Topiramate and Schizophrenia: Effects on Weight and Psychopathology

Not Applicable

Recruiting

• Conditions: Schizophrenia, Schizoaffective Disorder
• Interventions: Other: Placebo; Drug: Topiramate

• Registration Number: NCT02808533
• Lead Sponsor: Centre for Addiction and Mental Health

Brief Summary

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.

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 Timeline

• Study Start: 2016-05
• Study First Submitted: 2016-06-15
• Study First Submitted QC: 2016-06-17
• Study First Posted: 2016-06-21
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-20
• Last Update Posted: 2023-07-24
• Primary Completion: 2024-07
• Study Completion: 2024-07

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 50

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo will be dispensed on a biweekly basis, and pill counts conducted at each visit.
Topiramate	Topiramate	Topiramate will be dispensed on a biweekly basis, and pill counts conducted at each visit.

Primary Outcome Measures

Name	Time	Method
Weight loss	16 weeks	Measured in pounds

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Center for Addiction and Mental Health; 🇨🇦 Toronto, Ontario, Canada