The Developing Drug Story

The current crop of CEs were all discovered in the classic trial-and-error method of testing various chemicals in cells or animals until the desired effect is achieved. But how they work their magic is only partially understood. ADHD stimulants, such as Ritalin, Adderall, and Concerta, juice the prefrontal cortex with the neurotransmitters dopamine and norepinephrine, apparently improving concentration and attention. Provigil raises levels of norepinephrine in the same area, but additional dynamics are in play. In a 2008 Science paper, Minzenberg helped explain the mystery when he reported that functional MRIs show that the drug also defuses neuronal activity in the brain stem by way of an interconnected signaling network. "Provigil increases the activity in one part of the brain and reduces it in another part," Minzenberg says. "Even though they are far apart, both are necessary to cause the attention-stimulating effect."

Only with identification of such systems will rational drug design produce more selective and effective CEs. "Many of the next generation are being developed around the question, 'Here is a healthy system that effects cognition, how can we enhance or improve its effects—and then use that in disease studies?'" says Chatterjee.

More interesting is Cortex's so-called high-impact ampakine, which features the added bonus of increasing brain-derived neurotrophic factor (BDNF), a protein that promotes neurogenesis and the formation of long term memories. Lilly, GSK, and Pfizer are also exploring high-impact ampakines. But these potent compounds present safety problems, including seizures.

Varney is amused by media reports of ampakines as the next big thing in cosmetic neurology. "My own belief is that it is very difficult to improve cognition, and especially memory, in healthy people," he says.

The press has also heaped coverage on nicotinic-receptor agonists because of the off-beat equation of nicotine and health benefits. Whether the class deserves such attention is a question: No nicotinic-receptor agonist has made it to Phase III. Nicotine acts as a brain stimulant by binding to so-called nicotinic receptors, causing the release of the neurotransmitter acetylcholine, which in turn spurs attention to and retention of information. Leading in nicotinic-receptor drug development is Targacept, a spinoff of the tobacco company R.J. Reynolds's pharma research division. The North Carolina–based biotech has four Phase II candidates spread across ADHD, Alzheimer's, depression, and cognitive dysfunction in schizophrenia, all being codeveloped with AstraZeneca following a $200 million deal. But its lead product bit the dust in Phase II trials for cognitive dysfunction in Alzheimer's. Roche, Abbott, and EnVivo also have promising Phase II candidates.

Equally news-grabbing are studies linking the blocking of the brain's cannabinoid receptors to potential smart-drug development. This discovery has given second-chance hopes to the class of cannabinoid-receptor antagonists in which pharma invested so intensely as an anti-obesity treatment until Sanofi-Aventis' first-in-class Acomplia crashed and burned after reports of suicides and other psychiatric problems. Yet it seems plain that only extreme refinements will make these blunt instruments sufficiently selective to effect cognition without also messing with mood and other mental functions.

After safety concerns, the problem of trade-offs may be the highest hurdle for CE drug development. "Benefits in one area of cognition may come at a cost in another," concludes Reinoud de Jongh, psychopharmacologist and professor at Utrecht University in the Netherlands, in a comprehensive survey of current CE research published in 2008 in the journal Neuroscience and Biobehavioral Reviews. He also notes a third hurdle: "It's likely that there are different optimal levels of neurotransmitters for different types of cognitive tasks, and therefore enhancement may not be possible across all aspects of cognition at once."

San Diego–based Helicon Therapeutics is one of many biotechs attempting an end-run around this law of unintended consequences. Helicon is targeting a gene, dubbed CREB, responsible for the conversion of memory from short to long term (more than three hours). In theory, increasing the expression of CREB could speed up learning in healthy people or slow down memory loss in the aging. Helicon has said that its lead product has shown benefits in Phase II trials in enhancing recall without apparently impeding attention. Yet memory is far from the only brain function in which CREB is involved, and Helicon's efforts to prime the memory pump may cause cracks in the pipes elsewhere with extended use.