Demographic and clinical variables associated with response to clozapine in schizophrenia: a systematic review and meta-analysis

Clozapine is the only licensed pharmacotherapy for treatment-resistant schizophrenia. However, response to clozapine is variable. Understanding the demographic and clinical features associated with response to clozapine may be useful for patient stratification for clinical trials or for identifying patients for earlier initiation of clozapine. We systematically reviewed the literature to investigate clinical and demographic factors associated with variation in clozapine response in treatment-resistant patients with schizophrenia spectrum disorders. Subsequently, we performed a random-effects meta-analysis to evaluate differences in duration of illness, age at clozapine initiation, age of illness onset, body weight and years of education between clozapine responders and non-responders. Thirty-one articles were eligible for qualitative review and 17 of these were quantitatively reviewed. Shorter duration of illness, later illness onset, younger age at clozapine initiation, fewer hospitalisations and fewer antipsychotic trials prior to clozapine initiation showed a trend to be significantly associated with a better response to clozapine. Meta-analysis of seven studies, totalling 313 subjects, found that clozapine responders had a significantly shorter duration of illness compared to clozapine non-responders [g = 0.31; 95% confidence interval (CI) 0.06–0.56; p = 0.01]. The results imply that a delay in clozapine treatment may result in a poorer response and that a focus on prompt treatment with clozapine is warranted.

Effects of Smoking Status on Remission and Metabolic and Cognitive Outcomes in Schizophrenia Patients Treated with Clozapine

Background Even though clozapine is the recommended last-resort antipsychotic, many patients fail to respond and show treatment-refractory psychotic symptoms. Smoking has been suggested as a possible risk factor for poor clozapine response, hampering remission and negatively impacting somatic outcomes. Methods Our aim was to test whether smoking status is associated with remission rates and other symptomatic and somatic outcomes. We therefore assessed remission rates according to The Remission in Schizophrenia Working Group (RSWG) criteria, and metabolic and cognitive outcomes among patients with schizophrenia-spectrum disorders treated with clozapine for at least 6 months. For analyses, we grouped our cohort into 3 groups according to clozapine treatment duration (6 months, 2 years, 5 years). Results One hundred five patients were included in our analyses and grouped according to their clozapine treatment duration. In the 6-months analyses, patients who smoked were significantly more likely to be younger of age (p=0.002) despite on average shorter duration of clozapine treatment (p=0.041) and significantly more likely to be treated with mood-stabilizing co-medication (p=0.030) compared to nonsmokers. Remission rates (p=0.490), as well as a set of metabolic and cognitive variables did not differ between the 2 groups. A related pattern could be observed for the 2- and 5-years analyses. Conclusions Smoking behavior among clozapine-treated schizophrenia patients might delineate a cohort with an earlier onset of the disease. Nevertheless, most findings comparing disease-specific and clinical outcomes among smokers and nonsmokers were negative. Further research is needed to identify strategies to overcome insufficient remission rates in this patient group.

M215. FACTORS ASSOCIATED WITH CLOZAPINE RESPONSE AND RESISTANCE IN SCHIZOPHRENIA

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<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.

O11.6. THE ROLE OF SERUM GLUTAMATE AND ASPARTATE AS MARKERS FOR CLOZAPINE RESPONSE AND IN THE MECHANISM OF ACTION – DATA FROM HUMAN AND ANIMAL MODEL STUDIES

Abstract not included.

M212. A SYSTEMATIC REVIEW AND META-ANALYSIS OF CLINICAL VARIABLES ASSOCIATED WITH RESPONSE TO CLOZAPINE IN TREATMENT RESISTANT SCHIZOPHRENIA

Background Approximately one third of patients with schizophrenia display suboptimal response to two trials of non-clozapine antipsychotic medication and may be termed treatment resistant. Clozapine is the only licensed pharmacotherapy for treatment resistant schizophrenia, but response to clozapine is variable and can only be determined through a trial of treatment. Understanding demographic and clinical sources of varied response to clozapine may be useful in the optimisation of clinical treatment algorithms and stratification of patient groups for clinical trials of early use of clozapine. Methods We systematically reviewed literature to investigate clinical and demographic factors associated with variation in clozapine response. Articles were eligible for review if they reported differences in clozapine response as a function of baseline variables within patient samples of schizophrenia spectrum disorders. In a second step, a random-effects meta-analysis to study group mean differences in age, age of onset and duration of illness between clozapine responders and non-responders was performed. Results Thirty-one articles were eligible for qualitative review. The systematic review found that a poorer response to clozapine was associated with older age at clozapine initiation, younger age at illness onset and longer delay in clozapine initiation. A higher number of previous hospitalisations and antipsychotic trials prior to treatment with clozapine were also associated with poorer outcomes. Both systematic review and meta-analysis identified that longer durations of illness before clozapine initiation were associated with worse clinical outcomes. In a total sample of 313 participants (n = 158 responders), clozapine responders had a significantly shorter duration of illness than non-responders (g = - 0.31; 95% CI, 0.06 - 0.56; p = 0.02). Analysis was then limited to studies with a minimum follow-up period of 12 weeks to align with the recommended amount of time to monitor clozapine response. The difference in duration of illness between responder versus non-responder groups remained significant and overall effect size increased (g = - 0.42; 95% CI, 0.17 – 0.67; p < 0.001). Between study heterogeneity was low (Q = 3.59, I2 = 0%, P = 0.61). Discussion The results imply that delay in clozapine treatment is associated with worse response and support the view that initiation of clozapine earlier in illness may be beneficial. Although we cannot make causal assertions from the data presented, poor response to clozapine when prescribed after a longer delay is likely due to a combination of factors; including the effects of sustained active symptoms on neurobiological integrity, social functioning and self-care. Given evidence that early non-response to conventional antipsychotics predicts a later diagnosis of treatment resistance and poorer outcomes, identifying treatment resistance and prescribing clozapine earlier in the illness course would prevent unnecessary loss of time in the treatment of refractory psychosis. Current research into clinical variables associated with clozapine response is limited to few studies but future investigation into the predictive value of these variables is warranted. This is important given the relative ease and low-cost clinical information can be obtained from acutely unwell patient groups who may poorly tolerate more invasive research and clinical procedures.