M215. FACTORS ASSOCIATED WITH CLOZAPINE RESPONSE AND RESISTANCE IN SCHIZOPHRENIA
Authors: Lee Jimmy , Yin Yee Jie , Mei See Yuen , Tang Charmaine , Tat Ng Boon , Chowbay Balram , Remington Gary 
Published: May 2020

Abstract

Background
Clozapine remains the only antipsychotic with unique efficacy in treatment resistant schizophrenia (TRS). Considerable ongoing research and clinical efforts have focused on reducing barriers to clozapine use in a bid to increase rates of clozapine use to improve outcomes in TRS. However, less than half of individuals with TRS respond to clozapine, with the remainder categorised as clozapine resistant (CRS) or Ultra-resistant. It is important to deepen understanding on the development of CRS so we can identify them early, attempt to prevent/delay its onset and also explore novel treatments. In the present study, we sought to compare clozapine responders from CRS and identify factors which might be associated with CRS.

Methods
This study was conducted at the Institute of Mental Health, the only psychiatric facility with clozapine services in Singapore. Individuals with TRS on clozapine for at least 12 weeks and the capacity to give informed consent were enrolled into the study. Each participant underwent a clinical assessment on the Structured Clinical Interview DSM-IV-TR (SCID), Positive and Negative Syndrome Scale (PANSS) and Social Occupational Functioning Assessment Scale (SOFAS). We applied the Treatment Response and Resistance In Psychosis consensus criteria to define clozapine response and resistance. Brief Neurocognitive Assessment was done using the digit sequencing and symbol coding tasks from the Brief Assessment of Cognition in Schizophrenia (BACS). A fasting sample of blood was collected; assays for clozapine and norclozapine were performed using high performance liquid chromatography. To be classified as CRS, a participant must meet the below criteria: (i) not meeting symptom remission criteria on the PANSS using the Remission in Schizophrenia Working Group criteria, (ii) moderate and lower level of functioning on the SOFAS, and (iii) at least 12 weeks of clozapine treatment and plasma clozapine levels ≥ 350 ng/ml.

Results
A total of 91 participants were enrolled in this study and 67 (73.6%) met criteria for CRS. 1 in 4 clozapine responders had plasma clozapine levels not exceeding 350 ng/ml. There were no significant differences in age, sex, smoking status, age at onset of illness, clozapine adherence, antipsychotic polypharmacy rates and duration of clozapine use between clozapine responders and CRS. Compared to clozapine responders, individuals with CRS had statistically significantly lower BMI (26.4 vs. 23.4, p=0.008) lower rates of employment (79.2% vs. 35.8%, p&lt;0.001), and poorer cognitive function in both digit sequencing (-0.86 vs. -1.60, p=0.011) and symbol coding (-1.09 vs. -1.88, p=0.002) tasks. In a multivariate logistic regression model with age, sex, age at onset, BMI and cognition, only BMI (OR=0.88, p=0.043) and symbol coding (OR=0.48, p=0.019) were significant variables predicting clozapine resistance.

Discussion
Our study highlighted a high rate of CRS and suggests that poorer cognitive function, specifically in processing speed, might be associated with the development of clozapine resistance in schizophrenia. Additionally, it was interesting to note that a higher BMI was associated with clozapine response; this lends weight to existing metabolic and lipid hypotheses of schizophrenia.