New ADHD Pharmacologic Treatments Needed But Few Are On the Way

Behavior therapy can benefit most patients with attention deficit hyperactivity disorder (ADHD), but the vast majority of patients with the condition will still need pharmacotherapy to manage their symptoms and prevent the disorder from interfering with their lives. Yet little progress has been made in identifying effective agents for patients who don’t respond to the handful of existing medications.

“There are still pretty major gaps in optimal treatment of ADHD that potentially might be filled if we could find further ways of getting at the problem of ADHD,” said Glen Elliott, MD, PhD, chief psychiatrist and medical director of Children’s Health Council in Palo Alto, California. He noted that some interest has developed in GABA, a largely inhibitory neuroregulator, and glutamate, which is more excitatory, but not much has moved forward with these agents. Despite recent and continuing advances in understanding the condition, substantial knowledge gaps remain regarding ADHD’s etiology and neurobiology.

Russell Barkley, PhD, a clinical professor of psychiatry at the Medical University of South Carolina in Charleston, and a well-known clinician in the field, agreed, suggesting it might require more insight into genomic properties of the condition before any truly new drugs come along. 

“Some companies tried to make a nicotinic receptor agent, but the ones I know of failed during their clinical trials, so that type of drug doesn’t seem useful to pursue any further,” Barkley said. “I think drug companies are awaiting further results from molecular genetic studies that show specific candidate genes for ADHD and that affect brain development and pathway functioning in such a way that a drug might be useful to try and intervene in that pathway, but none are close to commercial development.”

The market currently offers 2 US Food and Drug Administration (FDA)-approved stimulants, methylphenidate and amphetamine, and 3 FDA-approved nonstimulants: atomoxetine, a norepinephrine reuptake inhibitor, and two alpha agonists, clonodine and guanfacine. Aside from the various formulation options of these 5 agents and drugs prescribed off-label such as bupropion, not much else offers clinical value in treating patients with ADHD.

Even among these options, nonstimulants have a lower efficacy rate, estimated at 40% to 45% compared with 65% to 85% with the stimulants, Elliott pointed out. “With the two classes of stimulants we currently have, it doesn’t matter what stimulant you start with. It will be beneficial, well tolerated, and have the effects you’ll be looking for in 65% of people,” Elliott said. “If it doesn’t work, and you try the other class, another 20% will respond better or else the side effect profile is better.”

It is the remaining 15% of children and, increasingly, adults, who do not respond to any of the approved medications who really need novel therapies. There are also the disadvantages of stimulants, such as their potential for misuse or abuse. And, in addition to side effects like suppressing appetite, affecting height, and potentially causing insomnia, stimulants only work for part of the day.

“Especially now that we’re looking toward adolescents and adults with ADHD, they need more treatment beyond 8-10 hours,” Elliott said,” but they need to be able to sleep, too.”

What’s Around the Corner

In the meantime, however, several companies are still exploring other options based on what is known, even if their products are chemically similar to existing therapies. At their annual conference in January, The American Professional Society of ADHD and Related Disorders (APSARD) hosted dozens of abstracts about ADHD, running the gamut from screening to neurobiology to recent developments in treatment. A significant percentage of the abstracts included preliminary results from clinical trials for drug therapies currently in the pipeline.

“Unfortunately the ones that have been coming out recently have really been [a] carbon copy of what we have, which isn’t all that useful,” Elliott said. Plenty of methylphenidate and amphetamine derivatives already exist, for example, “but there are clear ongoing problems that the current medications don’t address that some of the newer formulations are trying to,” he added.