Characterizing and Predicting Drug Effects on Cognition

Phase 4

Completed

Conditions: Cognitive Deficits

Interventions: Drug: Lorazepam
Other: Placebo
Drug: Topiramate 200mg
Drug: Topiramate 150mg
Drug: Topiramate 100mg

Registration Number: NCT01889602

Lead Sponsor: University of Minnesota

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Topiramate 100mg	Placebo	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.
Topiramate 150mg	Placebo	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.
Topiramate 200mg	Topiramate 200mg	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.
Topiramate 150mg	Topiramate 150mg	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.
Topiramate 100mg	Topiramate 100mg	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.
Topiramate 200mg	Placebo	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.
Topiramate 100mg	Lorazepam	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.
Topiramate 150mg	Lorazepam	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.
Topiramate 200mg	Lorazepam	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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in COWA Unique Word Count	Session 1 to Session 5	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.
Change From Baseline in Spontaneous Narrative Raw Word Count	Session 1 to Session 5	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.

Secondary Outcome Measures