First generation versus second generation (non-clozapine) antipsychotic drugs versus clozapine in schizophrenia: The CUtLASS trials [Abstract]

Background: Two non-commercially-funded, pragmatic, open, multisite, randomised, controlled trials (CUtLASS 1 and 2) were conducted in the UK NHS in order (i) to compare SGAs (other than clozapine) with FGAs, in people with schizophrenia requiring a change of treatment because of inadequate response or adverse effects and (ii) to compare clozapine with the class of other SGAs in people who had responded poorly to two or more prior antipsychotic drugs. The hypotheses were that SGA drugs would outperform FGA drugs; and clozapine would outperform other SGA drugs. Methods: Participants were aged 18-65 with DSM-4 schizophrenia and related disorders. In CUtLASS 1, participants were randomly allocated to either FGA or SGA classes (amisulpride, olanzapine, quetiapine, risperidone). In CUtLASS 2, participants were randomly allocated to clozapine, or to one of the other SGA drugs. The choice of individual drug within the allocated class was made in advance by the managing clinician. Randomised samples were 227 and 136 respectively. Outcomes were assessed blind to treatment allocation at 12, 26 and 52 weeks. Complete follow up assessments at one year were obtained in 81% and 87% of the samples respectively. Results: In CUtLASS 1, there were no advantages of SGA over FGA drugs. Participants in the FGA arm showed a trend toward greater improvements in QLS and PANSS scores. Participants reported no clear preference for either class of drug; costs were similar. In CUtLASS 2, an intent to treat comparison showed an advantage for commencing clozapine in QLS score at trend level (3.6 points; CI 0.5-7.7; p=0.08), and in PANSS total score that was statistically significant (4.9 points; CI 1.1-8.8; p=0.01), at one year. At 12 weeks, participants receiving clozapine reported that their mental health was significantly better compared with those receiving SGA drugs. Discussion: In people with schizophrenia whose medication is changed for clinical reasons, there is no clinical or cost advantage over one year in using non-clozapine FGA drugs rather than clozapine SGA drugs. Neither inadequate power nor patterns of drug discontinuation could account for this result. There is an advantage to commencing clozapine rather than other SGA drugs in terms of symptoms and patient preference over one year.