Early neutrophil trajectory following clozapine may predict clozapine response – Results from an observational study using electronic health records

By Kat Reed

Background:

Clozapine, an antipsychotic drug used for schizophrenia management, has been shown to have unique effectiveness in patients that are treatment resistant. In treatment with clozapine, a transient spike in neutrophils is often seen in patients, as this drug is known to cause immunological side effects. Additionally, an immunoglobin deficiency with is commonly paired with an increase in infections, particularly pneumonia, in patients being treated with clozapine.

When looking at comparisons between control groups and schizophrenia patients, neutrophils are shown to be elevated in those with schizophrenia; neutrophil spikes have also been detected in the first episode of psychosis.  The spikes in neutrophils have been shown to happen early within treatment by most studies, there is discourse as to if this elevation is in response to treatment of schizophrenia with clozapine.

Current Study & Results:

The goal of this study is to look at the neutrophil changes with patients who are being treated with clozapine, seeing if there is a relationship between neutrophil response and treatment of schizophrenia with clozapine.

Participants were found retrospectively, with this cohort taking their first treatment with clozapine and follow ups continuing for two years; this cohort consisted of 425 patients. The clozapine monitoring service was predominantly used to gather data for the neutrophil counts as baseline, 3 weeks, and 1 month time markers. Association between neutrophil trajectory at 1 month and 2-year treatment response, as well as baseline neutrophil count and response, was conducted via logistic regression.

93% (397) of the original cohort had viable neutrophil data during the first 6 weeks on the treatment course of clozapine. Three class models of neutrophil response were produced (low, high-normal, and high); the overall count of neutrophils varied between the classes, but all had a similar trajectory. Neutrophils belonging to the high-normal group were shown to have 40% neutrophil count, as well as having the odds of a positive response to clozapine be significantly increased.

The hypothesis of patients being more likely to respond to clozapine treatment if there is low-level inflammation, reflected in a high-normal neutrophil count, was supported. Response to clozapine was not restricted to patients with a higher baseline neutrophil count, making neutrophil count alone insufficient to predict treatment outcome. Clozapine may work differently than other antipsychotics in the patient group with treatment resistance, as suggested via its immunomodulatory properties, alongside the specific characteristics of TRS.

Moving Forward:  

There were several strengths within the study, such as the large size of the study. Due to this study known to be the largest database for demonstrating a relationship between clozapine and neutrophil count, there is a strong basis for generalizability from the data collected.  However, due to the study being retrospective, patients who ceased clozapine treatment before the 2-year end point were excluded from results.

It was also shown that there were lower illness severity scores at baseline with the low neutrophil count group, this may be indicative of the effect size of clozapine being reduced in this group. It should also be noted that there was an over-representation of patients of black ethnicities in the low neutrophil group, even with the study including ethnicity was controlled in the analysis. Future research could include exploring the relevancy of the current study’s hypothesis with the potential of the included patients in this low neutrophil group potentially having benign ethnic neutropaenia.

References:

Jones, R., Morales-Munoz, I., Shields, A., Blackman, G., Legge, S.E., Pritchard, M., Kornblum, D., MacCabe, J.H., Upthegrove, R., Early neutrophil trajectory following clozapine may predict clozapine response – Results from an observational study using electronic health records, Brain, Behavior, and Immunity (2023), doi: https://doi.org/10.1016/j.bbi.2023.07.012