Topiramate and Schizophrenia: Effects on Weight and Psychopathology

Study Overview
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Brief Summary
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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
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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: Topiramate-related effects on weight Topiramate-related effects on glucose tolerance and insulin sensitivity Topiramate-related effects on psychopathology and cognition Topiramate-related effects on adiposity

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

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Drug: Topiramate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topiramate<br>Topiramate will be dispensed on a biweekly basis, and pill counts conducted at each visit. | Drug: Topiramate<br>* 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.<br>* Other names: Topamax;|
| Placebo Comparator: Placebo<br>Placebo will be dispensed on a biweekly basis, and pill counts conducted at each visit. | Other: Placebo<br>* Placebo capsules visually identical to those containing topiramate will be administered.<br>|

What is the study measuring?
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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 |