Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect?

CONTEXT: Cognitive impairment in schizophrenia is frequent, involves multiple domains, and is enduring. Numerous recent clinical trials have suggested that second-generation antipsychotic medications significantly enhance cognition in schizophrenia. However, none of these studies included healthy controls undergoing repeated testing to assess the possibility that improvements might reflect simple practice effects. OBJECTIVE: To report the results on cognition of a randomized comparison of 2 widely prescribed second-generation antipsychotic medications, olanzapine and risperidone, in patients with first-episode schizophrenia and a healthy control group. DESIGN: Randomized clinical trial. SETTING: Hospital-based research units. Patients A total of 104 participants with first-episode schizophrenia and 84 healthy controls. MAIN OUTCOME MEASURES: Cognitive assessment of all study participants occurred at baseline, 6 weeks later, and 16 weeks later. Neurocognitive tests included measures of working memory and attention, speed, motor function, episodic memory, and executive function. RESULTS: No differential drug effects were observed. Of 16 cognitive measures, 9 demonstrated improvement over time and only 2 demonstrated greater rates of change than those observed in the healthy control group undergoing repeated assessment. The composite effect size for cognitive change was 0.33 in the healthy control group (attributed to practice) and 0.36 in the patients with first-episode schizophrenia. Improvements in cognition in the first-episode schizophrenia group could not be accounted for by medication dose, demographic variables, or intellectual level. CONCLUSIONS: The cognitive improvements observed in the trial were consistent in magnitude with practice effects observed in healthy controls, suggesting that some of the improvements in cognition in the first-episode schizophrenia group may have been due to practice effects (ie, exposure, familiarity, and/or procedural learning). Our results also indicated that differential medication effects on cognition were small. We believe that these findings have important implications for drug discovery and the design of registration trials that attempt to demonstrate cognitive enhancement.

DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients.

OBJECTIVE: All antipsychotics act on the dopamine D(2) receptor. The present study extends prior pharmacogenetic investigations of the D(2) receptor gene (DRD2) by examining, in first-episode schizophrenia patients, promoter region variation as a predictor of response time to two first-line atypical antipsychotics. METHOD: Patients experiencing their first episode of schizophrenia (N=61) were genotyped for two DRD2 promoter region polymorphisms (A-241G and -141C Ins/Del) and were randomly assigned to receive 16 weeks of treatment with either risperidone or olanzapine. Time until sustained response (two consecutive ratings without significant positive symptoms) for rare allele carriers versus wild types was examined by using Kaplan-Meier curves. RESULTS: Relative to wild type homozygotes, G carriers (A-241G) exhibited a significantly faster time until response, whereas -141C Del carriers took a significantly longer time to respond. Diplotype analysis revealed similar results. CONCLUSIONS: These findings suggest that variation in the D(2) receptor gene can, in part, explain variation in the timing of clinical response to antipsychotics in patients with first-episode schizophrenia.

Randomized comparison of olanzapine versus risperidone for the treatment of first-episode schizophrenia: 4-month outcomes.

OBJECTIVE: The authors compared 4-month treatment outcomes for olanzapine versus risperidone in patients with first-episode schizophrenia spectrum disorders. METHOD: One hundred twelve subjects (70% male; mean age=23.3 years [SD = 5.1]) with first-episode schizophrenia (75%), schizophreniform disorder (17%), or schizoaffective disorder (8%) were randomly assigned to treatment with olanzapine (2.5-20 mg/day) or risperidone (1-6 mg/day). RESULTS: Response rates did not significantly differ between olanzapine (43.7%, 95% CI=28.8%-58.6%) and risperidone (54.3%, 95% CI=39.9%-68.7%). Among those responding to treatment, more subjects in the olanzapine group (40.9%, 95% CI=16.8%-65.0%) than in the risperidone group (18.9%, 95% CI=0%-39.2%) had subsequent ratings not meeting response criteria. Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications. Extrapyramidal symptom severity scores were 1.4 (95% CI=1.2-1.6) with risperidone and 1.2 (95% CI=1.0-1.4) with olanzapine. Significantly more weight gain occurred with olanzapine than with risperidone: the increase in weight at 4 months relative to baseline weight was 17.3% (95% CI=14.2%-20.5%) with olanzapine and 11.3% (95% CI=8.4%-14.3%) with risperidone. Body mass index at baseline and at 4 months was 24.3 (95% CI=22.8-25.7) versus 28.2 (95% CI=26.7-29.7) with olanzapine and 23.9 (95% CI=22.5-25.3) versus 26.7 (95% CI=25.2-28.2) with risperidone. CONCLUSIONS: Clinical outcomes with risperidone were equal to those with olanzapine, and response may be more stable. Olanzapine may have an advantage for motor side effects. Both medications caused substantial rapid weight gain, but weight gain was greater with olanzapine.

Duration of untreated psychosis and time to treatment response for delusions and hallucinations.

OBJECTIVE: Duration of untreated psychosis is associated with time to treatment response among patients with schizophrenia. However, individual psychotic symptoms have not been investigated in this context. The authors examined the relationship between duration of untreated psychosis and time to response for hallucinations and delusions. METHOD: Data were available for 118 patients with first-episode schizophrenia in a longitudinal treatment study. Patients received open-label treatment with conventional antipsychotics and were followed for up to 5 years. Duration of untreated psychosis was correlated with time to response for delusions and hallucinations, and predictors of time to response were examined. RESULTS: Time to response for delusions was significantly longer than that for hallucinations. Duration of untreated psychosis was significantly correlated with time to response for delusions but not for hallucinations. In regression analyses, duration of untreated psychosis was the only predictor for time to response for delusions; it was not a predictor for hallucinations. CONCLUSIONS: The results suggest that duration of untreated psychosis may be specifically associated with time to response for delusions. This association may have clinical implications.

Pharmacological treatments for first-episode schizophrenia.

Studies with first-episode populations offer the unique opportunity to examine the effectiveness and side effects of medications without the confounding effects of prior medication use. This review focuses upon studies of (1) treatment of the initial episode, (2) maintenance treatment issues, (3) recovery, and (4) side effects. Response rates for the initial episode are high with both conventional and new-generation antipsychotics. However, we lack data directly comparing the new-generation agents with one another for treatment of the initial episode, and data about options for patients with treatment resistance at illness onset are very limited. With the most commonly used pharmacological therapies, the course of early-phase schizophrenia is characterized by repeated relapses and a low rate of recovery. Medication treatment is also associated with a variety of side effects. Of particular concern for treatment of first-episode patients are the metabolic side effects with the new-generation antipsychotics because they occur rapidly, are very distressful to adolescents and young adults, and have long-term medical consequences. Available data support maintenance treatment to prevent relapse, but questions remain about the optimal duration of maintenance treatment, whether there are differences among the new-generation agents for maintenance treatment, and balancing the benefits of maintenance antipsychotics with their long-term side effects.

Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder.

OBJECTIVE: Follow-up studies have found that a substantial number of patients with schizophrenia achieve full recovery (i.e., sustained improvement in both symptoms and social/vocational functioning) when examined decades after an index admission. This study addressed recovery during the crucial early course of the illness. METHOD: Subjects in their first episode of schizophrenia or schizoaffective disorder (N=118) were assessed at baseline and then treated according to a medication algorithm. Full recovery required concurrent remission of positive and negative symptoms and adequate social/vocational functioning (fulfillment of age-appropriate role expectations, performance of daily living tasks without supervision, and engagement in social interactions). RESULTS: After 5 years, 47.2% (95% CI=36.0%-58.4%) of the subjects achieved symptom remission, and 25.5% (95% CI=16.1%-34.7%) had adequate social functioning for 2 years or more. Only 13.7% (95% CI=6.4%-20.9%) of subjects met full recovery criteria for 2 years or longer. Better cognitive functioning at stabilization was associated with full recovery, adequate social/vocational functioning, and symptom remission. Shorter duration of psychosis before study entry predicted both full recovery and symptom remission. More cerebral asymmetry was associated with full recovery and adequate social/vocational functioning; a schizoaffective diagnosis predicted symptom remission. CONCLUSIONS: Although some patients with first-episode schizophrenia can achieve sustained symptomatic and functional recovery, the overall rate of recovery during the early years of the illness is low.

Clozapine as a first treatment for schizophrenia.

OBJECTIVE: The authors' goal was to explore whether clozapine given as the first antipsychotic treatment favorably affects the course of schizophrenia. METHOD: Thirty-four inpatients experiencing their first episode of schizophrenia or schizoaffective disorder were treated first with clozapine and then followed for up to 4 years. In a previous study, the authors followed patients experiencing their first episode of schizophrenia or schizoaffective disorder who were given fluphenazine as the first treatment. In the current study and the previous study, response criteria required sustained remission of positive symptoms. RESULTS: Nineteen of the 34 subjects met response criteria while taking clozapine. The median time to treatment response was 11 weeks (range=2-13). Using survival analysis, the authors determined that the cumulative response rate for the 34 patients was 66.4% at the end of 13 weeks, which is comparable to the response rate to fluphenazine in the previous study. All responses to clozapine occurred by 13 weeks. Eight (42%) of the clozapine responders discontinued clozapine before 6 months, and only six (32%) remained on clozapine for all of their time in the study. CONCLUSIONS: The authors found no benefit for clozapine over conventional antipsychotics for acute treatment of the first episode of schizophrenia or schizoaffective disorder. Long-term benefits could not be studied because of the high rate of early discontinuation of clozapine treatment.

Predictors of medication discontinuation by patients with first-episode schizophrenia and schizoaffective disorder.

BACKGROUND: Enhancing medication adherence early in the course of schizophrenia and schizoaffective disorder may substantially improve long-term course. Although extensively studied in multi-episode patients, little data exist on medication adherence by first-episode patients. METHOD: Medication adherence was assessed during the first year of treatment and following recovery from the first relapse in patients treated by a standardized medication algorithm. RESULTS: During the first year of treatment, patients with poorer premorbid cognitive functioning were more likely to stop antipsychotics (t=-2.54, df=75, p=0.01). Parkinsonian side effects increased the likelihood (hazard ratio=41.22; 95% CI=2.30, 737.89; p=0.01), and better executive function decreased the likelihood (hazard ratio=0.40; 95% CI=0.18, 0.88; p=0.02) that patients discontinued maintenance medication after a first relapse. CONCLUSION: Interventions to ameliorate cognitive deficits and Parkinsonian side effects may enhance treatment adherence.

Recognizing and managing antipsychotic drug treatment side effects in the elderly.

Although atypical antipsychotics differ from conventional antipsychotics in their decreased ability to cause reversible drug-induced movement disorders/motor side effects such as dystonia, drug-induced parkinsonism, and akathisia and potentially persistent drug-induced movement disorders/motor side effects such as tardive dyskinesia, no antipsychotic agent completely eradicates this risk. Antipsychotic agents are frequently used in facilities for the elderly and in general hospitals to treat older patients with behavioral problems. Drug-induced movement disorders are more common and more persistent in elderly patients than in younger patients, and this problem is exacerbated by the fact that antipsychotic medications are often misused by practitioners lacking adequate psychopharmacologic training. Movement disorders can be detrimental to an elderly patient's quality of life and may transform what were otherwise routine activities into difficult tasks. Educational programs are needed to teach primary care physicians, specialists, and patients and their families how to identify and manage drug-induced movement disorders in order to achieve safer and more efficacious care for elderly patients.

Incidence of tardive dyskinesia with risperidone or olanzapine in the elderly: results from a 2-year, prospective study in antipsychotic-naïve patients.

Tardive dyskinesia (TD) rates with second-generation antipsychotics (SGAs) are considered to be low relative to first-generation antipsychotics (FGAs), even in the particularly vulnerable elderly population. However, risk estimates are unavailable for patients naïve to FGAs. Therefore, we aimed to determine the TD incidence in particularly vulnerable, antipsychotic-naïve elderly patients treated with the SGA risperidone or olanzapine. The present work describes a prospective inception cohort study of antipsychotic-naïve elderly patients aged 55 years identified at New York Metropolitan area in-patient and out-patient geriatric psychiatry facilities and nursing homes at the time of risperidone or olanzapine initiation. At baseline, 4 weeks, and at quarterly periods, patients underwent assessments of medical and medication history, abnormal involuntary movements, and extra-pyramidal signs. TD was classified using Schooler-Kane criteria. Included in the analyses were 207 subjects (age: 79.8 years, 70.0% female, 86.5% White), predominantly diagnosed with dementia (58.9%) or a major mood disorder (30.9%), although the principal treatment target was psychosis (78.7%), with (59.4%) or without (19.3%) agitation. With risperidone (n=159) the cumulative TD rate was 5.3% (95% confidence interval (CI): 0.7, 9.9%) after 1 year (mean dose: 1.0±0.76 mg/day) and 7.2% (CI: 1.4, 12.9%) after 2 years. With olanzapine (n=48) the cumulative TD rate was 6.7% (CI: 0, 15.6%) after 1 year (mean dose: 4.3±1.9 mg/day) and 11.1% (CI: 0, 23.1%) after 2 years. TD risk was higher in females, African Americans, and patients without past antidepressant treatment or with FGA co-treatment. The TD rates for geriatric patients treated with risperidone and olanzapine were comparable and substantially lower than previously reported for similar patients in direct observation studies using FGAs. This information is relevant for all patients receiving antipsychotics, not just the especially sensitive elderly.