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


The final analysis sample included 450 patients (Figure 1). Fourteen (8.75%) clozapine-prescribed patients were found to be non-TRS (Supplementary Table 1) and were excluded from the main analysis. Among the 450 patients, 157 were TRS (34.9%) (including 11 TRS without clozapine, 3.6%). For the total FES sample of 1234 patients, adding the percentage of TRS patients prescribed clozapine (N = 146, 11.8%) plus the estimate of TRS not treated with clozapine (3.6%) yields an overall estimate of TRS to be approximately 15%. Among the total FES sample, 74 TRS patients were from the EIS group (12%) and 83 were from the SCS group (13.5%).

Development and Predictors of TRS

About 10% of TRS patients were treatment resistant from the illness onset. By the end of the third episode of illness (second relapse), TRS was present in 61% of patients who eventually developed this form of illness (Supplementary Figure 1).

Supplementary Figure 1.

Cumulative percentage of treatment-resistant schizophrenia (TRS) across episodes.
Note: Cumulative percentage calculated as (total number of patients developed TRS by the nth episode/total number of TRS patients) x 100%: around 10.2% of the TRS patients developed TRS at their first episode, 61% by the third episode and latest by the eleventh episode.

The overall premorbid social functioning was similar in the 2 groups of patients but was lower in adulthood (proximal to illness onset) in the TRS group (Table 1). The TRS group had a lower age of onset by approximately 1 year. History of substance use disorder did not differ and no difference in DUP between groups was noted.

The TRS patients had more severe positive symptoms during the first month of illness after presentation (Table 1). The duration of the first episode was longer by about 1 month. Over the first year, although only 16 patients (10% of TRS) were defined as TRS by the end of their first episode (Supplementary Figure 1), the mean DDD of antipsychotic medication was higher in TRS patients (Table 1). Repeated measures ANOVA found that TRS patients had a steady increase of DDD, while non-TRS had a stable DDD: the interaction of time and group was significant [F(1.602, 672.945) = 14.891, P < .001] (Supplementary Figure 2). The TRS patients had more relapses and longer hospitalization over the first year of treatment. Number of relapses, duration of hospitalization, and DDD over the first 2 years were also significantly higher in the TRS group. However, no difference in the number of TRS between EIS and SCS was found (Table 1).

Supplementary Figure 2.

Mean daily defined dosage (DDD) of month 1 (M1), month 2 to month 12 (M2 to M12) and month 13 to month 24 (M13 to M24) of treatment-resistant (TRS) and non-treatment-resistant (non-TRS) groups.

Cox regression analysis found that poor premorbid adjustment in early adulthood was associated with greater risk for TRS, as was a younger age of onset of illness (Table 2). Longer duration of the first episode, a greater number of relapses, and a higher dose of antipsychotic medication over the first 2 years were also found to be significant in the model. Survival analysis of the 450 patients showed that the proportion of TRS and time from the illness onset to becoming TRS were similar for patients treated in the EIS and SCS (log-rank χ 2 = 0.526, P = .468) (Supplementary Figure 3).

Supplementary Figure 3.

Kaplan-Meier survival plot for time to treatment-resistance in standard care and early intervention cohorts.

Development and Predictors of CR-TRS

Among the 157 TRS patients, 146 were ever prescribed with clozapine. Of these patients, 36 (24.7%) did not respond sufficiently and were described as CR-TRS; 91 patients were considered as nCR-TRS; 19 were excluded from subsequent analysis due to early clozapine termination as a result of intolerance (n = 14), or insufficient clozapine dosage (<350 mg) despite persistent positive symptoms (n = 5). The 11 TRS patients who were not prescribed with clozapine were also excluded from the following analysis.

The CR-TRS group showed more impairment in late adolescent social adjustment compared with the nCR-TRS group (Table 3). The clinical characteristics over the first 2 years of illness were similar between these 2 TRS subgroups (Supplementary Table 2). KM survival analysis (Figure 2) showed that the delay of clozapine prescription was longer in the CR-TRS group than in the nCR-TRS group (log-rank χ 2 = 3.871, P = .049), with an estimated mean time from TRS status to clozapine prescription of 11.82 months (95% CI = 6.23–17.40) for the CR-TRS group vs 7.23 months (95% CI = 4.60–9.85) for the nCR-TRS group. Patients in the SCS group had significantly greater delay of clozapine initiation (M = 8.60, SD = 11.45) compared with those in the EIS group (M = 8.05, SD = 15.85; U = 2159.0, P =.049). However, only a trend significance was seen (P = .091) with more CR-TRS patients in the SCS group than that in the EIS group.

Figure 2.

Kaplan-Meier survival plot for delay in clozapine prescription in non-clozapine-resistant (nCR-TRS) and clozapine-resistant (CR-TRS) patients.

Outcomes of TRS and Non-TRS 12 Years After Illness Onset

The interviewed and non-interviewed groups were compared (Supplementary Table 3) with no significant difference in basic demographics. The face-to-face interview found that CR-TRS had poorer clinical and functional outcomes compared with non-TRS and nCR-TRS; only negative symptoms were found to be significantly different between CR-TRS and non-TRS (Supplementary Table 4). Notably, 34.6% of non-TRS patients (N = 66) were considered clinically remitted based on operational criteria,[33] a similar proportion as in the nCR-TRS sample (N = 35, 38.5%). A total of 22 patients were deceased with 21 due to suicide. Logistic regression analysis suggested a significantly lower mortality of the group prescribed clozapine (P = .014) after controlling for gender, age of onset, intervention group, and number of relapses in the first 24 months (Supplementary Table 5).