An Exploratory Analysis of Immune and Inflammatory Response Associated With Clozapine

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

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 assess them 1x along with rating scales for psychosis and suicidality, the other entities which Clozapine has been shown to improve.

Study Overview

• Status: Recruiting
• Conditions: Treatment-resistant Schizophrenia
• Intervention / Treatment: Drug: Clozapine; Drug: Antipsychotics,Other (non-Clozapine)

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 1x for patients who are stable outpatients. Participants will be patients with treatment-resistant schizophrenia on clozapine treatment for at least 6 months 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 and have been on antipsychotic medication for at least 6 months. The study includes 1 visit including symptom rating scale assessments and laboratory draw for collection of serum samples and the visit also having more diagnostic assessments to assure proper enrollment. If the study results are positive meaning there is a difference between the two groups, 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 Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Walter H Stearns, MD; Phone Number: 6146853221; Email: walter.stearns@osumc.edu
• Study Contact Backup: Name: Craig J Parris, MS; Phone Number: 6146858623; Email: craig.parris@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University Harding Hospital
      • Contact: Craig J Parris, MS; Phone Number: 6146858623; Email: craig.parris@osumc.edu
      • Contact: Walter H Stearns, MD; Phone Number: 614-685-3221; Email: walter.stearns@osumc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• All participants:

  • Between 18 and 65 years of age
  • Physically healthy (no clinically significant unstable medical condition as confirmed by medical history and physical examination)
  • Able to give informed consent
  • Treatment-Refractory Schizophrenia

Clozapine treatment group (n = 30) Individuals treated with Clozapine consistently for a minimum of 6 months

Non-Clozapine treatment group Continued treatment with non-Clozapine antipsychotic but would be eligible for Clozapine with the provider/patient electing to not pursue such for clinical reasons, consistently treated for at least 6 months

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clozapine Arm; Patients will be on Clozapine for at least 6 months	Drug: Clozapine; We will assess inflammatory/immune marker labs
Active Comparator: Non-Clozapine arm; Patients will be on non-Clozapine antipsychotic for at least 6 months	Drug: Antipsychotics,Other (non-Clozapine); We will assess monitor inflammatory/immune marker lab; Other Names: Including Olanzapine, Risperidone, Paliperidone, Quetiapine, Aripiprazole, Ziprasidone, Lurasidone, Cariprazine, and all Typical antipsychotics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interleukin-6 (IL-6)	Comparison in interleukin-6 between Clozapine and non-Clozapine group	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other immune/cardiac markers	Comparison in hsCRP, interleukin-1β, interferon-γ, transforming growth factor-β, tumor necrosis factor between Clozapine and non-Clozapine group	Up to 1 year
Positive and Negative Syndrome symptom Scale	Comparison in psychosis rating scales (PANSS) between Clozapine and non-Clozapine group. Higher scores indicate more severe symptoms of psychosis. Score from 30-210	Up to 1 year
Self-injurious Thoughts and Behaviors Interviews	Comparison between Clozapine and non-Clozapine group in Suicidality rating scales. Scores on rating will be binary (yes/no) for suicidal ideation and also suicide attempts.	Up to 1 year

Collaborators and Investigators

• Sponsor: Ohio State University

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2023
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: January 20, 2023
• First Submitted That Met QC Criteria: February 22, 2023
• First Posted (Actual): February 23, 2023

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 4, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Schizophrenia, Treatment-Resistant; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Dopamine Agonists; Dopamine Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; GABA Agents; Adrenergic alpha-Antagonists; Adrenergic alpha-2 Receptor Antagonists; GABA Antagonists; Selective Serotonin Reuptake Inhibitors; Olanzapine; Aripiprazole; Paliperidone Palmitate; Quetiapine Fumarate; Risperidone; Ziprasidone; Lurasidone Hydrochloride; Clozapine; Cariprazine; Antipsychotic Agents
• Other Study ID Numbers: 2021H0388

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No