Cognitive safety
Why is cognitive assessment important in cognitive safety?
Why it is important to do research in cognitive safety?
Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. 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). However, many drug development programmes do not incorporate sensitive cognitive measurements.
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.
What is cognitive safety?
Cognitive functions are vital for everyday functioning, including in the workplace and in social situations. They are especially crucial in safety-critical scenarios, such as when driving a car, or operating machinery.
Detection of negative cognitive effects of pharmaceutical interventions is of vital importance from the perspective of patients, clinicians, and the public. 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 is 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.
Why is it important to do research in autism?
Individuals with autism spectrum disorder often exhibit cognitive deficits that reflect underlying abnormalities in brain structure and function5,6. Our recommended test battery for research of autism spectrum disorder’s assesses the core domains impaired in ASD, as well as those likely to be affected by novel interventions.
The search is on for treatments that can ameliorate the core symptoms of ASD, and cognitive impairment, in order to maximise long-term outcomes and quality of life for affected individuals.
What is autism?
Autism is a neurodevelopmental disorder associated with problems with social communication and/or interaction, and occurrences of restricted or repetitive patterns of behaviour, interests, or activities.
Autism was previously distinguished from Asperger’s syndrome, but the latest version of the Diagnostic and Statistical Manual (DSM-5) instead uses a broader ‘umbrella’ category of Autism Spectrum Disorder (ASD).
The condition affects approximately 1 in every 100 children. It is not fully known what causes autism but it is thought to include a mixture of environmental and genetic factors1.
The UK National Institute for Health and Care Excellence (NICE) has a number of guidelines regarding the recognition, diagnosis, and treatment of autism2-4. Generally speaking, people with autism should be supported via a multidisciplinary approach, by people with expertise in the disorder. This can involve support from clinical psychologists, nurses, occupational therapists, psychiatrists, social workers, speech and language therapists, and other support staff.
What is ADHD?
Attention-Deficit Hyperactivity Disorder (ADHD), otherwise known as hyperkinetic disorder, is a condition that affects people’s behaviour. ADHD can cause restlessness, trouble concentrating and impulsive behaviour1. For example, children with ADHD may blurt out answers in the classroom, fidget and find it impossible to keep still and struggle to focus on what a person is saying.
ADHD is the most common psychiatric disorder of childhood, affecting at least 5% of children globally. Symptoms persist into adulthood in up to 60% of childhood cases2.
For a diagnosis of ADHD to be given, the symptoms must be functionally impairing and occur in at least two distinct settings, for example at home and at school.
Considerable research has examined the long-term consequences of ADHD, highlighting its global importance for society. In a systematic review of the data, untreated ADHD was associated with poorer long-term outcomes across all categories considered: these included academic performance, job performance and employment status, self-esteem, quality of life, and risk of driving accidents3.
ADHD is a treatable psychiatric disorder, with medium to large effect sizes in terms of symptomatic improvement, versus control conditions, over the short-medium term4.
ADHD is often misdiagnosed, and is frequently comorbid with other mental (and physical health) disorders. First-line treatment options for ADHD can include consideration of psychotherapy and/or medication, but these should always be offered as part of a comprehensive package of care. The most appropriate treatment options and sequencing of treatment options can vary considerably depending on factors such as the age of the individual, severity of disease, and patient/family preference.
Why it is important to do research in ADHD?
The core symptoms of attention deficit disorders are cognitive in nature (inattention, hyperactivity, and/or impulsivity). These cognitive deficits often reflect underlying brain circuitry dysfunction (including prefrontal regions) and of neurochemical transmission, including the dopamine and noradrenaline/norepinephrine pathways5-9. Our recommended test battery for attention deficit disorders assesses the cognitive domains most likely to be impaired, as well as those likely to be affected by interventions.
Sample CANTAB test battery for cognitive safety
We have developed the cognitive battery listed below as a starting point to aid the discussion between our clinical scientists and the sponsor’s clinical team regarding your specific study protocol, clinical population and the study goals.
These batteries are designed for use in clinical trials aiming to assess cognition as a safety measure. They provide a broad overview of cognition by tapping into some of the key cognitive domains. Additionally, these tests have been shown to be sensitive to cognitive decline by pharmacological interventions, confirming their suitability for use in these trials to flag any potentially negative effects on cognition as soon as possible.
The two batteries (Phase I and II) are similar, with the Phase II battery including one extra test due to the decreased number of testing time points typically seen in these trials, thereby allowing for a greater total battery time.
Phase I Measures:
Processing speed
Working memory
Visual memory
Executive Function
The three tests within our Phase I battery have excellent psychometric properties, with test-retest reliabilities of 0.82 for processing speed, 0.7 for visual memory and reaction time, and 0.85 for working memory and executive function. The test panel is sensitive to acute pharmacologically induced cognitive impairment in healthy subjects.
Phase II Measures:
Processing speed
Sustained attention
Visual episodic memory
Psychomotor speed
Working memory
Pathology and functional impact of cognitive safety
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, 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.
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.
