Characterizing and Predicting Drug Effects on Cognition

Study Overview
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Brief Summary
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Cognitive impairment is a widely reported side effect of many commonly used drugs. Even a mild, untoward effect on an essential function such a linguistic behavior, a directly observable product of complex cognitive processes, is disruptive to daily life. Nevertheless, the mechanisms underlying a drug's impact on cognition are poorly understood. This lack of understanding impedes the ability to predict both the effects of drugs in development and the degree to which an individual is vulnerable to the cognitive impact of a particular agent. Topiramate (TPM, an antiepileptic drug) is, with increasing frequency, being prescribed for a range of conditions including migraine prophylaxis, obesity and pain. It is a prime example of a drug that causes speech and language problems severe enough in some patients to result in discontinuation of therapy. For reasons not well understood, TPM has a poorer cognitive profile than many of the older antiepileptic drugs. The investigators' rational for this study is that it will offer insight into the mechanisms underlying drug-induced cognitive deficits.

Detailed Description
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The investigators' long-term goal is to enhance clinical strategies and inform drug development in order to maximize the benefits of individual drug therapy while minimizing adverse cognitive/language-related side effects. The investigators' objective in this application is to elucidate the relationship among drug exposure as measured by plasma drug levels, its neurophysiological effects, and consequent effects on the cognitive processes observable in everyday language use. Using topiramate (TPM) as a prototype, the investigators will apply the tools of clinical pharmacology, computational linguistics, neuroscience, and engineering to the design and execution of randomized, double blind, crossover studies using three (3) doses of TPM, one (1) dose of a comparator drug (lorazepam-LZP) and a placebo. In order to isolate the cognitive effects of TPM from those possibly arising from an underlying medical condition, subjects will be healthy adults. The investigators will capitalize on an innovative system for automated language and speech analysis (SALSA) developed in our laboratory, to quantify the effects of TPM administration on effective language use, a crucial component of normal day-to-day functioning.

Official Title
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Characterizing and Predicting Drug Effects on Cognition

Conditions
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Cognitive Deficits

Intervention / Treatment
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* Drug: Lorazepam
* Other: Placebo
* Drug: Topiramate 100mg
* Drug: Topiramate 150mg
* Drug: Topiramate 200mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy men and women Ages 18-50 Women are post-menopausal or using approved birth control methods To control for brain lateralization of language functions, subjects need to have a dominant right hand. Exclusion Criteria: Presence of clinically significant cardiovascular, endocrine, hematopoietic, hepatic, renal, neurologic, and/or psychiatric disease including suicidality Vision or hearing impairments Current or a history of drug or alcohol abuse living outside of the Twin Cities Metropolitan area. The use of concomitant medications known to affect Topiramate (TPM), Lorazepam (LZP), or the use of any concomitant medications that may alter cognitive function Prior adverse reaction or prior hypersensitivity to TPM, LZP or related compounds A positive pregnancy test (administered to all women before enrollment, and prior to each study session). Subjects who have received any investigational drug within the previous 30 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topiramate 100mg<br>Participant will receive 3 single-dose treatments with 2-week washout between each treatment. At each of 3 treatments, participants will receive 100mg torpiramate, 2mg lorazepam, or placebo. Treatment order is randomized. All participants in this arm will receive all 3 treatments. | Drug: Lorazepam<br>* Lorazepam: 2mg, po, 1x<br>* Other names: Ativan;Other: Placebo<br>* Non-active placebo, po, 1x<br>Drug: Topiramate 100mg<br>* Topiramate: 100 mg, po, 1x<br>* Other names: Topamax;|
| Experimental: Topiramate 150mg<br>Participant will receive 3 single-dose treatments with 2-week washout between each treatment. At each of 3 treatments, participants will receive 150mg torpiramate, 2mg lorazepam, or placebo. Treatment order is randomized. All participants in this arm will receive all 3 treatments. | Drug: Lorazepam<br>* Lorazepam: 2mg, po, 1x<br>* Other names: Ativan;Other: Placebo<br>* Non-active placebo, po, 1x<br>Drug: Topiramate 150mg<br>* Topiramate: 150 mg, po, 1x<br>* Other names: Topamax;|
| Experimental: Topiramate 200mg<br>Participant will receive 3 single-dose treatments with 2-week washout between each treatment. At each of 3 treatments, participants will receive 200mg torpiramate, 2mg lorazepam, or placebo. Treatment order is randomized. All participants in this arm will receive all 3 treatments. | Drug: Lorazepam<br>* Lorazepam: 2mg, po, 1x<br>* Other names: Ativan;Other: Placebo<br>* Non-active placebo, po, 1x<br>Drug: Topiramate 200mg<br>* Topiramate: 200 mg, po, 1x<br>* Other names: Topamax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in COWA Unique Word Count | Study has 3 arms (100mg, 150mg, or 200mg topiramate) and 3 periods per arm (topiramate, 2mg lorazepam, or placebo). Topiramate (TPM), Lorazepam (LZP), or Placebo (PLA) was given to the participant at the beginning of Sessions 2, 3, and 4 (crossover design). No drug was given at Sessions 1 and 5. The baseline value was defined as the average of the values at Session 1 and Session 5. The change from baseline for Topiramate is the value at 2.5 hours post-dose at the Topiramate visit minus the value at baseline, divided by the value at baseline; similarly for Lorazepam and Placebo. | Session 1 to Session 5 | 
| Change From Baseline in Spontaneous Narrative Raw Word Count | Study has 3 arms (100mg, 150mg, or 200mg topiramate) and 3 periods per arm (topiramate, 2mg lorazepam, or placebo). Topiramate (TPM), Lorazepam (LZP), or Placebo (PLA) was given to the participant at the beginning of Sessions 2, 3, and 4 (crossover design). No drug was given at Sessions 1 and 5. The baseline value was defined as the average of the values at Session 1 and Session 5. The change from baseline for Topiramate is the value at 2.5 hours post-dose at the Topiramate visit minus the value at baseline, divided by the value at baseline; similarly for Lorazepam and Placebo. | Session 1 to Session 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers, Topiramate, Neurocognition, Drug-induced cognitive deficits