Steven Phillips, MD

It is important to understand that the use of any currently available pharmaceutical agents to enhance cognition is off-label and is limited by evidence of efficacy. Modafinil is a wake-promoting agent that has been used for narcolepsy and was researched for use in ADHD. While the exact mechanism is unknown, modafinil may exert its effect by modulating GABA- and glutamate-mediated neurotransmission, thereby resulting in reuptake inhibition of dopamine and norepinephrine.

Cognitive Enhancers in Children and Adolescents: What Psychiatrists Need to Know

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Which pharmacotherapeutic approaches have the most evidence for effectiveness in cognitive enhancement? Test your knowledge with this quiz.

Mini Quiz: Cognitive Enhancers

Cognitive enhancement is often characterized by attempts to increase the performance of cognitive functions, such as attention or memory, in healthy individuals. Defined by Juengst, enhancement is a term used to “characterize interventions designed to improve human form or functioning beyond what is necessary to sustain or restore good health.”

While humans and other species have consistently made efforts to improve from an evolutionary standpoint, what is relatively new is the impact of medications and technological advances in enhancing such efforts. Although personal enhancements such as cosmetic surgery have gained societal acceptance, interventions such as cognitive enhancement continue to be a matter of significant ethical, philosophical, and sociopolitical debate.

It is important to understand that the use of any currently available pharmaceutical agents to enhance cognition is off-label and is limited by evidence of efficacy.

. While stimulants are most often used to treat ADHD and narcolepsy, these medications have also been used off-label as an augmentation strategy in depression, to manage fatigue in patients with cancer, and to treat apathy in patients with dementia. Methylphenidate and dextroamphetamine are believed to work by allosteric inhibition of presynaptic dopamine and norepinephrine transporters, thereby preventing neurotransmitter reuptake and resulting in enhanced monoaminergic neurotransmission. In addition, amphetamines result in vesicular release of dopamine.

Methylphenidate and dextroamphetamine have been used successfully in a variety of formulations to manage symptoms of ADHD in children, adolescents, and adults. While effective, stimulants are associated with decreased appetite and weight, insomnia, headache, irritability, and mood changes, as well as palpitations, tachycardia, and substance abuse. Overall, analysis of existing studies provides no consistent evidence for neuroenhancement effects with methylphenidate, although evidence for a positive effect on memory, especially spatial memory, was observed in healthy individuals.

 As a result, based on current evidence, there may be only slight enhancing effects of stimulants in the healthy population, if any, and their use for enhancement may be countered by potential adverse effects.

. Modafinil is a wake-promoting agent that has been used for narcolepsy and was researched for use in ADHD. Some studies suggest that nearly 90% of modafinil use is by healthy, non–sleep-deprived individuals such as physicians, academics, and students.

 While the exact mechanism is unknown, modafinil may exert its effect by modulating GABA- and glutamate-mediated neurotransmission, thereby resulting in reuptake inhibition of dopamine and norepinephrine. Modafinil is not approved for use in ADHD because of its potentially life-threatening adverse effects.

Systematic reviews indicate that there is evidence of enhancing effects with modafinil, although such effects are moderate. Repantis and colleagues

 found that modafinil improved attention for well-rested individuals. In individuals who were sleep-deprived, the effects were even more pronounced, especially on wakefulness, memory, and executive functions. Interestingly, Baranski and colleagues

 reported that sleep-deprived individuals who took modafinil overrated their cognitive performance on tests and had an actual “overconfidence” effect.

 Cholinesterase inhibitors, especially donepezil, and the NMDA antagonist memantine have also been reviewed. While these medications were well tolerated, no consistent effect on cognitive enhancement was reported.

Growing evidence indicates a potential benefit of nonpharmacological cognitive enhancers. For example, brain training may slow the decline of daily functioning in elderly adults.

 Potential benefits for brain training in children with ADHD or dyslexia have also been observed.

. Caffeine works as an antagonist at adenosine receptors and has fairly well-known cognitive benefits. Mechanistically, adenosine binds to dopamine receptors and reduces the sensitivity of these receptors; as a result, when caffeine antagonizes the adenosine receptor, this allows for continued dopamine sensitivity, thus causing stimulation. Some of the common adverse effects reported with caffeine may include palpitations, headache, or insomnia; more severe adverse effects may include chest pain, supraventricular tachycardia, and ventricular arrhythmias. The use of caffeine in children is restricted because of the potential adverse effects. It is important to note that excessive caffeine intake from regularly drinking sodas may result in increased irritability in children.

. Aerobic exercise has been reported to improve attention, executive function, and memory.

 Similarly, anaerobic exercise has been linked to increased learning speed, and short bouts of physical activity have been associated with long-term memory improvements.

 reported that physical exercise in school-age children was associated with improved academic achievement, verbal and perceptual skills, and math skills. Potential neural mechanisms for these associations are increased hippocampal blood flow, volume, and connectivity, as well as improved resting efficiency of higher cognition areas.

. A potential function of sleep may be to enhance cognitive functions, especially memory. While one obvious comparison has been with subjects who are sleep-deprived, others have suggested that daytime naps, as short as 6 minutes, promote memory.

 REM sleep was found to selectively enhance neural circuits involved in creative problem-solving.

. Meditation may be associated with increased attention and cognitive flexibility, as well as processing speed, executive functioning, and general cognition

 Music may improve working memory, perceptual speed, and motor skills.

. In a study of children aged 8 to 11 years who had ADHD, Holmes and colleagues

 found that working memory training combined with medication improved visuo-spatial and central executive components. Improvements due to training persisted over 6 months. In another study, improvements across the domains of cognitive functioning were seen with cognitive remediation therapy in patients with schizophrenia.

. Non-invasive techniques such as transcranial magnetic stimulation (TMS) have been suggested to improve brain plasticity, and TMS to motor areas has been shown to improve motor learning. Depending on the area of stimulation, there has been benefit demonstrated in verbal fluency, visual-spatial attention, and speed of analogic reasoning.

There is increasing evidence that healthy individuals are using cognitive enhancers. Adolescents with ADHD may feel compelled to take stimulants to maintain an even footing with their peers when applying to colleges or finding employment. In cases in which effective treatment for ADHD allows a student to complete his or her education and achieve employment, or a patient with traumatic brain injury is effectively treated so as to prevent multiple hospitalizations, there is great benefit to society. In individuals who are cognitively healthy, however, the issues are more complicated.

While cognition-enhancing agents may be useful in professions in which one must maintain prolonged concentration, the risk of abuse-as well as cardiac risks and excessive weight loss-in otherwise healthy individuals may outweigh the benefits received from the drug. Although no studies have assessed the long-term effects of cognition-enhancing agents, there is concern that the use of stimulants may predispose an individual to substance abuse.

Integrating cognitive enhancers into your practice

As psychiatrists, we understand that unlike other “self-enhancement” strategies, the legitimacy of cognitive enhancement raises questions in ethical, legal, medical, and public health domains. In discussions with families, consider the differences between a therapeutic and an enhancement approach, benefits versus risks of enhancement strategies, and societal fairness in the availability of options. Whetstine

 reports that distinctions between therapy and enhancement can at times be blurred. Often, such discussions are modified by whether cognitive enhancements are regarded only as treatment and are covered by insurance, or whether they are considered to be similar to dietary supplements.

It has been debated that similar to other modes of enhancement, as long as individuals have been made aware of the risks and benefits, it may be somewhat paternalistic to restrict the use of cognitive enhancers for consenting patients. When considering how to incorporate pharmacological options into a care strategy, it is important first to conduct a thorough interview with the patient as well as to gather collateral information from the family if available. Understanding the patient’s family and medical history (including current and past substance use disorders) and how it relates to the current presentation can be of significant benefit when determining which agents to prescribe. The addition of nonpharmacological options makes for a well-rounded, multifaceted treatment approach.

While medications may be of some benefit, their use is currently limited by a relative lack of substantial research, especially on long-term safety and efficacy. On the other hand, good sleep, exercise, meditation, and a healthy diet are largely without adverse effects and may be of great use alone or in combination with pharmacotherapy. Nonpharmacological approaches are especially important when working with children. Physical exercise, good sleep, and meditation are the first-line approach to take in managing ADHD in children and adolescents.

In the past several years, drug diversion has emerged as a huge problem that parents must be aware of. It is important to caution parents and the patient about the illegal nature of diversion, and to consider the risk for other potential substance use disorders. Keeping parents involved allows for dialogue on the appropriate use of cognitive enhancers more consistently than medication-check office visits. Regular urine screening may be beneficial for monitoring, as needed. If available, prescription monitoring programs will show if the patient is filling the prescription regularly as well as inappropriately accessing multiple providers.

Dr. Phillips and Dr. Robinson are PGY-3 Residents, and Dr. Madaan is Associate Professor at the University of Virginia Health System, Charlottesville, VA. Drs. Phillips and Robinson report no conflicts of interest concerning the subject matter of this article. Dr. Madaan reports that he has received research support from Pfizer, Forest, Medgenus, Purdue, Sunovion, and Lundbeck; he receives royalties from Taylor & Francis (Routledge).

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 Holmes J, Gathercole SE, Place M, et al. Working memory deficits can be overcome: impacts of training and medication on working memory in children with ADHD. 

 Smith PJ, Blumenthal JA, Hoffman BM, et al. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. 

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Personal enhancements (eg, cosmetic surgery) have gained societal acceptance, but cognitive enhancement poses significant ethical, philosophical, and sociopolitical issues. 

Author | Steven Phillips, MD

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Mini Quiz: Cognitive Enhancers

Cognitive Enhancers in Children and Adolescents: What Psychiatrists Need to Know