Cognitive functions are vital for everyday functioning, in the workplace, academic environments, and socially. They are especially crucial in safety-critical scenarios, such as when driving a car, or operating machinery.
Detection of negative cognitive effects of interventions is of vital importance from the perspective of patients, clinicians, and the public1.
Cognitive safety signals are also an increasing focus of regulatory agencies including the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)1.
Assessment of the cognitive effects of medication is crucially important in drug development, licensing, and post-marketing surveillance. During drug development, objective measurement of cognitive effects can inform key decisions such as selection or rejection of compounds, choice of doses, and in support of the target indication(s).
Safety-relevant cognitive data are extremely valuable in support of regulatory submissions, and drug differentiation claims. Testing for cognitive function, motor skills, and mood, has been highlighted by the FDA as being important when conducting clinical trials for medications suspected to impact brain function2.
Assessment of cognitive safety in clinical drug development
Published in Drug Discovery Today
Pathology and functional impact of adverse cognitive effects
While the brain is insulated by the blood-brain barrier, many types of molecules can cross it, with direct effects on brain neurotransmitter systems (e.g. dopamine, glutamate, acetylcholine, serotonin) and consequent effects on cognition.
The integrity of the blood-brain barrier is not static, but is affected by dynamic brain regulatory mechanisms3, and also by brain pathologies and advancing age. Due to extensive cross-talk between the body and brain, drug compounds designed for non-CNS indications can still cause unwanted effects on cognition.
Medications that may negatively affect cognition via peripheral mechanisms include those affecting the cardiovascular system, respiratory system, immune system, hormones, glucose levels or glucose transportation, and cholesterol modifiers. For example, the FDA has highlighted the potential for statins to be associated with reversible cognitive side effects such as memory loss4.
Epidemiological data have demonstrated a post-marketing association between anticholinergic medications and cognitive impairments in older patients, especially when anticholinergic drugs are used in combination with some other medications5.
Since cognitive effects of interventions depend on baseline neurotransmitter function and cognitive performance, the absence of untoward safety signals in one target population (such as in middle-aged healthy volunteers) does not rule out untoward safety signals when the same compound is then used in distinctly different settings – for example, in children or elderly individuals, in people with physical or mental health morbidities, or in the case of polypharmacy.
Research and development in cognitive safety
Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. However, many drug development programmes do not incorporate sensitive cognitive measurements.
Medications can exert untoward cognitive effects both via direct effects on the brain (by crossing the blood-brain barrier) and via indirect actions (peripheral mechanisms in the body).
This field is still at an early stage, and precisely what designs should be adopted, what outcome measures should be used, and what statistical approaches are most appropriate will vary depending on the drug in question and the indication.
Even if a drug is shown to induce some cognitive impairment, it might still be beneficial to prescribe it; but pharmaceutical companies, regulators, clinicians, and patients need to understand the possible cognitive risks and their implications for everyday function.
Cognitive safety and tolerability white paper
This white paper looks at the assessment of cognitive safety in drug compounds.
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Roiser JP, Nathan PJ, Mander AP, Adusei G Zavitz KH, Blackwell AD. Assessment of cognitive safety in clinical drug development. Drug Discov Today. 2016 Mar;21(3):445-53.
Blackwell AD. Measuring cognitive effects: cognition in drug development and repositioning. Drug Discov Today. 2015 Apr;20(4):391-2
- Roiser JP, Nathan PJ, Mander AP, Adusei G Zavitz KH, Blackwell AD. Assessment of cognitive safety in clinical drug development. Drug Discov Today. 2016 Mar;21(3):445-53.
- FDA Guidance for Industry-Premarketing Risk Assessment, 2005 (UCM126958).
- Almutairi MM, Gong C, Xu YG, Chang Y, Shi H. Factors controlling permeability of the blood-brain barrier. Cell Mol Life Sci. 2016 Jan;73(1):57-77.
- Campbell N, Boustani M, Limbil T, Ott C, Fox C, Maidment I, Schubert CC, Munger S, Fick D, Miller D, Gulati R. The cognitive impact of anticholinergics: a clinical review. Clin Interv Aging. 2009;4:225-33.