Topiramate and Schizophrenia: Effects on Weight and Psychopathology

Topiramate in Treatment Refractory Psychotic Illness: Effects on Weight Gain and Psychopathology

Clozapine is the sole AP agent with superiority in treatment refractory schizophrenia, but it also is associated with the greatest risk of weight gain and other metabolic abnormalities. Topiramate, an anticonvulsant agent, possesses a weight-reducing effect. Furthermore, some studies have suggested that Topiramate may be associated with improvements in psychopathology in treatment refractory schizophrenia. Here the investigators propose to determine the role of topiramate for augmentation purposes (psychopathology) and as an adjunctive pharmacological intervention for weight loss in overweight/obese individuals with Ultra-Treatment Resistant Schizophrenia or Schizoaffective disorder taking clozapine.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia, Schizoaffective Disorder
• Intervention / Treatment: Drug: Topiramate; Other: Placebo

Detailed Description

Schizophrenia is a chronic illness characterized by social and vocational disruptive functioning. While >70% of individuals with first episode illness respond to antipsychotics (APs), there remains a subgroup left with persisting psychotic symptoms. For these individuals, clozapine (CLZ) is also the sole drug with treatment superiority, but also carries the greatest metabolic liability. Another complicating factor in those treated with CLZ is the observation that while effective in some, 40-70% of individuals fail to show significant improvement with CLZ, often leading to augmentation strategies. While controlled trials are, in general lacking, a number of agents have been suggested as useful. One such group of medications includes the anticonvulsants.

Topiramate represents one of the newer anticonvulsant agents approved for the treatment of epilepsy and prophylaxis of migraines. Importantly, topiramate possesses a weight-reducing effect that has been substantiated by a meta-analysis in non-psychiatric patients. Interestingly, topiramate has been studied as an adjunctive therapy in treatment-resistant schizophrenia with some evidence demonstrating small to moderate benefits with topiramate augmentation on psychopathology. However, these benefits must also be weighed against reports (primarily from epilepsy populations), that topiramate may cause cognitive dysfunction.

This study will examine:

1. Topiramate-related effects on weight
2. Topiramate-related effects on glucose tolerance and insulin sensitivity
3. Topiramate-related effects on psychopathology and cognition
4. Topiramate-related effects on adiposity

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Margaret Hahn, PhD, MD; Phone Number: 34368 416-535-8501; Email: margaret.hahn@camh.ca
• Study Contact Backup: Name: Quinn A Casuccio-Treen, BSc; Phone Number: 34719 416-535-8501; Email: quinn.treen@camh.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 1R8
      • Recruiting
      • Center for Addiction and Mental Health
      • Contact: Margaret K Hahn, MD; Phone Number: 34368 4165358501; Email: margaret.hahn@camh.ca
      • Contact: Quinn A Casuccio-Treen, HBSc; Phone Number: 34719 4165358501; Email: quinn.treen@camh.ca
      • Principal Investigator: Margaret K Hahn, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 59 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Schizophrenia or Schizoaffective disorder
• 17-59 years of age
• Clozapine treatment for at least 12 weeks at a dose 350 mg/d or greater and/or plasma clozapine levels of 300 ng/mL or greater
• CGI must be 4 or higher and/or GAF < 50
• BMI greater than or equal to 25

Exclusion Criteria:

• Alcohol use disorder
• Patients with liver, or renal dysfunction
• Females of child bearing age not on a regular contraceptive, females who are nursing
• Clinical or laboratory evidence of uncompensated cardiovascular, endocrine, hematological, or pulmonary disease.
• HbA1c > 9%, or symptomatic hyperglycemia with metabolic decompensation
• Prior lack of efficacy or tolerability of Topiramate
• Addition of new hypoglycemic or lipid lowering medication within 2 months of starting study
• Patients treated with Valproic Acid
• Patients treated with hydrochlorothiazide
• Switch in antipsychotic medications within 3 months of study entry
• Major medical or surgical event within the preceding 3 months
• History of renal stones
• Use of Carbonic Anhydrase Inhibitor
• History of glaucoma
• Acute Suicidal risk

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
Experimental: Topiramate; Topiramate will be dispensed on a biweekly basis, and pill counts conducted at each visit.	Drug: Topiramate; Topiramate capsules starting with 25 mg b.i.d with an incremental increase of 25 mg b.i.d weekly upto a maximum of 100 mg b.i.d.; Other Names: Topamax
Placebo Comparator: Placebo; Placebo will be dispensed on a biweekly basis, and pill counts conducted at each visit.	Other: Placebo; Placebo capsules visually identical to those containing topiramate will be administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight loss	Measured in pounds	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity	Measured through Oral Glucose Tolerance Test (pmol/L)	16 weeks
Psychopathology - Positive and Negative Syndrome Scale (PANSS)	Anchored scale to rate positive and negative psychiatric symptoms	16 weeks
Glucose Tolerance	Measured through Oral Glucose Tolerance Test (mmol/L)	16 weeks
Psychopathology - Brief Psychiatric Rating Scale (BPRS)	Anchored rating scale for psychiatric symptoms	16 weeks
Psychopathology - Clinical Global Impression (CGI)	Anchored scale to rate global impression of patient	16 weeks
Psychopathology - Global Assessment of Functioning (GAF)	Anchored scale to rate global functioning of patient	16 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visceral adiposity changes	Measured through MRI	Baseline and 16 weeks
Cognition - Brief Assessment of Cognition in Schizophrenia (BACS)	A standardized assessment of cognitive in patients with schizophrenia	16 weeks
Volumetric Brain changes	Measured through MRI	Baseline and 16 weeks
Hepatic adiposity changes	Measured through MRI	Baseline and 16 weeks

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Collaborators: Ontario Ministry of Health and Long Term Care
• Investigators: Principal Investigator: Margaret Hahn, PhD, MD, Centre for Addiction and Mental Health

Publications and helpful links

Helpful Links

• The Centre for Addiction and Mental Health (CAMH) is the leading mental health and addictions research facility in Canada, and one of the largest in the world.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: June 15, 2016
• First Submitted That Met QC Criteria: June 17, 2016
• First Posted (Estimated): June 21, 2016

Study Record Updates

• Last Update Posted (Estimated): July 24, 2023
• Last Update Submitted That Met QC Criteria: July 20, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Hypoglycemic Agents; Physiological Effects of Drugs; Anticonvulsants; Topiramate
• Other Study ID Numbers: 097/2015

Plan for Individual participant data (IPD)

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