Subjective experience and striatal dopamine D(2) receptor occupancy in patients with schizophrenia stabilized by olanzapine or risperidone

OBJECTIVE: The authors' goal was to study the relationship between subjective experience during treatment with olanzapine or risperidone and dopamine D(2) receptor occupancy in stabilized patients with schizophrenia. METHOD: Subjective experience, psychopathology, and extrapyramidal symptoms were assessed, and D(2) receptor occupancy was determined with [(123)I]iodobenzamide single photon emission computed tomography, in 22 patients whose schizophrenia was stabilized by olanzapine or risperidone. RESULTS: Subjective experience, depression, and negative symptoms were related to dopamine D(2) receptor occupancy, but extrapyramidal symptoms were not. CONCLUSIONS: These results provide preliminary evidence that negative subjective experience is related to high D(2) receptor occupancy. Longitudinal study is required because this relationship may have implications for dosing strategies.     

Olanzapine vs. risperidone in patients with first-episode schizophrenia and a lifetime history of cannabis use disorders: 16-week clinical and substance use outcomes

The purpose of this study is to compare the efficacy of olanzapine and risperidone for the acute treatment of first-episode schizophrenia patients with cannabis use disorders. This secondary analysis of a previously published study included 49 first-episode patients with a diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder and a co-occurring lifetime diagnosis of cannabis use disorders randomly assigned to treatment with either olanzapine (n = 28) or risperidone (n = 21) for 16 weeks. The olanzapine group did not differ significantly from the risperidone group for initial response rates of positive symptoms, and rates of cannabis use or alcohol use during the study. Positive symptoms and the Scale for Assessment of Negative Symptoms (SANS) global asociality-anhedonia scores improved over time but did not differ between study medications. In both groups, cannabis use during the study was higher in patients who used cannabis within three months of the admission. Thus, our results suggest that olanzapine and risperidone had a similar initial efficacy on psychotic symptoms and substance use in first-episode patients with co-occurring cannabis use disorders. If clinicians are choosing between olanzapine versus risperidone treatment for this population, their decision should be based upon factors other than symptom response and short-term substance misuse.     

Dopamine D2 receptor occupancy by olanzapine or risperidone in young patients with schizophrenia

A crucial characteristic of antipsychotic medication is the occupancy of the dopamine (DA) D2 receptor. We assessed striatal DA D2 receptor occupancy by olanzapine and risperidone in 36 young patients [31 males, 5 females; mean age 21.1 years (16-28)] with first episode schizophrenia, using [123I]iodobenzamide (IBZM) SPECT. The occupancy of DA D2 receptors was not significantly different between olanzapine and risperidone. However, in subgroups of most prescribed doses, DA D2 occupancy was higher in the risperidone 4-mg group (79%) compared to the olanzapine 15-mg group (62%). [123I]IBZM binding ratios decreased with olanzapine dose (r = -0.551; P < 0.01), indicating higher DA D2 receptor occupancy with higher olanzapine dose. Akathisia and positive symptoms were correlated with [123I]IBZM binding ratio (r = -0.442; P < 0.01; and r = -0.360; P < 0.05, respectively). Prolactin (PRL) levels were elevated in the risperidone, but not in the olanzapine group, at comparable D2 receptor occupancy levels. In the olanzapine group, PRL levels were correlated with [123I]IBZM binding ratio (r = -0.551; P < 0.01). In conclusion, both olanzapine and risperidone induce a high striatal D2 receptor occupancy, dependent on dose and group formation. The lower incidence of prolactin elevation with olanzapine, compared to risperidone, may not be attributed to a lower D2 receptor occupancy.     

Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics

OBJECTIVE: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics. METHOD: Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D(1) and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone. RESULTS: Mean striatal D(1) occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31). CONCLUSIONS: Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.     

Subjective experience and D2 receptor occupancy in patients with recent-onset schizophrenia treated with low-dose olanzapine or haloperidol: a randomized,double-blind study

OBJECTIVE: The authors tested the hypothesis that a dopamine D(2) receptor occupancy level between 60% and 70% in patients with recent-onset schizophrenia would result in optimal subjective experience. In addition, they sought preliminary evidence on whether subjective experience is better with low-dose olanzapine than with low-dose haloperidol. METHOD: Subjects (N=24) who met DSM-IV criteria for schizophrenia were randomly assigned to 6 weeks of double-blind treatment with either olanzapine, 7.5 mg/day, or haloperidol, 2.5 mg/day. Subjective experience, psychopathology, and extrapyramidal symptoms were assessed at baseline and at endpoint. After 6 weeks, D(2) receptor occupancy was assessed with [(123)I]iodobenzamide single photon emission computed tomography. RESULTS: The two study groups were similar at baseline. After 6 weeks, patients receiving olanzapine had a significantly lower mean dopamine D(2) receptor occupancy (51.0%, range=36%-67%) than those given haloperidol (65.5%, range=45%-75%). Receptor occupancy between 60% and 70% was associated with optimal subjective experience, and subjective experience improved significantly in the haloperidol group. CONCLUSIONS: A level of D(2) receptor occupancy between 60% and 70% is optimal for subjective experience of patients with recent-onset schizophrenia. Substantial interindividual variation in D(2) receptor occupancy was seen at fixed low-dose levels of olanzapine and haloperidol. Olanzapine, 7.5 mg/day, showed no superior subjective response over haloperidol, 2.5 mg/day. Olanzapine may need to be dosed higher than 7.5 mg/day for most patients with recent-onset schizophrenia, and haloperidol needs to be individually titrated in the very low dose range to reach optimal occupancy.     

Adverse subjective experience with antipsychotics and its relationship to striatal and extrastriatal D2 receptors: a PET study in schizophrenia

OBJECTIVES: Antipsychotic medications improve psychosis but often induce a state of dysphoria in patients. Blockade of the dopamine D(2) receptors, which is thought to mediate their efficacy, has also been implicated in producing this adverse subjective experience. The authors present the first double-blind controlled study to examine the relationship between striatal and extrastriatal dopamine D(2) receptor binding potential and occupancy values and adverse subjective experience. METHOD: Patients with recent-onset psychosis (N=12) were randomly assigned to low or high doses of olanzapine or risperidone. Subjective experiences, motor side effects, and striatal and extrastriatal dopamine D(2) receptors (determined with [(11)C]raclopride and [(11)C]FLB 457 PET scans, respectively) were evaluated after 2 weeks of continuous antipsychotic treatment. RESULTS: Higher dopamine D(2) receptor occupancy and binding potentials in the striatal (dorsal and ventral), temporal, and insular regions were associated with subjective experience. The finding was confirmed with two convergent methods of analysis (region-of-interest and voxel-based statistics), and the same relationship was observed using two different dopamine receptor measures (observed binding potential values and age- and sex-corrected occupancy values). CONCLUSIONS: Higher D(2) receptor occupancy is associated with negative subjective experience in patients taking risperidone or olanzapine. These negative subjective effects may be related to the high discontinuation rates seen in usual practice. Understanding the neurobiological mechanism of these negative subjective experiences and developing antipsychotics with novel (i.e., non D(2)) mechanisms may be critical in improving the treatment of psychosis.     

Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: A cross-sectional study

In treating schizophrenia, it has been established that 65-80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain response. In this study, daily peak and trough D2 receptor occupancy levels were estimated in clinically stable patients with schizophrenia (DSM-IV) who were receiving risperidone or olanzapine. Using two collected plasma samples, plasma antipsychotic concentrations at peak and trough were estimated with population pharmacokinetic techniques. Corresponding dopamine D2 receptor occupancy levels were then estimated, using a recently developed model. 35 subjects with stable schizophrenia completed the study (mean±SD age, 48.8±13.8years; male [N=14]; Asians [N=23], Caucasians [N=12]; risperidone [N=20] at 3.2±2.3mg/day, and olanzapine [N=15] at 9.2±4.9mg/day) between September and December 2010. 48.6% (N=17) did not achieve a continuous blockade of ≥65%. Moreover, 11.4% (N=4) did not achieve the 65% threshold at estimated peak concentrations. In conclusion, approximately half the subjects with stable schizophrenia did not achieve estimated continuous blockade of D2 receptor occupancy of ≥65%. The results suggest that sustained D2 receptor occupancy levels of ≥65% may not always be necessary for the maintenance treatment of schizophrenia.     

Obsessive-compulsive symptoms during treatment with olanzapine and risperidone: a prospective study of 113 patients with recent-onset schizophrenia or related disorders

OBJECTIVE: To determine whether severity of obsessive-compulsive symptoms (OCS) differs during treatment with olanzapine or risperidone and to establish whether duration of antipsychotic treatment is related to severity of OCS. METHOD: We conducted a prospective study of consecutively hospitalized young patients (mean age = 22.4 years) with DSM-IV schizophrenia or related disorders (N = 113) who were treated with olanzapine or risperidone. Olanzapine or risperidone was randomly prescribed for patients who were drug-naive or were treated with typical antipsychotics before admission (N = 36). Patients who had started olanzapine (N = 39) or risperidone treatment (N = 23) prior to admission continued with that medication if they showed initial clinical response. Patients who prior to admission started olanzapine (N = 6) or risperidone (N = 9) but showed no response or suffered from adverse effects switched at admission to risperidone or olanzapine, respectively. Medical records, parents, and patients revealed information on duration of treatment and compliance with olanzapine or risperidone prior to admission. The Yale-Brown Obsessive Compulsive Scale (YBOCS) was administered at admission and 6 weeks thereafter. RESULTS: At baseline and 6-week assessments, OCS were found in about 30% of 106 evaluable cases and 15% met DSM-IV criteria for obsessive-compulsive disorder. No differences in OCS were found in the patients randomly assigned to olanzapine or risperidone. The 35 subjects treated with olanzapine at both assessments had significantly (p = .01) more severe OCS at week 6 than the 20 subjects treated with risperidone at both assessments. Duration of treatment with olanzapine was significantly (p < .01) related to severity of OCS. CONCLUSION: There are no differences in the short-term propensity of olanzapine or risperidone to induce or exacerbate OCS. However, severity of OCS was associated with duration of treatment with olanzapine.     

Treatment with olanzapine, risperidone or typical antipsychotic drugs in Asian patients with schizophrenia

OBJECTIVE: To examine clinical outcomes in Asian patients with schizophrenia receiving monotherapy with olanzapine, risperidone or typical antipsychotics in naturalistic settings. METHOD: In this report, data from the first 12 months of the prospective, observational, 3-year Intercontinental Schizophrenia Outpatient Health Outcomes study are presented for patients from participating Asian countries (Korea, Taiwan and Malaysia) who were started on, or switched to, monotherapy with olanzapine (n = 484), risperidone (n = 287) or a typical antipsychotic drug (n = 127) at baseline. RESULTS: At 12 months, overall reduction in the score of Clinical Global Impressions-Severity of Illness rating scale was greatest with olanzapine (p < 0.001 vs typical agents), followed by risperidone (p = 0.007 vs typical agents) treatment. Olanzapine treatment was found to have significantly better effects than typical agents on negative and depressive symptom scores, and significantly greater improvements than risperidone on negative and cognitive symptoms. The occurrence of extrapyramidal symptoms was least likely with olanzapine (p < 0.001 vs typical agents, and p = 0.012 vs risperidone), while the estimated odds of tardive dyskinesia were greatest in the typical treatment group (p = 0.046 vs olanzapine, and p = 0.082 vs risperidone). Mean weight increase was greater for olanzapine-treated patients compared with the other agents (p = 0.030 vs typical agents and p < 0.001 vs risperidone). The risk of menstrual disturbance was relatively high with risperidone when compared with olanzapine treatment (p < 0.001). CONCLUSIONS: The results of this observational study indicate that, in Asian patients with schizophrenia, olanzapine may offer benefits when compared with typical agents or risperidone. However, the significantly greater odds of weight gain should be considered in the clinical management of olanzapine-treated patients.     

Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone

BACKGROUND: Alcohol and cannabis use disorders worsen the course of schizophrenia. While the typical antipsychotics are of limited value in controlling substance use in schizophrenic patients, previous studies suggest that the novel antipsychotic clozapine (CLOZ) may decrease their substance use. We describe a retrospective study of the effects of the novel antipsychotics risperidone (RISP) and clozapine on alcohol and cannabis use in patients with schizophrenia or schizoaffective disorder and comorbid alcohol and/or cannabis use disorder. METHOD: This study involved retrospective assessment of abstinence (cessation of alcohol and cannabis use) in 41 patients treated with either risperidone (n=8) or clozapine (n=33) for at least 1 year. In 32 of these 41 patients, information was available on whether abstinence occurred during the 1-year period. RESULTS: Abstinence rates were significantly higher in patients treated with clozapine than in those treated with risperidone (54% vs. 13%, p=0.05). The nine patients treated for at least 1 year, but excluded from the analysis because time of cessation of use was not known, had all stopped alcohol/cannabis use during clozapine treatment. DISCUSSION: While the limitations of this retrospective study must be recognized, the data suggest that comorbid patients treated with clozapine are more likely to abstain from alcohol and cannabis use than are those treated with risperidone. Further prospective studies will be required to confirm these intriguing results.     

A randomized, flexible-dose, quasi-naturalistic comparison of quetiapine, risperidone, and olanzapine in the short-term treatment of schizophrenia: the QUERISOLA trial

This was a randomized, flexible-dose, rater-blind, parallel-group, quasi-naturalistic trial comparing the efficacy, safety, and tolerability of quetiapine, risperidone, and olanzapine in patients with schizophrenia hospitalized for severe psychotic symptoms. Seventy-five patients were randomized to quetiapine (n=25), risperidone (n=25), or olanzapine (n=25). Mean doses at Week 8 were: 590.0 mg/day quetiapine; 5.1 mg/day risperidone; 15.1 mg/day olanzapine. Four quetiapine, five risperidone, and five olanzapine patients discontinued prior to Week 8. There were no significant differences between groups in the primary efficacy measures of improvement from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 8 in the per protocol (PP) population and the number of completers who experienced >or=40% improvement on the same scale. PP and intent-to-treat analyses showed significant improvement from baseline in each component of a PANSS-derived battery, without significant differences between treatments. No quetiapine patients, one risperidone, and four olanzapine patients reported an adverse event (AE) of moderate intensity; no severe AEs were reported. A linear mixed model for repeated measures showed an effect of treatment on body weight, with significant differences favoring quetiapine over risperidone and olanzapine. Simpson-Angus Scale scores were significantly worse with risperidone compared with both olanzapine and quetiapine at Week 3 and compared with quetiapine thereafter. Use of concomitant medications for anxiety or tension was significantly less frequent with quetiapine. In conclusion, quetiapine, risperidone, and olanzapine have similar efficacy in schizophrenia, but there are drug-specific differences for some AEs and in the use of concomitant medication that differentiate these agents.     

Use of atypical antipsychotics in a Veterans Affairs hospital

In a retrospective chart review, efficacy and drug costs were compared in 91 consecutive outpatients receiving risperidone (n=70) or olanzapine (n=21) at the Veterans Affairs Medical Center in Syracuse, NY. Between-group differences in background characteristics, diagnoses (schizophrenia in more than half of each group) and antipsychotic efficacy [Clinical Global Impressions (CGI) scale scores] were not significant. The mean doses were 3.6+/-2.4 mg/day of risperidone and 10.7+/-7.6 mg/day of olanzapine. The VA costs of these mean doses were S3.32/day for risperidone and $6.67/day for olanzapine. Mean duration of treatment was significantly longer for risperidone (21 months) than for olanzapine (13 months). Incidence of parkinsonian symptoms (14% of both risperidone and olanzapine patients) and tardive dyskinesia (3% of risperidone patients and 5% of olanzapine patients) was similar in the two groups. Akathisia tended to occur more often in patients receiving olanzapine than risperidone (14% versus 3%, P=.08). The results of this retrospective survey indicate that, in comparable VA populations of patients with psychotic and other disorders, risperidone and olanzapine are equally efficacious but olanzapine may be more likely to produce akathisia and is twice as expensive as risperidone.     

奥氮平与利培酮治疗精神分裂症首次发病患者的疗效

目的:探讨奥氮平与利培酮治疗首发精神分裂症的疗效以及对生活质量的影响。方法:68例首发精神分裂症患者随机分为奥氮平组和利培酮组各34例,分别给予奥氮平和利培酮治疗8周,随访6个月。于治疗前后采用阳性与阴性症状量表(PANSS)及治疗中出现的症状量表(TESS)评定疗效及不良反应;于治疗6个月前后,采用生活质量综合评定问卷(GQOLI)评定生活质量。结果:两组PANSS评分治疗后均有显著下降(P<0.05或P<0.01)。奥氮平组GQOLI总分及各维度与利培酮组GQOLI总分及躯体功能、心理功能维度治疗前后差异均有统计学意义(P均<0.01);两组间比较,治疗前两组GQOLI评分差异无统计学意义,6个月后随访,在躯体功能及社会功能差异有统计学意义(P均<0.01)。结论:奥氮平与利培酮治疗首发精神分裂症疗效相当,但奥氮平在提高生活质量方面略优于利培酮。     

Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone

OBJECTIVE: Clinical factors predicting weight change in patients with schizophrenia and related disorders during acute treatment with the antipsychotic drugs olanzapine, risperidone, and haloperidol were sought through retrospective analyses. METHOD: Six-week body-weight data from 2 trials, study 1 comparing olanzapine and haloperidol (N = 1,369) and study 2 olanzapine and risperidone (N = 268), were analyzed. Effects of 8 clinically relevant covariates--therapy, clinical outcome (Brief Psychiatric Rating Scale), baseline body mass index (BBMI), increased appetite, age, gender, race, and dose--on weight were compared. RESULTS: In study 1, olanzapine (vs. haloperidol) therapy, better clinical outcome, lower BBMI, and nonwhite race significantly affected weight gain. Effects of increased appetite and male gender on weight gain were significant for olanzapine but not for haloperidol. In study 2, better clinical outcome, lower BBMI, and younger age significantly affected weight gain. Increased appetite was more frequent during olanzapine treatment than during haloperidol, but not significantly different from risperidone. Significant differences in effect on weight change were found between olanzapine and haloperidol but not between olanzapine and risperidone. No evidence was found that lower antipsychotic drug doses were associated with lower weight gain. CONCLUSION: This report identifies predictive factors of acute weight change in patients with schizophrenia. Similar factors across antipsychotic drugs in predicting greater weight gain included better clinical outcome, low BBMI, and nonwhite race. Factors differing between conventional (haloperidol) and atypical (olanzapine) agents included increased appetite and gender. Choice of atypical antipsychotic drug (olanzapine vs. risperidone) was of minor importance with regard to influence on acute weight gain.     

Improvement of schizophrenic patients' subjective well-being under atypical antipsychotic drugs

Recent research indicates that subjective well-being is a major determinant of medication compliance in schizophrenia. However, it is yet unresolved whether atypical neuroleptics differ regarding subjective side-effects. A self-report instrument has been constructed to evaluate 'subjective well-being under neuroleptics' (SWN). The primary aims of the present study were to develop a short form of the SWN and to investigate the extent to which the atypical antipsychotic improves the patient's subjective well-being.The short form of the SWN was constructed following an item analysis based on data from 212 schizophrenic patients medicated with either typical or atypical antipsychotics. The short form of the SWN showed sufficient internal consistency and good construct validity. The SWN was only moderately correlated with positive and negative syndrome scale (PANSS) scores or changes in psychopathology (r=-0.20 to -0.37). SWN-ratings in patients receiving olanzapine were superior compared to those of patients medicated with either clozapine or risperidone on three of five domains of well-being. Clozapine reduced global psychiatric symptoms significantly more than risperidone. It is concluded that the assessment of subjective well-being under antipsychotic treatment provides an independent outcome measure which is relevant to compliance.     

Sexual dysfunction associated with second-generation antipsychotics in outpatients with schizophrenia or schizoaffective disorder: an empirical evaluation of olanzapine, risperidone, and quetiapine

OBJECTIVE: Evaluate sexual dysfunction, as measured by the Arizona Sexual Experience Scale (ASEX), in olanzapine-, quetiapine-, and risperidone-treated outpatients with schizophrenia or schizoaffective disorder. METHOD: The sexual functioning of 238 outpatients (age> or =18 years) with diagnoses of schizophrenia or schizoaffective disorder who took quetiapine (n=57), olanzapine (n=94), or risperidone (n=87) was evaluated with a one-time rating of the ASEX. The dose range for each treatment group was 5 to 40 mg/day (M=16.6 mg/day, SD=7.4) for olanzapine; 1 to 8 mg/day (M=3.9 mg/day, SD=1.6) for risperidone; and 50 to 900 mg/day (M=376.8 mg/day, SD=213.4) for quetiapine. Antipsychotic group designation was based on medication treatment at study entry (i.e., non-random assignment). Participant characteristics were collected to test for treatment group differences and for potential associations with severity of sexual dysfunction. The primary data analysis was a mixed linear model analysis of covariance with age, gender, and presence/absence of antidepressant known to cause sexual dysfunction included as covariates. RESULTS: There was a significant treatment effect on severity of sexual dysfunction, as measured by ASEX total scores (p=.04). The adjusted average ASEX total scores were lower in the quetiapine (M=17.80) than in the risperidone (M=19.69) or olanzapine (M=20.34) groups. Individual comparisons of the treatments on adjusted average ASEX total scores indicated a significant difference between olanzapine and quetiapine (p=.04), but no difference between risperidone and quetiapine (p=.17) or olanzapine and risperidone (p=.76). CONCLUSIONS: Quetiapine was associated with less severe sexual dysfunction than olanzapine and risperidone (albeit the effect between risperidone and quetiapine was not statistically significant). Olanzapine and risperidone were associated with a comparable degree of sexual dysfunction. Patients in all three treatment groups, nonetheless, experienced a moderately high degree of sexual dysfunction. Because the patients were not randomized, conclusions must be interpreted within the context of the quasi-experimental design.     

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.