A Prospective, Exploratory Analysis of Immune and Inflammatory Response Associated With Clozapine

Sponsor

Ohio State University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05741502

Collaborator

(none)

Enrollment

Location

Arms

38.4

Anticipated Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The specific aim of this protocol is to compare Clozapine treatment vs Non-Clozapine antipsychotic treatment in a population of treatment-refractory individuals with schizophrenia. Specifically, it is to test if Clozapine leads to a decrease in levels of inflammatory markers, namely interleukin-6 but with an exploratory view of other markers. Clozapine has superior efficacy and is the only medication approved for treatment-refractory schizophrenia in addition to decreasing the risk of suicidal behavior as well. It is unclear why Clozapine has increased efficacy from a mechanistic viewpoint. We will look at the role of inflammatory markers and prospectively track them over the course of 4 months in 4 week intervals along with rating scales for psychosis and suicidality, the other entities which Clozapine has been shown to improve.

Condition or Disease	Intervention/Treatment	Phase
Treatment-resistant Schizophrenia	Drug: Clozapine Drug: Antipsychotics,Other (non-Clozapine)	Phase 4

Detailed Description

This study is designed to investigate if treatment with the antipsychotic Clozapine is associated with changes in various immune and inflammatory biomarkers when compared to treatment with non-Clozapine antipsychotic treatments. Clozapine is a uniquely efficacious treatment of psychotic disorders, the only effective agent in approximately 30-40% of individuals with treatment refractory symptoms. Clozapine, unlike other antipsychotic drugs, often precipitates a unique, multi-systemic inflammatory response most widely recognized in the cardiovascular system but also likely the central nervous system (CNS) which is tied into its unique side effect profile but might also account for its increased efficacy. Schizophrenia spectrum disorders affect about 1% of the population with around 30-40% of those diagnosed with symptoms refractory to standard, non-Clozapine antipsychotic treatment. We will measure various inflammatory markers at baseline and at 4 week intervals during antipsychotic treatment for a duration of 4 months. Treatment with Clozapine requires weekly serum measurements of different labs during the first 6 months of treatment and the additional markers for the study will be drawn in concurrence with clinically required blood draws. Participants will be patients with treatment-resistant schizophrenia deemed eligible for clozapine treatment referred from OSU's outpatient clinic with a comparator group also referred from Ohio State University, having shown treatment resistant symptoms but with provider/patient electing not to use clozapine for clinically relevant reasons. The study includes 5 visits with each visit including symptom rating scale assessments and laboratory draws for collection of serum samples and the initial visit having more diagnostic assessments to assure proper enrollment . If the study results are positive, it would help elucidate the potential mechanisms by which Clozapine works and demonstrates increased efficacy for those with treatment-refractory schizophrenia, a severely debilitating, life long illness with marked disability. This would also allow for further studies to explore this mechanism and the role of inflammation and the immune system as well.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Parallel open-label groups of Treatment-Refractory schizophrenia patients treated with Clozapine or non-Clozapine drugParallel open-label groups of Treatment-Refractory schizophrenia patients treated with Clozapine or non-Clozapine drug

Masking:

None (Open Label)

Masking Description:

Open Label

Primary Purpose:

Diagnostic

Official Title:

A Prospective, Exploratory Analysis of Immune and Inflammatory Response Associated With Clozapine Versus Non-Clozapine Antipsychotics in Individuals With Treatment-resistant Schizophrenia

Anticipated Study Start Date :

Mar 20, 2023

Anticipated Primary Completion Date :

Mar 1, 2026

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Clozapine Arm Patients will be placed on Clozapine and titrated as clinically needed and followed for 4 months.	Drug: Clozapine We will monitor inflammatory/immune marker labs periodically
Active Comparator: Non-Clozapine arm Patients will be continued on non-Clozapine antipsychotic and followed for 4 months.	Drug: Antipsychotics,Other (non-Clozapine) We will monitor inflammatory/immune marker labs periodically Other Names: Including Olanzapine, Risperidone, Paliperidone, Quetiapine, Aripiprazole, Ziprasidone, Lurasidone, Cariprazine, and all Typical antipsychotics

Arm

Intervention/Treatment

Experimental: Clozapine Arm

Patients will be placed on Clozapine and titrated as clinically needed and followed for 4 months.

Drug: Clozapine

We will monitor inflammatory/immune marker labs periodically

Active Comparator: Non-Clozapine arm

Patients will be continued on non-Clozapine antipsychotic and followed for 4 months.

Drug: Antipsychotics,Other (non-Clozapine)

We will monitor inflammatory/immune marker labs periodically

Other Names:

Including Olanzapine, Risperidone, Paliperidone, Quetiapine, Aripiprazole, Ziprasidone, Lurasidone, Cariprazine, and all Typical antipsychotics

Outcome Measures

Primary Outcome Measures

Interleukin-6 (IL-6) [4 months]
Change in interleukin-6 from baseline to endpoint in each arm i.e. before and after treatment with Clozapine or before study initiation and at the end of the study for non-Clozapine antipsychotic group.

Secondary Outcome Measures

Other immune/cardiac markers [4 months]
Change in hsCRP, interleukin-1β, interferon-γ, transforming growth factor-β, tumor necrosis factor, from baseline to endpoint in each arm i.e. before and after treatment with Clozapine or at study initiation and at the end of the study for non-Clozapine antipsychotic group.
Positive and Negative Syndrome symptom Scale [4 months]
Change in psychosis rating scales (PANSS) from baseline to endpoint in each arm i.e. before and after treatment with Clozapine or at study initiation and at the end of the study for non-Clozapine antipsychotic group. Higher scores indicate more severe symptoms of psychosis. Score from 30-210
Self-injurious Thoughts and Behaviors Interviews [4 months]
Suicidality Rating Scale change from baseline to endpoint in each arm i.e. before and after treatment with Clozapine or at study initiation and at the end of the study for non-Clozapine antipsychotic group. Scores on rating will be binary (yes/no) for suicidal ideation and also suicide attempts.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

All participants:
Between 18 and 40 years of age
Physically healthy (no clinically significant medical condition as confirmed by medical history and physical examination)
Able to give informed consent
Treatment-Refractory Schizophrenia

Clozapine treatment group (n = 30)

Newly initiating treatment with Clozapine for the first time and have not yet been given more than 4 days (96 hours) of the Clozapine before initial lab work obtained Non-Clozapine treatment, active comparator group (n = 30)
Continued treatment with non-Clozapine antipsychotic but would be eligible for Clozapine with the provider/patient electing to not pursue such for clinical reasons

Exclusion Criteria:

Clinically significant medical condition; cardiovascular, pulmonary, endocrine, or renal condition requiring in depth medical treatment
Active or recent (within 4 weeks) bacterial or viral infection
Chronic viral infection (hepatitis, HIV)
History of autoimmune, or chronic inflammatory condition
Current treatment with lithium
Treatment with Clozapine in the past 6 months
Current treatment with immunomodulatory or anti-inflammatory therapy
Vaccination within the past 3 months
Current alcohol or substance use disorder of moderate or severe severity
Intellectual disability (i.e. intelligence quotient <70)
Unwilling or unable to sign informed consent document
Pregnancy
Any patient deemed ineligible by PI discretion