Predictors of Treatment-Resistant and Clozapine-resistant Schizophrenia

A 12-Year Follow-up Study of First-Episode Schizophrenia-Spectrum Disorders

Sherry Kit Wa Chan; Hei Yan Veronica Chan; William G. Honer; Tarun Bastiampillai; Yi Nam Suen; Wai Song Yeung; Ming Lam; Wing King Lee; Roger Man King Ng; Christy Lai Ming Hui; Wing Chung Chang; Edwin Ho Ming Lee; Eric Yu Hai Chen


Schizophr Bull. 2021;47(2):485-494. 

In This Article

Abstract and Introduction


Studies on the long-term development and early predictors of treatment-resistant schizophrenia (TRS) and clozapine-resistant TRS (CR-TRS) in patients with first-episode schizophrenia-spectrum disorders (FES) are limited and have not considered the impact of early intervention services (EIS). This study aimed to explore the development of TRS and CR-TRS among patients with FES over 12 years of follow-up. Of the 1234 patients with FES, 15% developed TRS. A total of 450 patients with schizophrenia or schizoaffective disorder were included in a nested case-control study (157 TRS and 293 non-TRS). Younger age of onset, poorer premorbid social adjustment during adulthood, longer duration of first episode, a greater number of relapses, and a higher antipsychotic dose in the first 24 months were associated with earlier TRS. CR-TRS patients, constituting 25% of TRS patients, had a poorer premorbid social adjustment in late adolescence and longer delay before clozapine initiation compared with non-CR-TRS. CR-TRS had poorer clinical and functional outcomes at 12-year follow-up. However, TRS patients on clozapine had a lower mortality rate compared with non-TRS patients. EIS did not have a significant impact on the development of TRS, but patients in the EIS group had a shorter delay of clozapine initiation. Results suggested that neurodevelopmental factors, early clinical characteristics, and requirement for higher antipsychotic dose may be associated with TRS development, highlighting multiple pathways leading to this form of illness. Specific interventions including relapse prevention and early initiation of clozapine during the early course of illness may reduce the rate of TRS and improve patient outcomes.


Schizophrenia affects 1% of the population and is the eighth leading cause of disability-associated life years lost.[1] Studies suggest that about 20%–30% of patients do not respond to standard antipsychotic medication and are considered to have treatment-resistant schizophrenia (TRS).[2–4] Patients with TRS have poorer functional outcomes, including higher rates of unemployment and worse quality of life,[5,6] and were found to have 3- to 11-fold higher direct healthcare costs than the schizophrenia population as a whole, mostly attributable to higher rates of hospitalization.[6,7] Understanding the mechanisms of TRS development and identifying patients who are likely to have TRS onset early in the course of illness may be important to expedite targeted interventions to those at higher risk. Thus, understanding the early predictors of TRS would be crucial.

A recent systematic review[8] found 12 studies reporting predictors of TRS; however, the length of follow-up was less than 5 years or unreported in half of these. Since TRS may develop over as long as a decade,[3,9] a shorter duration of follow-up may limit the likelihood of capturing those who develop TRS later in the course of the illness. Most of the predictors examined were basic demographics; the only consistent predictor was a younger age of onset.[8] Among the 6 studies with longer than 10 years of follow-up, only 2 followed cohorts of first-episode psychosis patients. Systematic explorations of clinical features of illness and early treatment outcomes as predictors were limited. One of the possible reasons for inconsistency in identifying predictors, and the wide range of TRS rates in different studies is the variation in the definition of TRS. Although the framework defining TRS always includes "insufficient response" and "adequate antipsychotic treatments," definitions of these features vary among studies.[10] Consensus agreement on the definition of TRS for research was obtained only recently.[11]

Clozapine is one of the most effective antipsychotic drugs for TRS.[12] However, due to its side-effect profile, clozapine is only recommended for patients with TRS and as third-line treatment in most developed countries and regions, including Hong Kong.[13,14] Despite the established efficacy of clozapine, about 30%–70% of patients with TRS[4,15] have a poor or no response to clozapine and are considered as clozapine-resistant schizophrenia (CR-TRS). In clinical practice, studies suggest that only 30% of TRS patients receive clozapine treatment,[16] and the long delay in clozapine initiation is common.[17] Understanding factors contributing to the poor clozapine response and the origins of CR-TRS may facilitate our understanding of the illness and intervention decisions. A systematic review of 96 studies on biological predictors of clozapine response failed to find any consistent predictors.[18] A more recent meta-analysis[19] found that younger age, fewer negative symptoms at onset, and paranoid schizophrenia subtypes were associated with better response to clozapine. However, to our knowledge, there are no studies reporting clinical predictors of CR-TRS from the first episode.

Worldwide, early intervention services (EIS) for psychosis has been established with an aim to improve the long-term outcomes of patients by providing intensive and comprehensive intervention during the first 2–3 years after the first onset of psychosis. Although the benefits of EIS on short-term clinical and functional outcomes are convincing,[20] long-term outcomes are less consistent.[21] Some described improvements in longitudinal functioning[22,23] and less mortality related to suicide,[24] without an impact on long-term symptom improvement. None explored the impact of EIS on rates of TRS. The EIS in Hong Kong was implemented as a publicly available, regionwide service in 2001, providing 2-year phase-specific intervention for patients aged 15–25 years with the first-episode psychosis.[25]

The current study aimed to explore the pattern of development of TRS and CR-TRS among patients with schizophrenia-spectrum disorder over 12 years or more following their first onset of illness. Demographic and early clinical characteristic predictors of the development of TRS and CR-TRS as well as the impact of the EIS on rates of and time of developing TRS were specifically explored. Clinical and functional outcomes of TRS and CR-TRS were studied. The findings could help to identify risk factors for TRS and CR-TRS, contribute to understanding mechanisms, and inform the planning of targeted care pathways to improve long-term outcomes of patients with first-episode schizophrenia-spectrum disorders (FES).