MEASURING IMPAIRMENT: VALIDATED TEST METHODS FOR ASSESSING SEDATING MEDICATIONS Gary G. Kay, Ph.D. Associate Clinical Professor of Neurology Director, Neuropsychology Division Georgetown University School of Medicine Washington, DC & President Washington Neuropsychological Institute Washington, DC FDA/NTSB PUBLIC HEARING: Transportation Safety and Potentially Sedating or Impairing Medications, November 14-15, 2001, Washington, DC

Definition of Sedation  Depression of brain functioning by a medication, manifested by:  sleepiness, drowsiness, fatigue  slowed brain activity  reduced wakefulness  impaired performance

Evaluating Sedation  Self-report measures  Physiologic measures  Performance measures

Evaluating Sedation  Self-report measures  Diary Cards  Rating Scales, Mood Inventories  Visual Analog Scales  Personal Data Assistant (Palm Pilot)  Prescription Event Monitoring

Evaluating Sedation: Self-Report Measures Problems with self-report  Subjectivity  Self-report bias  Validity – Self-report frequently is not consistent with physiological and performance evidence of sedation

Cognitive Performance: Changes From Baseline in Non-Sleepy Patients Day 1 Treatment Effects Kay, et al. AAAAI Factor Divided attention/working memory Vigilance Speed Factor Score (mean change from baseline) DiphenhydramineLoratadinePlacebo

Evaluating Sedation: Physiologic Measures  EEG (e.g., continuous EEG for microsleeps)  Evoked potentials (e.g., P300)  Functional brain imaging (e.g., PET and fMRI)  Multiple sleep latency test (MSLT)  Activity monitors (e.g., wrist actigraph)

MULTIPLE SLEEP LATENCY TEST AVERAGE NUMBER OF MINUTES TO FALL ASLEEP p=.003 p=.007

SELF-REPORTED SLEEPINESS STANFORD SLEEPINESS SCALE (8:30 AM TEST) p=.04

Functional MRI: Mental Arithmetic Test Starbuck, et al. AAAAI Change From Baseline to Day 3 of AM - PM Dosing: Frontoparietal Brain Activation P =.009 P = Pixel activation Placebo CP 8 mg/TF CP 12 mg/TF

Evaluating Sedation: Performance Measures  Simulation (e.g., driving, flying)  Cognitive testing*  Psychomotor testing* *Computer-based cognitive and psychomotor testing is employed by pharmaceutical industry and FDA to assess CNS effects

Comparison of the Acute and Steady-State Effects of Loratadine, Diphenhydramine, and Placebo  Assess the cognitive, psychomotor, and subjective effects of these antihistamines.  Determine the relationship between self- reported sedation and cognitive performance. Kay, et al. Arch Intern Med Subjects (N=98) were randomly assigned to one of the 3 treatment groups:  10 mg loratadine  50 mg diphenhydramine on Day 1, followed by 25mg 4x/day on Days 2-5  placebo

Day 1: Change in Factor Scores Factor scores, z-score units Better functioning Poorer functioning Kay, et al. Arch Intern Med Mood & sedationSpeed Working memory Divided attention Diphenhydramine Loratadine Placebo

Vigilance: Continuous Performance Test Accuracy Day 1 Results Kay, et al. Arch Intern Med CPT accuracy, % Diphenhydramine Loratadine Placebo

VIGILANCE: Capacity to sustain attention under conditions of minimal arousal (e.g., monotonous tasks). DIVIDED ATTENTION: Ability to perform simultaneous mental activities; also referred to as dual tasking. WORKING MEMORY: Ability to hold information temporarily in one’s head for purposes of using the information in a calculation, or other mental activity. CRITICAL COGNITIVE DOMAINS FOR DEMONSTRATING SEDATION

Consistent Neuropsychological Findings with Sedating Medications  Tests of vigilance (i.e., lapses of attention) appear to be the most sensitive measures for detecting the sedation effects that may contribute to accidents.  Psychomotor effects (i.e., disruption of tracking) appear to persist (for weeks) after adaptation has occurred to cognitive effects.

Summary  Sedating medications can cause impairment in the absence of sleepiness.  Sedating (OTC and Rx) medications don’t only cause sleepiness. They impair alertness, cognitive and psychomotor functioning.  Sedating effects may carry over to the following day even when medications are taken at night.  Vigilance, divided attention, and working memory are especially vulnerable to sedating medications  Assessment of sedation effects (and consumer/ prescriber information about sedation) should be based on more than self-report findings.