A total of 168 patients were referred by 60 clinicians to the trial; 32 were not randomized due to ineligibility (n = 7; 4%) or refusal of consent (n = 25; 15%).
Of the 136 patients, 67 (49%) were randomly assigned to receive clozapine and 69 (51%) randomly assigned to receive an SGA drug. Baseline demographic characteristics of the randomized sample were comparable on most variables (). By chance, the mean QLS was higher (better) in the clozapine-allocated group. shows the drugs prescribed within each treatment arm, plus mean end doses. Prior to randomization to the SGA arm, 44 patients (64%) were being treated with a first-generation drug; 30 of these via a depot (some had received more than 1 antipsychotic drug concurrently). The remaining patients were receiving a (non-clozapine) SGA. No patients were treated with clozapine prior to randomization. There were no differences in pattern of chosen drug within the SGA arm according to category of prior antipsychotic drug. All participants in both arms underwent a change in medication as a result of randomization.
Baseline Characteristics of Participants by Treatment Arm
Drugs Prescribed by Treatment Arm and Details of End Doses
Participant Flow and Follow-Up
shows the flow of participants through the trial. The follow-up interview assessment rate was 87% at 1 year, compared with the projected rate of 85%. One death occurred in the SGA arm. Overall, 7% withdrew from the study, and 4% were lost to follow-up at 1 year. There were 4 cases of unblinding (3%), where the assessor became aware of the class of drug that the patient was currently receiving. Of those randomized to clozapine, 36 (54%) remained on clozapine at the end of 1 year, at a mean dose of 333 mg (median 300 mg) daily. Of those randomized to the SGA arm, 39 (57%) remained on an SGA at the end of 1 year, although this was a different SGA drug in 4 cases. A total of 15 patients assigned to the SGA arm went on clozapine before the end of the trial. Overall rates of antipsychotic polypharmacy fell to 8% at week 52 (6 SGA patients/5 clozapine patients).
and give the QLS data at each time point, together with patterns of nonmissing data and mean changes in QLS scores from baseline. The missing data patterns for PANSS scores were practically identical. also gives mean changes in the PANSS scores from baseline. presents the results of the analyses using longitudinal GEE models. The intention to treat (ITT) treatment arm difference for the primary outcome (QLS) is not statistically significant, and only 1 of the differences for the secondary outcomes is statistically significant (that for the PANSS). Weight gain occurred similarly in both arms over 1 year: in the clozapine arm, a mean of 7.72 kg (SD 13.65, median 6.30, range −34.5 to +61.7) and in the non-clozapine SGA arm, a mean of 7.05 kg (SD 9.60, median 5.30, range −14.4 to +31.7).
Post-Randomization Missing Value Patterns for Quality of Life Scale (QLS) Totals, by Treatment Arm
Primary Outcome: Quality of Life Scale (QLS)
Main Secondary Outcome: Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores
Estimates of Treatment Effect for Primary and Secondary Outcomes (difference between means, clozapine minus SGA, common to all 3 follow-up times)
The participant satisfaction questionnaire was completed by 79% of patients in both treatment arms at both the 12-week and the 52-week follow-up assessments. A greater improvement in mental health at 12 weeks was reported by those who had been randomized to receive clozapine compared with those randomized to receive an SGA drug (p = .048, Mann-Whitney U-test).
Overall, there were higher costs at 1 year for people allocated to initiation of clozapine therapy (mean cost $62 523; £33 796, SD £34 296) rather than SGA therapy (mean cost $52 555; £28 408, SD £32 828). These differences were not statistically significant. Of these costs, 4.0% and 3.3% respectively were due to antipsychotic drug costs, and 81% and 84% respectively were due to psychiatric inpatient costs. At the time of trial recruitment and until 2003 the UK license for clozapine stipulated inpatient commencement. To correct for this, the data were adjusted to exclude the costs of inpatient care for the purpose of commencing clozapine, giving an adjusted 1-year figure of £33 157 ($61 340), SD£34 740.
Finally, we examined the possible effects of treatment arm switches within the first 12 weeks of post-randomization follow-up. Summary statistics for the change in QLS and PANSS scores from baseline to week 12 are shown in . The ITT effects, conditional on location and relevant baseline score, and assuming that data are missing completely at random, for the 12-week QLS and PANSS scores are 2.08 (SE 2.28) and −5.98 (SE 2.24), respectively. They are consistent with the results presented in —the effect on PANSS being statistically significant, that on QLS not. The “As Treated” estimates are 0.38 (SE 2.33) and −1.16 (SE 2.37) for 12-week QLS and PANSS scores, respectively. Comparing outcomes in only those patients who stayed in their allocated arms, the “Per Protocol” estimates of the treatment effects on QLS and PANSS scores are 2.18 (SE 2.88) and −5.19 (SE 2.76), respectively. None of the “As Treated” or “Per Protocol” effects are statistically significant. Finally, the ATR (instrumental variable) estimates of the effect of receiving clozapine as opposed to the other SGAs are 4.83 (SE 5.39) and −13.81 (SE 5.99) for QLS and PANSS, respectively. In comparison with the last 2 estimates, the corresponding ITT estimates are attenuated by the treatment switches. The ATR estimates adjust for this attenuation, but the statistical significance of the effects is more or less the same as the corresponding ITT results.
The Effects of Treatment Arm Crossover Before Week 12