUSION: Clozapine may alter smoking behaviors in chronic schizophrenics.