Study: Substantial Deficiencies in Capture of Cognitive Safety in Drug Trials


Despite nearly one-third of reversible dementia cases being drug induced, cognitive safety is a neglected aspect of clinical trials.

A recent study reveals that, despite nearly one-third of reversible dementia cases being drug induced, cognitive safety is a neglected aspect of clinical trials. Of those trials analyzed, even most trials involving drugs affecting the central nervous system (CNS) lacked assessment of cognitive safety.

Lund University researchers pared down randomized clinical trials from the clinical trials registry to those relevant by excluding classes such as vaccines, stem cells, and drugs intended for cognitive improvement. The researchers then evaluated the relevant drug trials’ protocols for the presence and methods of cognitive safety assessment and inclusion of pertinent findings in drug literature.

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Most trials that evaluated cognitive function used spontaneous reporting as the only detection method. However, clients and family are unreliable sources for reporting drug-induced cognitive impairment (DICI). Participants might fear treatment cessation, while caregivers could miss or misinterpret behavior.

Trials that employed validated assessment methods often failed to use instruments fit to effectively evaluate change in cognition. For instance, the Mini-Mental State Examination (MMSE) isn’t sufficiently sensitive, and the Wechsler Adult Intelligence Scale doesn’t effectively evaluate cognitive function. Even trials for drugs known to affect cognition, including esketamine and lacosamide, used these inappropriate methodologies, according to the study findings.

The researchers’ analysis also revealed that one cannot make assumptions regarding the inclusion of cognitive safety in clinical trials based on a drug’s lifespan. In other words, whether a drug is new on the market or has been around for decades, there is a good chance its cognitive effects were inadequately evaluated.

Furthermore, findings of cognitive impairment do not necessarily make it into the prescribing information, as is the case for tepotinib and abemaciclib. Formal clinical trial publications have similar exclusions.

DICI’s effects, including aphasia and memory loss, are extensive for patients and families. Consequent diagnoses can lead to additional therapies, which is particularly notable when considering that polypharmacy is a risk factor for DICI.

Based on their findings, the Swedish research team calls for action from multiple angles. Regulatory agencies should stipulate that all clinical trials actively assess each area of cognitive function when they involve drugs that do or could affect the CNS. Additionally, a neuropsychologist should be the one to determine appropriate assessment methods.

Clinical drug trials rely on objective methods to assess physical safety, such as by using electrocardiograms to determine cardiac safety. Cognitive safety as well deserves evaluation not by questionnaire or observation by family, but rather by methodologies validated within the field of neuropsychology.


Reimers A, Ljung H. Cognitive Safety is Largely Ignored in Clinical Drug Trials: A Study of Registered Study Protocols. Drug Saf. Published online November 16, 2023. doi:10.1007/s40264-023-01378-1

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