Neural Biomarkers of Clozapine Response

Clozapine has consistently shown to be a superior drug for psychosis in patients who do not respond to other treatments, but its mechanism of action remains unknown. The overall goal of this study is to examine the functional neural circuitry that underlies successful treatment with clozapine, which may lead to the identification of biomarkers that will allow for more efficient use of clozapine, as well as additional treatment targets for patients with refractory illness.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Schizoaffective Disorder; Treatment-resistant Schizophrenia

Detailed Description

A large number of patients with chronic psychotic disorders continue to have symptoms following unsuccessful trials with first-line antipsychotic drugs. For these patients with refractory psychosis, clozapine has consistently demonstrated superior efficacy. Clozapine is often underutilized and administered late in a patient's course of treatment, which leads to increased morbidity, unnecessary medication trials, and increased health care expenditure. Meanwhile, the mechanism of action underlying clozapine's novel effects remains unknown and has not been studied with modern neuroimaging methods. Identifying the neural mechanisms by which clozapine exerts its effects may lead to biomarkers that will facilitate efficient utilization of the drug, and introduce novel treatment targets. In patients with refractory psychotic symptoms, the proposed study will use resting-state and task-based functional MRI (fMRI) to examine the neural circuitry of efficacious treatment with a trial of clozapine. Patients will undergo fMRI scanning both before and after 12 weeks of treatment, with the aims of determining: baseline patterns of resting-state functional connectivity and task-based activation that predict response to treatment; and changes in resting-state and task-based functional circuitry associated with efficacious treatment. Results of this proposal may lead to biomarkers that will optimize treatment algorithms for psychotic disorders and facilitate drug development for refractory psychosis.

• Study Type: Observational
• Enrollment (Actual): 41

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Wpic/Upmc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with schizophrenia or schizoaffective disorder who have failed treatment with two antipsychotic drugs and are beginning treatment with clozapine.

Description

Inclusion Criteria:

1. Current positive symptoms rated ≥4 (moderate) on one or more of these Brief Psychiatric Rating Scale items: hallucinatory behavior, unusual thought content and conceptual disorganization.
2. Patient has failed two trials of treatment with antipsychotic drugs and the patient's clinical team is initiating clozapine.
3. Age of 18 to 50.
4. Patient is competent and willing to sign informed consent.
5. For female patients, negative pregnancy test and agreement to use a medically accepted birth control method.
6. Diagnosis of schizophrenia or schizoaffective disorder

Exclusion Criteria:

1. Serious neurological or endocrine disorder.
2. Any medical condition which requires treatment with a medication with psychotropic effects
3. Significant risk of suicidal or homicidal behavior
4. Cognitive or language limitations, or any other factor that would preclude subjects providing informed consent
5. Contraindications to treatment with clozapine (e.g. failed response in past, or history of adverse reactions to treatment).
6. Contraindications to magnetic resonance imaging (e.g. pacemaker).
7. Female patients who are pregnant or breast feeding.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in resting state functional connectivity with efficacious clozapine treatment	The investigators will examine the functional circuitry associated with a reduction of psychotic symptoms assessed with the Brief Psychiatric Rating Scale.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline prediction of clozapine response	The investigators will use a pattern of baseline functional connectivity to predict successful reduction of psychotic symptoms.	12 weeks

Collaborators and Investigators

• Sponsor: University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2017
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: March 6, 2017
• First Submitted That Met QC Criteria: March 6, 2017
• First Posted (Actual): March 10, 2017

Study Record Updates

• Last Update Posted (Actual): January 7, 2021
• Last Update Submitted That Met QC Criteria: January 6, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders
• Other Study ID Numbers: PRO16110369

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: No
• Studies a U.S. FDA-regulated device product: No