Trajectories of Treatment Response as Window Into the Heterogeneity of Psychosis: a Longitudinal Multimodal Imaging Study

NCT ID: NCT03442101

Last Updated: 2026-01-12

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Total Enrollment: 156 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2018-04-01
• Study Completion Date: 2026-12-31

Brief Summary

Psychosis is a heterogeneous disorder and present treatment only works for a limited number of patients. In order to identify new therapeutic targets, this study will longitudinally characterize the underlying pathologies in those with poor treatment response using complimentary brain imaging modalities.

Detailed Description

Schizophrenia is a heterogeneous disorder that likely involves multiple underlying pathological mechanisms, which has plagued attempts to identify rational therapeutic targets. All available antipsychotic drugs (APD) are dopamine receptor antagonists, but clinical response is variable, with a third of patients being partial responders, and a third non-responders. Arguably, those who respond well to APD have primarily dopaminergic abnormalities but it is imperative to also characterize the specific underlying pathologies in those with poor response in order to unravel the heterogeneity of psychosis and effectively develop new treatments. The investigators propose to longitudinally follow treatment response to APD for eight months in medication-naïve first episode psychosis (FEP) subjects using complementary brain imaging techniques.

The investigators have already identified provisional markers for several different pathophysiological mechanisms underlying psychosis, including abnormalities in glutamate, brain connectivity, and neurodevelopment that they can track with brain imaging. In addition, the investigators propose to study the changes that occur in the brain in early compared to delayed treatment responders and changes that occur over time in response to treatment. By characterizing treatment trajectories and their relationship to baseline pathophysiologic alterations, the investigators will further complement their mechanistic understanding of the heterogeneity of psychosis.

The investigators propose to study 117 well-characterized FEP subjects who are medication naïve and treat them with the most frequently used APD for 32 weeks. The investigators will follow a rigorous longitudinal design to capture treatment response whereby those without an adequate response after 16 weeks of treatment will be switched to another APD for 16 weeks. All patients will be scanned four times: at baseline and after 6, 16, and 32 weeks of treatment. The investigators will use (1) proton MR Spectroscopy (MRS), (2) task and resting state functional MRI and (3) MRI and diffusion weighted imaging (DWI) to measure brain biochemistry, function and structure. Using several imaging modalities has the potential to interrogate different neurobiological aspects of treatment response and will offer greater opportunities for clustering the patterns and combinations of the underlying pathologies in those with poor response.

Deconstructing the heterogeneity of psychosis has broad implications for the identification of specific targets for drug development, and to lay the groundwork needed to conduct therapeutic trials on patients characterized by their specific underlying psychopathology.

Conditions

Psychosis

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Treatment group

These participants are newly diagnosed with psychosis.

Patients with psychosis will be treated with known antipsychotic medication

Intervention Type: DRUG

Subjects with first episode psychosis will be treated with risperidone, the most frequently used antipsychotic drug (APD) for 32 weeks. The study will follow a rigorous longitudinal design to capture treatment response whereby those without an adequate response after 16 weeks of treatment will be switched to aripiprazole, another APD for 16 weeks. All patients will be scanned four times: at baseline and after 6, 16, and 32 weeks of treatment.

Interventions

Patients with psychosis will be treated with known antipsychotic medication

Subjects with first episode psychosis will be treated with risperidone, the most frequently used antipsychotic drug (APD) for 32 weeks. The study will follow a rigorous longitudinal design to capture treatment response whereby those without an adequate response after 16 weeks of treatment will be switched to aripiprazole, another APD for 16 weeks. All patients will be scanned four times: at baseline and after 6, 16, and 32 weeks of treatment.

Intervention Type: DRUG

Other Intervention Names

Brain imaging scans will be obtained 4 times during the study

Eligibility Criteria

Inclusion Criteria

• A diagnosis of first episode psychosis
• Never been treated with an antipsychotic medication
• Between the age of 17 and 35

Exclusion Criteria

• Inability to sign informed consent assessed by the Evaluation to sign - - Consent form
• Poorly controlled acute or chronic medical and neurological conditions
• History of head trauma with loss of consciousness for >2 minutes
• Clinically significant depression, hypomania, or mania
• Active substance abuse or dependence (except for nicotine)
• Suspected substance-induced psychosis
• Treatment with drugs known to affect brain glutamate levels
• Pregnant females

• Minimum Eligible Age: 17 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Dr. Adrianne C Lahti

Professor of Psychiatry

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Adrienne Lahti, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Locations

Sparks Center

Birmingham, Alabama, United States

Countries

United States

References

Maximo JO, Briend F, Armstrong WP, Kraguljac NV, Lahti AC. Salience network glutamate and brain connectivity in medication-naive first episode patients - A multimodal magnetic resonance spectroscopy and resting state functional connectivity MRI study. Neuroimage Clin. 2021;32:102845. doi: 10.1016/j.nicl.2021.102845. Epub 2021 Sep 29.

Reference Type: DERIVED

PMID: 34662778 (View on PubMed)

Maximo JO, Nelson EA, Armstrong WP, Kraguljac NV, Lahti AC. Duration of Untreated Psychosis Correlates With Brain Connectivity and Morphology in Medication-Naive Patients With First-Episode Psychosis. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Feb;5(2):231-238. doi: 10.1016/j.bpsc.2019.10.014. Epub 2019 Nov 9.

Reference Type: DERIVED

PMID: 31902581 (View on PubMed)

Other Identifiers

R01MH113800

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB-300000959

Identifier Type: -

Identifier Source: org_study_id