Patients With First-Episode Schizophrenia Should Receive Clozapine Early in Disease Progress

Results from an epidemiological cohort study reinforced the long-term benefits of introducing patients with schizophrenia to clozapine therapy early in their disease course. These findings were published in the Journal of Psychiatric Research.

This analysis was a 10-year follow-up of the Programa de Atención a Fases Iniciales de Psicosis (PAFIP) (Care Program for the Initial Phases of Psychosis) study which was conducted at the University Hospital Marqués de Valdecilla in Santander, Spain.

Patients (N=218) with first-episode nonaffective psychosis were randomized to receive specialized interventions in 3 clinical trials. Long-term outcomes were compared between patients who received clozapine (n=35) with other antipsychotics (n=183).

The clozapine and other antipsychotics cohorts comprised 78.2% and 53.5% men (P =.001). They were aged mean 24.7 (SD, 6.28) and 29.2 (SD, 8.73) years at psychosis onset (P =.004), aged 26.1 (SD, 8.36) and 30.4 (SD, 9.01) years at PAFIP enrollment (P =.010), 93.3% and 79.7% were diagnosed with schizophrenia. A total of 62.9% and 42.6% had elementary level education (P =.028), and 60% and 35% were unemployed (P =.005), respectively.

At baseline, clozapine and other antipsychotic users did not differ significantly for the Clinical Global Impression (CGI; mean, 6.37 vs 6.30; P =.460), the Young Rating Scale (YMRS; mean, 13.37 vs 12.66; P =.482), the Calgary Depression Scale for Schizophrenia (CDSS; mean, 3 vs 2.41; P =.221), the Brief Psychiatric Rating Scale (BPRS; mean, 65.63 vs 62.21; P =.114), or the Scale for the Assessment of Positive Symptoms (SAPS; mean, 14.2 vs 13.48; P =.235) instrument scores but the clozapine group had higher Scale for the Assessment of Negative Symptoms (SANS) scores (mean, 9.83 vs 7.31; P =.022).

At 10 years, clozapine was associated with greater improvements to the CGI (F, 12.0; P =.001) and SANS (F, 9.27; P =.003).

Among the clozapine group, individuals who initiated treatment in the first (median, 323 days; n=11), second (median, 1441.5 days; n=12), and third (median, 2398 days; n=12) tertiles following clinical symptoms, 10-year change in CGI was greater for the second compared with the third tertile (P =.043) and change in YMRS was greater in the first compared with the third tertile (P =.015) and the second compared with the third tertile (P =.005).

Clozapine was associated with higher rates of metabolic syndrome (χ2, 6.13; P =.013) and when comparing the 2 groups using the Scale of Secondary Effects (UKU) scale subgroups, clozapine associated with more daytime sleepiness (χ2, 18.84; P <.001), sialorrhea (χ2, 70.21; P <.001), weight gain (χ2, 11.16; P =.011), fatigue (χ2, 10.24; P =.017), orthostatic vertigo (χ2, 9.36; P =.025), and constipation (χ2, 10.26; P =.017).

This study may have been biased as medication adherence was self-reported.

The study authors concluded, “Our findings reinforce the early evaluation of treatment-resistant schizophrenia in patients with a first episode of psychosis and support clozapine be quickly considered as a treatment in the first episode of schizophrenia, not differing greatly in side effects with respect to olanzapine. More studies based on larger samples are needed to replicate and progress in this area, as well as to better understand the possible biological differences among subjects with early or late resistance to treatment.”


Moreno-Sancho L, Juncal-Ruiz M, Vazquez-Bourgón J, et al. Naturalistic study on the use of clozapine in the early phases of nonaffective psychosis: a 10-year follow-up study in the PAFIP-10 cohort. J Psychiatr Res. 2022;153:292-299. doi:10.1016/j.jpsychires.2022.07.015