Predictors of Treatment-Resistant and Clozapine-Resistant Schizophrenia: A 12-Year Follow-up Study of First-Episode Schizophrenia-Spectrum Disorders

Abstract

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.

Cross-sectional study comparing cognitive function in treatment responsive versus treatment non-responsive schizophrenia: evidence from the STRATA study

“…27 Trajectory modelling of cognitive performance in first episode psychosis has observed deficits in executive function performance, relative to controls, with these remaining stable over illness duration. 71 However, deficits in verbal knowledge and memory became more apparent and exaggerated relative to controls following the first episode. 72 Similar exaggerated declines following the first episode have also been observed in measures of verbal memory.…”

How to Make an Effective Offer of Clozapine

“…1 In fact, reports indicate that 15%-20% of patients in their first episode do not respond to standard antipsychotic treatment and meet the definition of TRS. 2 Early intervention services have been shown to have many advantages in terms of reduction in relapse and hospitalization rates and improved functional outcomes. 3 Although these services do not necessarily prevent the onset of TRS, they can facilitate earlier identification and implementation of clozapine.…”

“…3 Although these services do not necessarily prevent the onset of TRS, they can facilitate earlier identification and implementation of clozapine. 2 This is important, as several studies suggest that clozapine is more likely to be effective if introduced soon after the emergence of treatment resistance. 2,4 The reality is that most patients experience TRS for many years with multiple trials of nonclozapine antipsychotics before clozapine is implemented, and many patients never receive a trial of clozapine.…”

“…2 This is important, as several studies suggest that clozapine is more likely to be effective if introduced soon after the emergence of treatment resistance. 2,4 The reality is that most patients experience TRS for many years with multiple trials of nonclozapine antipsychotics before clozapine is implemented, and many patients never receive a trial of clozapine. 4 The delay of introducing clozapine may not only reduce the chances of response if tried later on, but also result in an avoidable excessive burden of disease in these individuals.…”

Taiwan Expert Consensus Recommendations for Switching to Aripiprazole Long-Acting Once-Monthly in Patients with Schizophrenia

“…Evidence suggests that around 15-30% of patients with schizophrenia fail to respond to standard antipsychotic treatment and are considered to have treatment-resistant schizophrenia (TRS) [14][15][16]. Clozapine has been approved as an effective treatment for TRS [17].…”