Cognitive Enhancers in Neuroscience Medicine

Neuropsychiatric disorders cause impairment via multiple pathways. One pathway to impairment is cognitive impairment via attention problems, cognitive slowing and memory disruption.

Barbara Sahakian and colleagues recently published an interesting manuscript examining the issue of cognitive enhancement.

Their review begins by summarizing some of the research related to cognitive enhancement in four neuropsychiatric syndromes. I will summarize their main points by specific disorder.

Alzheimer's Disease (AD)

• Acetylcholinesterase inhibitors such as donepezil have been specifically developed to enhance and slow deterioration of cognitive function in AD
• NMDA receptor agonists such as memantine can also enhance cognitive function and these types of cognitive enhancement agents are typically used in later stages of the disease
• Early identification and early use of cognitive enhancement agents is estimated to decrease the cost of AD by $5000 per individual

Parkinson's Disease (PD)

• Cognitive impairment and dementia are commonly found in PD
• Dopamine agonists such as methylphenidate have been used in PD for treatment of fatigue and cognitive impairment but can worsen impulsivity/compulsive gambling problems
• Atomoxetine may hold promise in PD for psychomotor slowing, global cognition and executive functioning
• Anticholinesterase inhibitors and memantine have shown only marginal improvement in cognition in studies of PD subjects

Attention Deficit Hyperactivity Disorder (ADHD)

• Stimulant treatment of ADHD with drugs such as methylphenidate is effective in 60-70% of children and adults with ADHD
• However, new non-stimulant drug development is needed to address issues of stimulant abuse and non-response
• Methylphenidate improves spatial working memory performance in both individuals with ADHD and healthy volunteers
• Modafinil and atomoxetine may improve response inhibition in ADHD but appear to have limited effects on sustained attention and working memory

Schizophrenia

• Cognitive deficits are a hallmark of schizophrenia and the target of drug and non-drug intervention studies
• Modafanil has shown some early promise in schizophrenia with at least one study showing improvements in working memory, cognitive flexibility, emotion recognition, dorsolateral prefrontal cortex function
• Acetylcholinesterase inhibitors have shown limited effect on cognition in schizophrenia
• Non-drug interventions such as cognitive enhancement techniques (i.e. video games) may hold promise in schizophrenia

The authors go on to describe the results of a computer game study of cognition in schizophrenia using an iPad. I will describe the results of this study in my next post.

Readers with more interest in this manuscript can access the free full-text version by clicking on the PMID link in the citation below.

Follow the author on Twitter: @WRY999

Photo of Roman ruler Marcus Aurelius on horse from author's files.

Sahakian BJ, Bruhl AB, Cook J, Killikelly C, Savulich G, Piercy T, Hafizi S, Perez J, Fernandez-Egea E, Suckling J, & Jones PB (2015). The impact of neuroscience on society: cognitive enhancement in neuropsychiatric disorders and in healthy people. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 370 (1677) PMID: 26240429

Drug Development for Cognitive Enhancement

AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate)

Cognitive enhancement seeks to improve cognitive function in healthy adults.  Although medicine typically focuses on treatment of medical disorders, a significant effort is underway to explore the mechanism of human attention, concentration, memory and other cognitive functions.  


Cognitive enhancement does not replace other methods of cognitive performance.  There is no substitute for repetitive practice and learning content through reading, writing, speaking and physical activity.  Cognitive enhancement looks to maximize performance without serious adverse effects risk.  The development of drugs and model molecules related to basic brain is expanding.  


This is really not a new area as man has been using dietary aids to enhance cognition for thousands of years.  Perhaps the best, but not the only, example of this is use of caffeine.  Caffeine can increase performance on a number of tests of cognitive function as well as extend the duration of time for productive activity.


Cognitive enhancement candidate drugs include extension of drug used in attention-deficit hyperactivity disorder (ADHD) as well as drugs designed to reduce the rate of cognitive decline in Alzheimer's disease and other dementias.  This class of pharmacology has been label the nootropic drugs.  de Jongh and colleagues from Utrecht University in the Netherlands recently summarized current and future targets for enhancing cognition.   Here is the listing of drugs from their review:


Currently available enhancers
Donepezil-an anticholinesterase inhibitor indicated for Alzheimer's disease with evidence of improved flight simulator performance after training older pilots
Modafanil-seen as a wakefulness enhancer with FDA approval for those shift work sleep disorder.  Effective at extending helicopter pilot performance effectiveness up to 36 continuous hours.
Dopamine agonists (d-amphetamine, bromocriptine, pergolide)-appears to improve working memory, particularly for those with memory problems or the COMT genotype val/val associated with reduced prefrontal dopamine levels
Guanfacine- Alpha 2 adrenergic receptor agonist approved for ADHD in the U.S. Inconsistent findings of improved memory and executive function 
Methylphenidate--Improves prefrontal cortical function in rodents but ineffective for age related cognitive decline found in older human research volunteers


Future targets
AMPA receptors-Ampakines are drugs that enhance fast excitatory neurotransmission by modulating AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate see diagram above)-type glutamate receptors--effective in improving memory and performance after sleep deprivation in monkeys.  Also effective improving memory in healthy elderly (65-75 years of age) human study.
NMDA receptors-D-cycloserine, a partial agonist at the NMDA receptor enhances memory and has been effective in increasing the speed of response to psychotherapy as noted in previous Brain Post commentary here.
CREB (cAMP response element binding protein)-cAMP response element protein a crucial compound in long-term memory formation.  Has problems with adverse effects (anxiety and depression) outside of brain amygdala. 


Mood and pro-social behavior
Antidepressants-may have some ability to increase social behaviors in those without depression, also felt to improve "hassle tolerance"
Oxytocin-increases pro-social behaviors such as pair bonding and maternal care.  Leads to increased trust in others in social game simulations.


Research in this area carriers some significant ethical challenges that will need discussion and consideration.  Nevertheless, look for additional research into "nootropic" drug development.


DEJONGH, R., BOLT, I., SCHERMER, M., & OLIVIER, B. (2008). Botox for the brain: enhancement of cognition, mood and pro-social behavior and blunting of unwanted memories Neuroscience & Biobehavioral Reviews, 32 (4), 760-776 DOI: 10.1016/j.neubiorev.2007.12.001