Correlates of substance misuse in patients with first-episode schizophrenia and schizoaffective disorder.

OBJECTIVE: To identify factors associated with substance misuse in first-episode patients with schizophrenia or schizoaffective disorder. METHOD: Twenty-seven patients with a past or current history of substance misuse were compared with 91 patients with no history of misuse on demographic and psychopathological measures before being treated for their first episode of psychosis, and on cognitive measures after 6 months of treatment. RESULTS: There were no statistically significant differences between groups for sex, schizophrenia subtype, marital status, education, family history of schizophrenia, course of illness, age of onset, baseline symptoms, time to treatment response, medication side effects, attention span, memory and executive functioning. However, dual diagnosis patients were found to have a higher parental social class, better premorbid cognitive functioning, higher IQ and better language skills. CONCLUSION: First-episode patients with a history of substance misuse have higher intellectual functioning, which may be associated with higher premorbid socioeconomic status and cognitive functioning.

Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates.

OBJECTIVE: Neuropsychological impairments are well documented in schizophrenia and are important targets of treatment. Information about the severity and pattern of deficits after treatment for the first psychotic episode and about relationships between these deficits and syndromal characteristics remains limited. METHOD: Comprehensive neuropsychological assessments including 41 individual tests were given to 94 patients with first-episode schizophrenia after initial stabilization of psychosis and to a comparison group of 36 healthy volunteers. Profiles of neuropsychological deficits and the relationship of deficits to sex and handedness were examined. Correlations of neuropsychological deficit with a broad range of historical and clinical characteristics, including outcome, were explored. RESULTS: Patients had a large generalized neuropsychological deficit (1.5 standard deviations compared to healthy volunteers). Patients also had, superimposed on the generalized deficit, subtle relative deficits (less than 0.5 standard deviation compared to their own average profile) in memory and executive functions. Learning/memory dysfunction best distinguished patients from healthy individuals; after accounting for this difference, only motor deficits further distinguished the groups. Patients with higher neuropsychological ability had only memory deficits, and patients with lower ability had both memory and executive deficits. No sex differences were observed beyond the normal advantage for men in motor speed. Dextral patients had less severe generalized deficit. Severity of residual symptoms was associated with greater generalized deficit. Executive and attentional deficits were most linked to global functional impairment and poor outcome. CONCLUSIONS: The results document a large generalized deficit, and more subtle differential deficits, in clinically stabilized first-episode patients. Learning/memory deficits were observed even in patients with less severe generalized deficit, but the pattern was unlike the amnestic syndrome and probably reflects different mechanisms. Executive and attentional deficits marked the more severely disabled patients, and may portend relatively poor outcome. Failure to develop typical patterns of cerebral dominance may increase the risk for greater generalized deficit.

Side effects of antipsychotic drugs. Avoiding and minimizing their impact in elderly patients.

Antipsychotic drugs are very useful in treatment of psychosis and severe agitation in the elderly. Their use for other behavioral problems is contraindicated. Antipsychotics have many potential side effects (e.g., sedation, cardiovascular effects, anticholinergic effects, incontinence, reduced appetite, such motor disturbances as drug-induced parkinsonism, akathisia, dystonia, TD). Prevention, by using the minimum dose and duration of treatment possible, is the key to managing motor side effects. If prevention fails, drug-induced parkinsonism and dystonia may improve with use of anticholinergics, and akathisia may improve with use of benzodiazepines or low-dose propranolol. There is no proven treatment for TD, which is most likely to be observed during dose reduction or after discontinuation of antipsychotic drugs. Compared with older agents, newer antipsychotic drugs are less likely to cause parkinsonism, akathisia, and dystonia and may cause TD less often. More research is needed to clarify use of the new drugs in the elderly.

Obstetric complications predict treatment response in first-episode schizophrenia.

BACKGROUND: Understanding the role of obstetric complications (OCs) in schizophrenia could potentially shed light on the heterogeneity in the aetiology and course of schizophrenia. Many investigators have reported an association between OCs and schizophrenia, but few have examined the association between OCs and treatment outcome. We investigated this question in a sample of patients studied during their first episode of schizophrenia, schizoaffective or schizophreniform disorder. METHOD: OC histories were obtained for 59 patients participating in the Hillside First Episode Study. Cox proportional hazards regression analysis was used to estimate the effect of OCs on treatment response during the first episode of schizophrenia. RESULTS: Twelve of the 59 patients (20%) had positive histories of OCs. This group exhibited lower rates of treatment response than those with negative OC histories (hazard ratio controlling for sex = 0.28; 95% CI = 0.13, 0.62). The positive OC group also had significantly greater lateral ventricle volume, baseline disorganization and number of live births. The effect of OC history on treatment response held when these three variables were controlled for. CONCLUSION: A history of obstetric complications predicted poor response to treatment in the first episode of schizophrenia. This large effect was based on a small sample of 59 patients. Thus, replication is called for.

Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder.

OBJECTIVE: This study examined the treatment response of patients with first-episode schizophrenia and schizoaffective disorder and potential predictors of response. METHOD: First-episode patients were assessed on measures of psychopathology, cognition, social functioning, and biological parameters and treated according to a standardized algorithm. RESULTS: One hundred eighteen patients (52% male, mean age 25.2 years) entered the study. The cumulative percentage of patients responding by 1 year was 87%; the median time to response was 9 weeks. The following variables were significantly associated with less likelihood of response to treatment: male sex, obstetric complications, more severe hallucinations and delusions, poorer attention at baseline, and the development of parkinsonism during antipsychotic treatment. Variables not significantly related to treatment response were diagnosis (schizophrenia versus schizoaffective disorder), premorbid functioning, duration of psychotic symptoms prior to study entry, baseline disorganization, negative and depressive symptoms, baseline motor function, akathisia and dystonia during treatment, growth hormone and homovanillic acid measures, psychotic symptom activation to methylphenidate, and magnetic resonance measures. CONCLUSIONS: Patients with first-episode schizophrenia and schizoaffective disorder have high rates of response to antipsychotic treatment; there are specific clinical and pathobiologic predictors of response.

Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder.

BACKGROUND: We examined relapse after response to a first episode of schizophrenia or schizoaffective disorder. METHODS: Patients with first-episode schizophrenia were assessed on measures of psychopathologic variables, cognition, social functioning, and biological variables and treated according to a standardized algorithm. The sample for the relapse analyses consisted of 104 patients who responded to treatment of their index episode and were at risk for relapse. RESULTS: Five years after initial recovery, the cumulative first relapse rate was 81.9% (95% confidence interval [CI], 70.6%-93.2%); the second relapse rate was 78.0% (95% CI, 46.5%-100.0%). By 4 years after recovery from a second relapse, the cumulative third relapse rate was 86.2% (95% CI, 61.5%-100.0%). Discontinuing antipsychotic drug therapy increased the risk of relapse by almost 5 times (hazard ratio for an initial relapse, 4.89 [99% CI, 2.49-9.60]; hazard ratio for a second relapse, 4.57 [99% CI, 1.49-14.02]). Subsequent analyses controlling for antipsychotic drug use showed that patients with poor premorbid adaptation to school and premorbid social withdrawal relapsed earlier. Sex, diagnosis, obstetric complications, duration of psychotic illness before treatment, baseline symptoms, neuroendocrine measures, methylphenidate hydrochloride challenge response, neuropsychologic and magnetic resonance imaging measures, time to response of the initial episode, adverse effects during treatment, and presence of residual symptoms after the initial episode were not significantly related to time to relapse. CONCLUSIONS: There is a high rate of relapse within 5 years of recovery from a first episode of schizophrenia and schizoaffective disorder. This risk is diminished by maintenance antipsychotic drug treatment.

Obstetric complications in schizophrenia, schizoaffective disorder and normal comparison subjects.

Previous studies have indicated that obstetric complications (OCs) may be risk factors for schizophrenia, but findings are inconsistent, and data about other diagnostic groups are relatively scarce. We compared the obstetric histories of subjects with schizophrenia, major affective disorder and normal controls. Our subjects included 61 schizophrenia, 26 schizoaffective, 28 major affective disorder patients and 21 normal controls. OCs were rated on the McNeil-Sjöström Scale using data from mothers reports and for a subsample from hospital and birth certificate records. The frequency of OCs did not differ statistically between diagnostic groups at any stage or for the three stages combined. OCs of at least level 4 were found in 69% of schizophrenia patients, 62% of schizoaffective patients, 68% of major affective disorder patients and 71% of the normal comparison group. OCs of at least level 5 were found in 23% of schizophrenia patients, 23% of schizoaffective patients, 21% of the major affective disorder patients and 14% of the normal comparison group. Our findings indicate that the etiologic significance of OCs may not be specific to schizophrenia.

Prospective study of tardive dyskinesia in the elderly: rates and risk factors.

OBJECTIVE: The purposes of this study were to investigate the rate (incidence) of tardive dyskinesia in elderly patients beginning treatment with antipsychotic medication and to identify risk factors for development of tardive dyskinesia in this age group. METHOD: A group of 261 neuroleptic-naive patients aged 55 or above were identified at the time they were starting antipsychotic drug treatment. This group is the complete study group; a preliminary report based on the first 160 patients was published previously. Patients were evaluated at baseline and followed up at 3-month intervals for periods ranging from 3 to 393 weeks. Assessments included abnormal involuntary movements, extrapyramidal signs, psychiatric symptoms, and medical and drug treatment histories. RESULTS: The cumulative rates of tardive dyskinesia were 25%, 34%, and 53% after 1, 2, and 3 years of cumulative antipsychotic treatment. A greater risk of tardive dyskinesia was associated with history of ECT treatment, higher mean daily and cumulative antipsychotic doses, and presence of extrapyramidal signs early in treatment. Differences in tardive dyskinesia rates between diagnostic groups found in univariate analyses were attenuated when the authors controlled for these variables. CONCLUSIONS: Tardive dyskinesia rates for patients beginning treatment with conventional antipsychotics in their fifth decade or later are three to five times what has been found for younger patients, despite treatment with lower doses. Alternative treatments need to be investigated.

Clozapine reduces rehospitalization among schizophrenia patients.

A number of studies have reported reduced rehospitalization for patients on clozapine. This article adds to that literature by mining the clozapine database at Hillside Hospital. The sample consisted of 81 schizophrenia patients who entered Hillside on a typical neuroleptic and then had their medication changed to clozapine. We ascertained the number of inpatient hospitalizations before starting clozapine and compared this with the number of hospitalizations after starting clozapine. We also followed an age- and gender-matched comparison group of other schizophrenia patients who entered Hillside at approximately the same time. Results indicate that the mean number of rehospitalizations while on a typical neuroleptic was 2.03 (1.93)/year, whereas it was only .56 (.97/year after the commencement of clozapine treatment; t(80) = 5.78, p < .001. A 95% confidence interval for the superiority of clozapine over standard neuroleptic treatment as measured in rehospitalizations/year is (1.0, 2.0). The decrease in hospitalization rate of .4 (1.6)/year (pre-index date minus post-index date) for the comparison group was also statistically significant [t(80) = 2.3, p < .03]; the 95% confidence interval for this decrease over time is (.1, .8). The pre-post change was much greater for the clozapine patients than comparison patients. A 2 x 2 repeated measures analysis of variance (ANOVA) contrasting the comparison group to the clozapine patients both before and after the index date indicates a significant time by group interaction (F(1.80) = 22.35, p < .001), thus documenting the greater relative decrease in rehospitalization rate in the clozapine group.

Relapse and rehospitalization during maintenance treatment of schizophrenia. The effects of dose reduction and family treatment.

BACKGROUND: Previous studies have examined dose reduction and family treatment in schizophrenia, but none has examined their interaction. This study assessed the impact of dose reduction of antipsychotic medication and family treatment on relapse and rehospitalization during maintenance treatment. METHODS: Subjects were 313 male and female outpatients at 5 centers with a DSM-III-R diagnosis of schizophrenia or schizoaffective disorder. In a 3 x 2 design, subjects were randomized to 1 of 3 medication strategies using fluphenazine decanoate under double-blind conditions: continuous moderate dose (standard) (12.5-50 mg every 2 weeks); continuous low dose (2.5-10 mg every 2 weeks); or targeted, early intervention (fluphenazine only when symptomatic). Subjects also were randomized to 1 of 2 family treatment strategies (supportive or applied). Supportive family management involved monthly group meetings. The more intensive applied family management involved monthly group meetings and home visits where communication and problem-solving skills were taught. Patients and families were treated and assessed for 2 years. RESULTS: Both continuous low-dose and targeted treatment increased use of rescue medication and relapse; only targeted treatment increased rehospitalization. This pattern was consistent across both family treatments; there were no differences between family treatments. CONCLUSIONS: These findings reaffirm the value of antipsychotic medication in preventing relapse and rehospitalization. The absence of family treatment differences may be because both conditions engaged families.

Incidence and correlates of tardive dyskinesia in first episode of schizophrenia.

BACKGROUND: There is controversy over whether tardive dyskinesia (TD) is solely a consequence of antipsychotic drug treatment or in part may reflect an intrinsic aspect of the disease process. Pathophysiologic factors could, independently or in concert with drug effects, lead to the development of dyskinetic signs. METHODS: We studied prospectively 118 patients in their first episode of psychosis who were treatment-naive or had less than 12 weeks of antipsychotic drug exposure at study entry. Patients received standardized antipsychotic drug treatment and were evaluated for up to 8 1/2 years with regular assessments of psychopathologic signs and symptoms and side effects. RESULTS: The cumulative incidence of presumptive TD was 6.3% after 1 year of follow-up, 11.5% after 2 years, 13.7% after 3 years, and 17.5% after 4 years. Persistent TD had a cumulative incidence of 4.8% after 1 year, 7.2% after 2 years, and 15.6% after 4 years. Taken individually, both antipsychotic drug dose, entered as a time-dependent covariate, and poor response to treatment of the first psychotic episode were significant predicters of time to TD. When antipsychotic drug dose and treatment response were examined together, treatment responders had significantly lower hazards for presumptive TD than nonresponders (hazard ratio, 0.29; 95% confidence interval, 0.09 to 0.97). Dose was a trend-level predicter, with each 100-mg chlorpromazine equivalent unit increase in dose associated with a 5% increase in the hazard of presumptive TD (hazard ratio, 1.05; 95% confidence interval, 0.99 to 1.11). CONCLUSION: Poor response to the treatment of a first episode of psychosis and, to a lesser extent, antipsychotic drug dose are important factors in the development of TD. This suggests that there may be a disease-related vulnerability to TD manifest with antipsychotic drug exposure. Potential pathophysiologic factors might include neurodevelopmentally induced structural neuropathologic characteristics, sensitization of nigrostriatal dopamine neurons, and the induction of glutamatergically mediated neurotoxic effects.

Subject selection biases in clinical trials: data from a multicenter schizophrenia treatment study.

To evaluate subject selection biases in clinical trials, demographic characteristics (gender, race, and age) of subjects at different phases of evaluation for a multicenter maintenance trial in schizophrenia were examined. Six thousand twelve diagnostically appropriate subjects were screened for the study; of these, 1,320 met eligibility criteria and 528 (9% of the screened sample) entered the study. Women, blacks, and older subjects were more likely not to meet eligibility criteria; women and older subjects were more likely and blacks were less likely to refuse study participation. Overall, compared with the screened population, the sample of subjects who entered the study contained proportionately fewer women (33 vs. 43%), more blacks (48.5 vs. 41%), and fewer older subjects (mean age of the entered sample was 29.4 +/- 7.4 vs. 34.8 +/- 11.3 years for the screened population). Having identified these selection factors, a second goal was to assess the potential clinical relevance of selection biases of these magnitudes on clinical trials using models of hypothetical studies with different degrees of selection bias. These showed that selection biases would rarely change overall study outcomes to a clinically relevant degree. However, in our models, selection biases did limit the ability to make inferences about results for select small subgroups of the study population. Investigators should consider collecting data on the recruitment process to allow estimation of the effects of selection biases on the generalizability of their findings.

Neuroleptic treatment of elderly patients.

Data from an ongoing longitudinal study of the development of tardive dyskinesia were analyzed to examine the indications for neuroleptic treatment, continuity of treatment and dosage, and the effects of treatment on ratings of psychopathology and cognitive functioning during the first year of followup. Subjects were 266 elderly patients who had just begun neuroleptic treatment. Patients were predominantly (75%) female; their mean (+/- SD) age was 76.9 (+/- 9.2) years. A psychiatric diagnosis was recorded for 44 percent, primarily major depressive disorder; organic mental syndrome was diagnosed in 65 percent of the patients. Symptom ratings indicated 82 percent of the patients had psychosis, with or without agitation. Haloperidol was prescribed for 68 percent of the patients. Most were on neuroleptic medication continuously during the first month of followup; the average starting dose was 80 mg/day in chlorpromazine equivalent units. Symptom ratings at 1 month and 6 months showed significant improvement from baseline; ratings of dementia were unchanged.

Does clozapine cause tardive dyskinesia?

BACKGROUND: The authors attempted to determine if chronic exposure to clozapine can cause tardive dyskinesia. METHOD: Twenty-eight schizophrenic or schizoaffective patients with no prior history of definite tardive dyskinesia were treated with clozapine for at least 1 year, and their ongoing modified Simpson Dyskinesia Scale ratings were analyzed. These data were then compared with those of another group of similarly diagnosed patients who were treated with a conventional neuroleptic for at least 1 year. RESULTS: Two patients in the clozapine-treated group (both of whom had ratings of questionable tardive dyskinesia at baseline) were later rated by the modified Simpson Dyskinesia Scale as having mild tardive dyskinesia on at least two consecutive ratings 3 months apart. Although there was uncertainty about whether clozapine definitely caused the tardive dyskinesia in those two patients, a survival analysis comparing the clozapine-treated group with the neuroleptic-treated group showed a lower risk of tardive dyskinesia developing in the clozapine-treated group. CONCLUSION: This study was unable to definitively conclude whether clozapine causes tardive dyskinesia. However, if cases do develop, the risk of tardive dyskinesia is likely to be less with clozapine than with typical neuroleptics.

Diabetes and development of tardive dyskinesia.

Diabetes mellitus has been identified as a possible risk factor for tardive dyskinesia. The authors examined 160 elderly individuals who were beginning neuroleptic treatment; 24 had diabetes and 136 did not. After 43 weeks of neuroleptic exposure, the cumulative incidence rates of tardive dyskinesia were 54.1% (SE = 5.6%) for the diabetics and 25.6% (SE = 16.1%) for the nondiabetics.

Prospective study of tardive dyskinesia incidence in the elderly.

OBJECTIVES: To investigate the incidence of tardive dyskinesia in elderly individuals beginning treatment with antipsychotic drugs and to identify risk factors for the development of tardive dyskinesia in the elderly. DESIGN: A cohort of previously neuroleptic-naive patients was identified at the time of initiation of antipsychotic drug treatment. Patients were evaluated at baseline and followed up at 3-month intervals for periods ranging from 3 to 119 weeks. SETTING: Subjects were recruited from the psychiatric and geriatric medical services of two medical centers, a geriatric institute, and three nursing homes in the metropolitan area of New York City, NY. PATIENTS: Two hundred fifteen individuals older than 55 years have entered the study thus far. Preliminary data are presented for 160 patients who were followed up for at least 1 month. Their age range was 57 to 99 years (mean, 77 years). Seventy-two percent were women and 87% were white. Sixty-seven percent of patients had a diagnosis of organic mental syndrome and 42% had a psychiatric diagnosis. INTERVENTIONS: A naturalistic, longitudinal, repeated assessment paradigm was employed. Assessments included abnormal involuntary movements, extrapyramidal signs, psychiatric symptoms, and medical and drug treatment histories. MAIN OUTCOME MEASURE: The incidence of tardive dyskinesia was determined using a standardized rating instrument and survival analysis. RESULTS: The incidence of neuroleptic-induced dyskinesia was 31% (95% confidence interval, 20%, 42%) after 43 weeks of cumulative neuroleptic treatment. Psychiatric (as opposed to organic) diagnosis and presence of extrapyramidal signs early in treatment were associated with increased tardive dyskinesia vulnerability.

The prevalence of tardive dyskinesia.

A total of 2250 subjects from psychiatric and geriatric settings was examined for abnormal involuntary movements by the same team of trained raters employing a standard examination technique and rating scale. "Spontaneous" dyskinesia rates were 1.3% among 400 healthy elderly people surveyed at senior citizens centers, 4.8% among medical geriatric inpatients and ranged from 0 to 2% among psychiatric patients never exposed to neuroleptics. For samples of neuroleptic-treated patients, prevalence rates ranged from 13.3% among patients at a voluntary psychiatric hospital to 36.1% among state hospital patients. Logistic regression analyses revealed a large effect of age on tardive dyskinesia prevalence and an interaction of age with sex. Among younger subjects, men had higher rates; among subjects over age 40, rates were higher for women. Edentulousness and presence of other neurological disorders were possible contributors to high rates for the elderly. Even with control for age, sex and duration of neuroleptic exposure, prevalence differed markedly across study site.