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


Among the whole FES sample of this study (N = 1234), 13% (N = 160) were prescribed clozapine. A total of 450 patients with FES were included in the nested case-control study with 157 as TRS and 293 were non-TRS. Patients with younger age of onset, poorer premorbid social adjustment during adulthood, longer duration of first-episode, a greater number of relapses, and a higher level of DDD of antipsychotic medication in the first 24 months had an increased risk of developing TRS earlier. Among the TRS patients prescribed clozapine, 25% were clozapine resistant (CR-TRS). The CR-TRS patients had a poorer premorbid social adjustment in late adolescence and longer delay of clozapine initiation compared with nCR-TRS. CR-TRS had poorer clinical and functional outcomes at 12-year follow-up. Significantly more non-TRS patients died from suicide compared with patients prescribed with clozapine.

The rate of TRS in the whole FES sample over 12 years is estimated to be 15%. Because of the design of EIS service, the current study is limited to patients with age of first service contact between 15 and 25 years old. Despite the younger age and limited age range, the TRS rate of the current study is relatively lower compared with the previous studies that had samples of wider age ranges and mostly adult population.[34–36] Inasmuch as comorbid substance use is suggested as a possible predictor of treatment resistance,[37] the much lower substance use rate (8.6%) of the current sample compared with most of the previous studies (30%)[34,35] could be a contributing factor. The variation of TRS definition in previous studies may be another factor. Some of the previous studies used clozapine prescription as a proxy indicator;[38] others used lack of treatment response despite adequate antipsychotic treatment based on clinical records.[36] The current study followed the principle of the consensus TRS definition[11] while also considering the naturalistic clinical use of clozapine. Notably, the clozapine prescription rate reported here (13%, N = 160) is similar to the previous population-based cohort study of Danish national registry data (13.2%).[34] The use of new criteria and low rate of substance use might also explain the relatively lower rate of CR-TRS (25%) compared with previous reports of 30%–40%.[15,39]

To our knowledge, this is the first study exploring the development of TRS and CR-TRS in the same FES sample with follow-up beyond 10 years. Even within the limited range of age in our sample, younger age of onset of illness was found as a risk factor for TRS, consistent with a recent systematic review.[8] Premorbid adjustment, particularly in the social domain during adulthood, was a predictor of TRS with a trend level of significance for the overall premorbid social adjustment; no effect was observed for academic domains. This echoed previous studies suggesting an association between poor premorbid social functioning and TRS,[37,40,41] with social domains of premorbid adjustment showing a stronger relationship with clinical outcomes, while academic domains more clearly associated with cognitive function.[42,43] Compared with nCR-TRS patients, CR-TRS patients had poorer premorbid social adjustment during late adolescence. Overall, younger age of onset and poorer premorbid social functioning supported the role of neurodevelopmental risk factors for TRS. Premorbid social impairment might be more related to the development of the clozapine-resistant type of TRS.

Clinical features of illness and provision of treatment in the early years after onset also play important roles. Longer duration of the first episode and a higher level of positive symptoms in the first month were risk factors for subsequent TRS, corroborating findings from a previous study.[34] Higher antipsychotic dosage in the first 2 years was associated with TRS. We also found that TRS patients had a continuous increase in DDD of antipsychotic medications over the first 2 years, compared with a stable DDD for non-TRS patients. This may suggest the development of tolerance to the antipsychotic medication in the TRS patients, possibly implicating dopamine supersensitivity in the development of TRS.[44,45] However, another possible explanation could be that these patients are less responsive to dopaminergic antagonists and have an illness with different neurochemical pathophysiology. Furthermore, TRS patients had more relapses compared with the non-TRS patients and over 60% of TRS development occurred within the first 2 episodes of relapse. This highlights the importance of relapse prevention and management of the first few relapses.

CR-TRS had poorer clinical and functional outcomes compared with non-TRS and nCR-TRS patients. The clinical remission rates of non-TRS and nCR-TRS were similar. This suggested that these young TRS patients who are not resistant to clozapine had compatible long-term clinical outcomes as non-TRS patients. Delay in clozapine prescription was a modifiable difference between CR-TRS and nCR-TRS; CR-TRS patients had about 5 months more delay than nCR-TRS patients. This supports previous literature[39,46] indicating that delay in clozapine prescription decreases the likelihood of response to clozapine, highlighting the importance of early prescription of clozapine for TRS patients and the implications for longer-term outcomes of TRS. Similar to previous studies,[47,48] this study also demonstrated lower all-cause mortality for TRS patients prescribed with clozapine. This further emphasizes the potential benefit of clozapine for patients with schizophrenia.

EIS was found to have no measurable impact on the development of TRS but patients in the EIS group had a shorter delay of clozapine prescription. A subgroup of patients may continue to do poorly even with the intensive care provided by EIS.[22] Identifying this subgroup of patients early in the course of illness and developing targeted interventions are a clinical priority. The findings of the current study highlight that patients with early age of onset, poor premorbid social functioning, more severe symptomatology, and poor response to antipsychotic treatment during the first episode may be more likely to develop TRS. Furthermore, relapses in the first 2 years were also significantly associated with TRS. Developing a specific relapse prevention and management program together with strategies to reduce the delay of clozapine prescription within EIS may be important for preventing the development of TRS and improving outcomes.

Strengths of the study were the long follow-up of FES patients, use of an updated consensus definition of TRS and CR-TRS, and comparison of EIS and SCS groups. However, the inclusion criteria of the study and the age limit of the EIS restricted the generalizability of the study results. The attrition rate of the follow-up assessment might also introduce selection bias though the basic demographics and clinical variables between the interviewed and non-interviewed groups were not significant. The historical control design may have introduced a cohort effect leading to the bias of results. Patients' medication adherence was not measured systematically nor were clozapine plasma levels obtained. This may have limited the reliability of the rates of TRS and CR-TRS estimated in the study. As the baseline and early clinical variables were obtained from clinical records, the reliability of this information depends on the quality of the records. The small sample size of the study, particularly the CR-TRS sample, might limit the power of the study to identify risk factors.