Topiramate and Schizophrenia: Effects on Weight 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.

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

Eligibility Criteria:
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