Topiramate and Schizophrenia: Effects on Weight and Psychopathology

Overview

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.

Full Title of Study: “Topiramate in Treatment Refractory Psychotic Illness: Effects on Weight Gain and Psychopathology”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Outcomes Assessor)
  • Study Primary Completion Date: July 2024

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

Interventions

  • 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: Placebo
    • Placebo capsules visually identical to those containing topiramate will be administered.

Arms, Groups and Cohorts

  • Experimental: Topiramate
    • Topiramate will be dispensed on a biweekly basis, and pill counts conducted at each visit.
  • Placebo Comparator: Placebo
    • Placebo will be dispensed on a biweekly basis, and pill counts conducted at each visit.

Clinical Trial Outcome Measures

Primary Measures

  • Weight loss
    • Time Frame: 16 weeks
    • Measured in pounds

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 17 Years

Maximum Age: 59 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Centre for Addiction and Mental Health
  • Collaborator
    • Ontario Ministry of Health and Long Term Care
  • Provider of Information About this Clinical Study
    • Principal Investigator: Margaret Hahn, Clinician-Scientist – Centre for Addiction and Mental Health
  • Overall Official(s)
    • Margaret Hahn, PhD, MD, Principal Investigator, Centre for Addiction and Mental Health
  • Overall Contact(s)
    • Margaret Hahn, PhD, MD, 416-535-8501, margaret.hahn@camh.ca

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