A Randomized Double-Blind Study of Risperidone and Olanzapine in the Treatment of Schizophrenia or Schizoaffective Disorder.

(American Journal of Psychiatry 2001; 158:765–774)

Robert R. Conley, M.D

comparing the clinical effects of newer antipsychotics in people with schizophrenia

Ramy Mahmoud, M.D., M.P.H.

Centre:USA

As risperidone and olanzapine are most commonly used drugs in our set up, so, which one to choose in day to day practice.

Knowledge of comparative efficacy, eps, adeof these 2 drugs help us to decide.

well tolerated and efficacious.

half of all new prescriptions

Large separate trials>Both superior to haloperidol in amelioration of negative symptoms and that risperidone is superior in amelioration of the positive symptoms of schizophrenia.

Advantages in alleviating refractory symptoms, negative symptoms, depression, and suicidal behavior have been reported.

Second-generation drugs do provide clear advantages in terms of fewer adverse effects, particularly drug-induced parkinsonism, akathisia,and tardive dyskinesia.

Not much done methodologically in establishing the relative merits of specific drugs in these multiple domains of interest (6).

Establishing relative efficacy and safety

Both reduced positive and negative symptoms, with no significant between-group differences except on one of multiple measures of negative symptoms, where olanzapine was superior to risperidone.

More olanzapine than risperidone participants were rated as treatment responders (defined as >40% reduction in scores on the Positive and Negative Syndrome Scale), and fewer reported adverse events.

Equally effective as acute treatments.

Risperidone was more effective for treatment of psychotic symptoms at 6 months, but otherwise the 2 medications were equally effective in the routine clinical care of patients with schizophrenia.

If low (<6 mg/day) doses of risperidone are used, the 2 medications have comparable rates of parkinsonian side effects.

The safety and efficacy of risperidone and olanzapine were compared in a double-blind trial that used doses widely accepted in clinical practice.

A multicenter, randomized, double-blind, parallel-group study in 41 sites in the united states.

2 excluded.

Auditing of all 377 participant files.

Informed consent.

Oral antipsychotics were discontinued 1wk before and depot 1 cycle ago.

Risperidone (2–6 mg/day) or olanzapine(5–20 mg/day) for 8 weeks.

Inclusion criteria◦ DSM-IV diagnosis of schizophrenia or schizoaffective disorder.◦ baseline Positive and Negative Syndrome Scale (12) score of 60 to

120 (calculated by using 1–7 scoring).◦ 18–64 years.◦ Outpatients or inpatients hospitalized ≤4 weeks.◦ Informed consent.

Exclusion criteria DSM-IV axis I diagnosis other than schizophrenia or

schizoaffective disorder. DSM-IV diagnosis of substance abuse in the 3 months before

selection. CNS disease mood stabilizers or antidepressants, Clozapine for 4 wks Sensitive or resistant to RSPD/OLNZ

DAYS RISPERIDONE(mg/day) OLANZAPINE(mg/day)

1-2 2 10

3-7 2-4 5-10

8-14 2-6 5-15

15-56 2-6 5-20

once a week visit

EPS(Extrapyramidal Symptom Rating Scale)

Psychopathology(Positive and Negative Syndrome Scale, total scores and scores on five Positive and Negative Syndrome Scale factors)

Baseline and at weeks 2, 4, 6, and 8 (or withdrawal).

Overall by CGI/ severity by CGI change scale.

Clinical improvement=PANSS≥20% reduction

Adverse events (weekly) Vital signs and Standard lab tests

(randomization and weeks at 2, 4, 6, and 8 or withdrawal).

ECG (screening and at week 8 or withdrawal)

self-assessment questionnaires(baseline and week 8 or withdrawal)

symptoms potentially related to prolactin in three areas (menstrual changes, breast or chest symptoms, and male sexual function).

The 5%, two-tailed significance level.

Between-group comparisons(investigator, baseline values, PANSS Scale and EPS Scale) and age> single multivariate F test

Within-group differences> paired t tests.

Results at week 8 (observed-case analysis) and endpoint (missing data estimated by carrying the last observation forward).

Overall differences in categoric measures> chi-square test.

Ratio of beneficial to adverse changes> Dividing the reduction from an above-normal score at baseline to a normal score by the increase from a normal score at baseline to an above normal score.

Between-treatment risk ratios> the previous ratio for the risperidone group divided by the value for the olanzapine group.

Most participants were men (72.7%, N=274).

Mean age of the group was 40.0 years (SD=10.8), 86.2% (N=325)

65.5% of those had the paranoid type, N=213), and 79.0% (N=298) were outpatients.

Baseline PANSS score of the group was 80.9 (SD=13.0).

No significant differences in background characteristics between the two treatment groups, except that the participants who received olanzapine were slightly younger than those who received risperidone.

Similar proportions of the participants in the two treatment groups completed the study.

Mean duration of treatment was 45.8 days (SD=18.8) in the risperidone group and 48.9days (SD=16.5) in the olanzapine group.

Trial >4.8 mg/day (SD=1.2) of risperidone and 12.4mg/day (SD=4.6) of olanzapine.

Endpoint mean doses were 4.7 mg/day (SD=1.4) of risperidone and 13.1 mg/day (SD=5.1) of olanzapine; endpoint median doses were 4 mg/day and 10 mg/day, respectively.

Distribution of the modal daily doses was as follows: 2 mg of risperidone was received by 6.9% of the risperidone participants(N=13), 4 mg by 47.3% (N=89), and 6 mg by 45.7% (N=86);5 mg of olanzapine was received by 10.1% of the olanzapine participants (N=19), 10 mg by 51.3% (N=97), 15 mg by 18.5% (N=35), and 20 mg by 20.1% (N=38).

Severity of extra pyramidal symptoms (Extra pyramidal Symptom Rating Scale total scores) was significantly reduced from baseline to week8 and endpoint in both treatment groups, with no significant between-group differences.

Anti parkinsonian medications were received by 32.4% of the risperidone participants (N=61) and 28.0% of the olanzapine participants (N=53) during the trial (Cochran-Mantel- Haenszel χ2=1.30, df=1, p=0.26).

On all PANSS measures, score reductions from baseline were significant at treatment week 2 and throughout the study (p<0.01)

Significantly greater improvement on two Positive and Negative Syndrome Scale factors (positive symptoms and anxiety/depression) was seen in participants receiving risperidone than in those receiving olanzapine (p<0.05)

Clinical improvement, 50.7% of the risperidone group (N=69) and 47.6% of the olanzapine group (N=68) at week 8 and in 45.4% and 44.5%, respectively, at endpoint (N=79 for the risperidone group; N=81 for the olanzapine group).

Risperidone than of olanzapine 20%–40% reductions in the PANSS scores at both week 8 and endpoint, and these between group differences were significant at the 40% reduction level at week 8 (25.4% [N=34] for the risperidone participants versus 16.0% [N=23] for the olanzapine participants ;and at endpoint (24.0% [N=42] for the risperidone participants versus 15.5% [N=28] for the olanzapine participants; χ2=4.79, df=1, p<0.03). Few patients achieved 50% symptom reduction.

No significant between group differences. At week 8, 45.1% of the risperidone group (N=60) and 40.0% of the olanzapine group (N=58) were rated as much or very much improved. At endpoint, 40.1% (N=71) and 35.9% (N=65), respectively, were so rated.

Serious adverse events were experienced by 8.0% of the risperidone participants (N=15) and 11.6% of the olanzapine participants (N=22)

Dry mouth (11.2% of the risperidone participants [N=21] and 22.2% of the olanzapine participants [N=42]).

At endpoint, the mean weight gain was 7.2 lb (SD=11.2) in the olanzapine group versus 3.4 lb (SD=7.8) in the risperidone group (F=14.26, df=1, 282, p<0.001)

The mean body mass index increase was 1.1 kg/m2 (SD=1.7) in the olanzapine group versus 0.5 kg/m2 (SD=1.2) in the risperidone group (F=15.72, df=1, 282, p<0.001).

Increase in body weight of ≥7% was seen in 27.3% of the olanzapine participants (N=44 of 161) and 11.6% of the risperidone participants (N=18 of 155)

Risk ratios for change were worse for olanzapine in relation to liver transaminases and lipid profiles and worse for risperidone in relation to prolactin.

ECG> Between-group difference was not significant (F=2.09, df=1, 287, p=0.15).

Both treatments were well tolerated and efficacious. The frequency and severity of extrapyramidal symptoms were similar in the two treatment groups. Greater reductions in severity of positive and affective symptoms were seen with risperidone than with olanzapine treatment among study completers. There was no measure on which olanzapine was superior. Greater weight gain was associated with olanzapine than with risperidone treatment.

Title reflects what the study has examined.

This study improves previous findings.

Original, bigger than other, helps to remove pitfalls of previousstudies, relevant.

As therapy related>>RCT

A multicenter,randomized, double-blind, parallel-group,so Systemicbias minimized.

Adequate sample size> 41 sites in the united states

Tools are valid(DSM4,PANSS,EPS scale and SEVERITY score, CGI andseverity)

Assessment blind, outcomes meaningfully measured.

Relevant data presented.

Compared with already present datas, difference is present andsignificant.

Valid conclusions and Its relevant in our setting.

Title is not appropriate, as a good title should not contain description of study design.

Objective of study should also contain dose range of drug also, not merely clinically effective dose.

Review of literature about comparison of 2 drugs is very less, also all from same region.

Why PANSS 60 to 120,not explained.

Oral antipsychotics stopped only 1wk before, depot I cycle before which may be in blood during study.

Drug dosing regime is not clear, as weekly range may lead to difference drug dose in different population.

Few table contents are not discussed anywhere in between study.

Thank you