In clinical drug development, understanding the relationship between cognition, sedation, and wakefulness is crucial to making decisions about the safety and efficacy of new medicines. As researchers and sponsors increasingly focus on optimizing wakefulness and managing sleepiness, cognitive assessment is becoming an important marker of central nervous system function.
This blog explores some insights and methodologies that can help improve clinical trial teams with decision-making in this area.
Why Teams are Conducing Cognitive Assessments in Sleep Trials
In sleep medicine, cognitive assessments are being used to inform decisions about mechanism of action, dosing, length of effect, and consequences on thinking of new therapeutic compounds.
By measuring the speed and accuracy of carefully selected aspects of thinking, researchers can better understand how medicines designed to facilitate or inhibit the brain systems that underly wakefulness also affect the ability of individuals to process information from the external environment and the internal milieu.
2 Key Concepts When Assessing Cognition in Sleep Trials
Reaction Time Testing:
Of the cognitive tests shown to be sensitive to the effects of sedation, measures that test speed of performance using reaction time are often very informative for clinical trial teams.
Studies involving benzodiazepines such midazolam and lorazepam using reaction times as their main performance measure show that substantial cognitive deterioration occurs at peak drug effects, and then improves quickly as the drugs are cleared. Furthermore, the magnitude of this drug-related-decline increases with drug dose.
This sensitivity makes speeded performance a useful index of sedative drug effects.
Subjective vs. Objective Measures:
One important difference in the effects of drugs that alter sleep/wake cycles in humans is that the effects on cognition can be different when cognition is measured using objective neuropsychological tests, and when it is assessed by having individuals rate their own abilities, which is known as subjective cognition.
Importantly, the assessment of sleepiness—which is a cornerstone assessment in studies of drugs that act on sleep/wake cycles—is also a subjective rating. Often, participants’ subjective feelings of sleepiness—or their subjective rating of thinking—does not align with their performance on objective neuropsychological tests of cognition.
This indicates that it is important to consider both subjective and objective aspects of cognition and sleepiness in experiments evaluating the effects of new drugs.
Examples and Data Insights from Sleep Trials
1. Benzodiazepine Studies¹⁺²
Data from studies examining the effects of benzodiazepine drugs on sedation and cognition indicate how different doses impact cognitive performance and subjective sleepiness.
For example, the speed of performance on tests of attention show significant deterioration at one hour post-dose, while subjective ratings of sleepiness of sedation do not always algin with the timing of this decline.
2. Sleep Restriction Studies³
It is important to remember that the effects of sleep restriction on cognitive performance are profound.
Subjective rating scales of sleepiness—like the Karolinska Sleepiness Scale—as well as objective cognitive tests, indicate that substantial impairment in cognition emerges after 14 hours of wakefulness, with sustained attention being particularly vulnerable. Interestingly, individuals rate their sleepiness as having increased prior to this timepoint.
3. Lemborexant and PVT⁴
The cognitive impacts of Lemborexant were evaluated using the Psychomotor Vigilance Task (PVT) and other tests. In healthy adults, substantial drug-related cognitive decline was observed for doses of the drug that ultimately were not taken forward to full development. Thus, the effects on cognition provided information into decisions about balancing efficacy against the safety of drugs.
Wrapping things up…
The assessment of cognition using objective neuropsychological tests plays an important role in evaluating the effects of changes in sleepiness and wakefulness in clinical trials of licensed and novel drugs. By utilizing these assessments, researchers can gain deeper insights into the cognitive impacts of drugs, aiding in the development of safer and more effective treatments for disorders of sleep/wake cycles.
As the field continues to evolve, ongoing research and standardization efforts will be essential in optimizing cognitive measurement and enhancing drug development processes.
Understanding the nuances of cognition in relation to sedation and wakefulness can significantly improve clinical trial outcomes, ultimately leading to better therapeutic options for patients.
Want to learn more?
Access & watch the full webinar recording of presenter Prof. Paul Maruff on “Using Cognition to Understand Effects of Medicines Used to Optimize Sleep or Wakefulness” here: https://www.cogstate.com/webinars/using-cognition-to-understand-effects-of-medicines-used-to-optimize-sleep-or-wakefulness/
References:
- Collie A, Maruff P, Snyder PJ, Darekar MA, Huggins JP. Cognitive testing in early phase clinical trials: outcome according to adverse event profile in a Phase I study. Hum Psychopharmacol. 2006 Oct;21(7):481-8. doi: 10.1002/hup.799. PMID: 16952205.
- Chen X, Jacobs G, de Kam ML, Jaeger J, Lappalainen J, Maruff P, Smith MA, Cross AJ, Cohen A, van Gerven J. AZD6280, a novel partial γ-aminobutyric acid A receptor modulator, demonstrates a pharmacodynamically selective effect profile in healthy male volunteers. J Clin Psychopharmacol. 2015 Feb;35(1):22-33. doi: 10.1097/JCP.0000000000000251. PMID: 25493397.
- Maruff, Paul. “Use of cognition to guide decisions about the safety and efficacy of drugs in early-phase clinical trials.” Translational Medicine in CNS Drug Development, 2019, pp. 219–227, https://doi.org/10.1016/b978-0-12-803161-2.00015-1.
- Landry I, Nakai K, Ferry J, Aluri J, Hall N, Lalovic B, Moline ML. Pharmacokinetics, Pharmacodynamics, and Safety of the Dual Orexin Receptor Antagonist Lemborexant: Findings From Single-Dose and Multiple-Ascending-Dose Phase 1 Studies in Healthy Adults. Clin Pharmacol Drug Dev. 2021 Feb;10(2):153-165. doi: 10.1002/cpdd.817. Epub 2020 May 28. PMID: 32468649; PMCID: PMC7891412.
