Treating Schizophrenia by Correcting Abnormal Brain Development

Addition of Tiagabine to Second-Generation Antipsychotics in the Treatment of Recent-Onset Schizophrenia by Modification of Developmental Reorganization of the Prefrontal Cortex

The purpose of this study is to determine whether treatment with tiagabine (Gabitril) during the early course of schizophrenia can fundamentally correct the brain deficits associated with the disease.

This study is funded by the National Institutes of Health.

Study Overview

• Status: Active, not recruiting
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Placebo; Drug: Tiagabine

Detailed Description

It is hypothesized that enhancement of GABA neurotransmission during the early course of the illness by tiagabine (Gabitril), a GABA transporter GAT-1-specific inhibitor and a FDA-approved anticonvulsant, will improve both clinical symptoms and working memory in schizophrenia. This improvement is postulated to be the result of tiagabine-mediated modification of the developmental synaptic pruning of prefrontal cortical circuitry. The occurrence of circuitry modification after tiagabine treatment will be assessed by the following independent methodologic approaches: MRI morphometric analysis of prefrontal gray matter volume and fMRI measurements of brain activity patterns during performance of tasks that probe working memory.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 25 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Meets criteria for the diagnosis of schizophrenia, with onset of psychotic symptoms within the past 3 years.
• Currently on second-generation antipsychotics for at least 3 months.
• Age 18-25, otherwise healthy.

Exclusion Criteria:

• Diagnosis of schizoaffective disorder.
• Has failed two or more clinically adequate antipsychotic trials.
• History of seizures or any neurologic disorders.
• Pregnant or nursing women.
• Known HIV infection.
• Actively suicidal.
• History of any substance dependence.
• Currently meets criteria for substance abuse/dependence.
• Other MRI exclusion criteria per Radiology Department protocols.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Antipsychotic plus study drug; Half of the subjects will receive the study medications in addition to their ongoing antipsychotic regimen.	Drug: Tiagabine; Up to 36 mg daily; Other Names: Antipsychotic
Placebo Comparator: Antipsychotics plus placebo; Half of the subjects will receive placebo in addition to their antipsychotic regimen.	Drug: Placebo; Placebo; Other Names: Antipsychotic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurocognitive Functions-Working Memory	Working memory will be assessed using the n-back working memory test	Working memory will be assessed at baseline and at 6-month time point to see if working memory changes after 6 months compared to baseline measurement
Neurocognitive Functions-Executive Function	Executive function, which is a complex form of working memory, will be assessed using the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) battery	Executive function will be assessed at baseline and at 6-month time point to see if executive function changes after 6 months compared to baseline measure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical symptoms	Positive and negative symptoms will be quantified using PANSS (positive and negative symptom scale)	Symptoms will be assessed at baseline and at 6-month time point to see if symptoms change after 6 months compared to baseline measures

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: T.-U. Wilson Woo, M.D., Ph.D., Beth Israel Deaconess Medical Center, Harvard Medical School

Publications and helpful links

General Publications

• Woo TU, Crowell AL. Targeting synapses and myelin in the prevention of schizophrenia. Schizophr Res. 2005 Mar 1;73(2-3):193-207. doi: 10.1016/j.schres.2004.07.022.
• Woo TU, Whitehead RE, Melchitzky DS, Lewis DA. A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5341-6. doi: 10.1073/pnas.95.9.5341.
• Woo TU, Spencer K, McCarley RW. Gamma oscillation deficits and the onset and early progression of schizophrenia. Harv Rev Psychiatry. 2010 May-Jun;18(3):173-89. doi: 10.3109/10673221003747609.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2003
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimated): September 16, 2005

Study Record Updates

• Last Update Posted (Actual): June 7, 2023
• Last Update Submitted That Met QC Criteria: June 5, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Treatment; fMRI; Cognition; Brain development
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; GABA Agents; Anticonvulsants; GABA Uptake Inhibitors; Antipsychotic Agents; Tiagabine
• Other Study ID Numbers: 2004P000078