Topiramate and Schizophrenia: Effects on Weight and Psychopathology

  • End date
    Dec 29, 2023
  • participants needed
  • sponsor
    Centre for Addiction and Mental Health
Updated on 23 February 2022


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.


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

Condition Schizophrenia, Schizoaffective Disorder
Treatment Placebo, Topiramate
Clinical Study IdentifierNCT02808533
SponsorCentre for Addiction and Mental Health
Last Modified on23 February 2022


Yes No Not Sure

Inclusion Criteria

Schizophrenia or Schizoaffective disorder
-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
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