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


Research Sample and Setting

As the Hong Kong EIS was implemented regionwide, a historical control study design was adopted (supplementary methods provide detail on the service). A total of 617 patients with a diagnosis of FES consecutively enrolled in the EIS for the first time between July 1, 2001 and June 30, 2003 were identified from the centralized hospital database (Clinical Management System [CMS]). The same number of patients who received the standard care service (SCS) between July 1, 1998 and June 30, 2001 in Hong Kong was identified from the same CMS system and matched individually by sex, diagnosis, and age with the EIS sample. Patients with substance-induced psychosis, organic conditions, or intellectual disability and those who received prior psychiatric treatment for more than 1 month were excluded from the study. Details of the matching and basic demographic information were reported previously.[24] Using this cohort of 1234 FES patients, a nested case-control study design was adopted to determine the predictors for TRS and CR-TRS.

Research Procedure

A 4-phase approach was adopted for identifying TRS patients. In the first phase, clozapine prescription was considered as the initial proxy indicator of treatment resistance. Using the CMS, a detailed screening of medication history of all patients was conducted from the first contact with the service through June 2015, and 158 patients (12.8%) ever prescribed clozapine (the clozapine group) were identified. A non-clozapine comparison group was then formed by random selection from the remaining patients using a 1:2 ratio, considering that patients in this group may be treatment resistant without having been prescribed clozapine. A total of 316 patients were identified as non-clozapine patients. The total sample for the nested case-control study was 474.

In the second phase, all written clinical notes of the sample (N = 474) were screened for diagnosis at the time of study and any evidence of clozapine prescription for over 12 years. Five of the 158 patients treated with clozapine and 5 of the non-clozapine patients were subsequently excluded as they did not fulfill the inclusion criteria of diagnosis for the study. The clinical note screening identified 7 patients from the comparison group prescribed with clozapine, and these were reassigned to the clozapine group. Therefore, the total sample was 464, with 160 clozapine patients and 304 non-clozapine patients (Figure 1).

Figure 1.

Flowchart of the screening and interview process. FEP, first-episode psychosis; EI, early intervention; SC, standard care; TRS, treatment-resistant schizophrenia.

In the third phase, a detailed case note review using a standardized data entry form was conducted for all participants from the first contact with service until June 2015. Information obtained includes demographics, baseline and longitudinal clinical variables, and antipsychotics prescribed. The baseline clinical variables include baseline diagnosis, duration of untreated psychosis (DUP), positive and negative symptom severity in the first month after presentation using the Clinical Global Impressions-Schizophrenia (CGI-SCH) scale,[26] and duration of the first episode (defined by the start of the treatment to the time point of CGI-SCH positive symptom severity score of ≤2 and being discharged from hospital if admission was required). DUP is the period (in days) from the first emergence of psychotic symptoms until the use of effective psychiatric treatment as determined by clinicians. Clinical variables from the first year and initial 24 months following presentation include the duration of hospitalization and number of relapses. Relapse was operationally defined as an increase of CGI-SCH positive scores, from 1 to 3 or from 4–6 to 5–7, followed with hospitalization or adjustment of antipsychotic medication.[27] Dosage and duration of antipsychotics prescribed for the entire duration were documented, and chlorpromazine equivalent dose[28] and daily defined dose (DDD)[29] were calculated. The clozapine prescription pattern includes clinician-documented reasons for clozapine prescription, clozapine start and end date (if any), reasons for termination if any, and maximum dose of clozapine.

Finally, all patients were approached for a face-to-face interview. Information including symptom severity measured with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS),[30] functioning measured with the Social and Occupational Functioning Assessment Scale (SOFAS),[31] and premorbid functioning rated with the Premorbid Adjustment Scale.[32] Mortality information was obtained from the CMS and coroner's court reports. Informed consent was obtained from all eligible patients. The study had institutional ethics approval from all 7 hospital clusters in Hong Kong.

Definition of TRS and CR-TRS

The definition of TRS and CR-TRS was based on the principles of a consensus report.[11] TRS status was operationalized as having clozapine prescribed for clinically determined TRS or schizoaffective disorder and having persistent moderate positive psychotic symptoms (CGI-SCH positive score ≥ 4) after at least 2 trials of antipsychotics with chlorpromazine equivalent dose of ≥600 mg per day for ≥6 weeks. For those without a clozapine prescription, TRS status was determined upon scoring ≥4 on any PANSS positive symptom item for ≥12 weeks with a moderate functioning impairment (SOFAS < 60) and a history of at least 2 trials of antipsychotics above a chlorpromazine equivalent dose of ≥600 mg per day for ≥6 weeks. The time point when these criteria were fulfilled was considered as the onset of TRS. Delay of clozapine initiation was the time difference between the TRS onset and clozapine initiation. CR-TRS status was determined when patients on clozapine scored 4 or greater on the CGI-SCH scale in spite of sufficient clozapine dosage (350 mg) for ≥6 weeks and having any PANSS positive symptom item scored ≥ 4 for ≥12 weeks at interview. Though the CMS provided records of medications that have been picked up by patients, reliable adherence information was not able to be obtained retrospectively based on clinical records systematically; therefore, adherence was not taken into consideration in the definition.

Statistical Analysis

The Kolmogorov-Smirnov test was used to test for normality of data. To compare univariate differences in baseline demographic, clinical and premorbid adjustment variables between TRS and non-TRS groups, Mann-Whitney U, and chi-square tests were performed. As patients became TRS at different time points, Cox proportional hazard regression analysis was used to identify the predictors of TRS. The time function was calculated as the number of months from the FES onset to the onset of TRS. Variables that were significantly different between TRS and non-TRS groups were included as the independent variable in Cox proportional hazard regression analyses. Hazard ratios with 95% confidence intervals were calculated. Kaplan-Meier (KM) plots with log-rank analysis were used to explore the difference in time to TRS between EIS and SCS groups. Repeated measures ANOVA was conducted to explore the differences in DDD between TRS and non-TRS over the first 2 years.

Mann-Whitney U and chi-square tests were used to assess univariate differences in baseline demographic, clinical, and premorbid adjustment variables between CR-TRS and non-clozapine-resistant TRS (nCR-TRS) groups. The effects of clozapine prescription time on the status of CR-TRS and nCR-TRS were explored using KM plots with log-rank analysis, with time function calculated as the number of months from the determination of TRS to the date of clozapine prescription, described as the delay of clozapine prescription in this study.

Clinical outcomes assessed by face-to-face interviews were compared between TRS and non-TRS using Mann-Whitney U tests, and between CR-TRS, nCR-TRS, and non-TRS using Kruskal-Wallis tests with Bonferroni-corrected post hoc pairwise comparisons. Logistic regression analysis was performed to explore the effects of age of onset, gender, clozapine use, service cohorts, and number of relapses on mortality. All statistical analyses were performed with SPSS version 25. Details of inter-rater reliability are reported in the supplementary method section.