Subject:
ADHD

Short Description:
Is Nicotine an Effective Treatment for ADHD? Three Studies Weigh In

Background:
If you want to watch a new drug wend its way to market, you might start watching the literature for ABT-809, a nicotinic receptor partial agonist and proposed novel approach to the treatment of ADHD. To that end, two recent clinical trials are interesting reads. The nicotinic receptor has five subunits that can vary from location to location, and presumably from purpose to purpose. It seems that different subunit combinations mediate different behaviors and different neurotransmitters, and that makes them an interesting focus for drug design. The alpha-4, beta-2 nicotinic receptor appears to induce the release of dopamine stored at neural synapses and induces the firing of dopaminergic neurons. When people quit smoking, they have a variety of symptoms, including lack of concentration. People with ADHD are more likely to be smokers (although this may be our own making—prior stimulation with amphetamine makes nicotine more reinforcing in rats), and smoking relieves the symptoms of ADHD in patients who have it. Nicotine has also been shown to improve attention in Alzheimer’s patients, improve abnormal sensory gating and attention in patients with schizophrenia, and enhance working memory. To refresh your memory, a partial agonist reduces the response of the target cell rather than completely blocking it, more like a dimmer than a light switch. ABT-089 is a partial agonist of the alpha-4, beta-2 subtype of the nicotinic receptor, which seems to play a role in depression, locomotion (specifically too much locomotion), pain, and fear-associated learning, among other things (Piccioto et al, Neuropsychopharmacology 2000;22(5);451–465). In the first study, which focused on adults with ADHD (Apostol G et al, Psychopharmacology (Berl) 2011;Jul 12, online ahead of print), five different doses of ABT-089 were evaluated in a double-blind, randomized cross-over design. That is, within each group, half of patients were given placebo for four weeks and half active compound. Then there was a two week wash out period in which neither was administered. Finally, for the next four weeks, the subjects were given the opposite of what they had previously received: placebo if they had drug, drug if they had placebo. There were about 20 subjects in each group. Doses were 2 mg, 5 mg, 15 mg, 40 mg and 80 mg daily. All subjects met criteria for ADHD and nothing else and were washed out from any psychotropic medication they had been using. The primary outcome was CAARS:Inv, an adult ADHD scale with subscales in inattention and hyperactivity. There were several drop-outs and interestingly, many of these were smokers. To cut to the chase, there was a statistically significant improvement in total CAARS:Inv scores in the higher doses, with effect sizes of 0.29 for the 40 mg group and 0.30 for the 40 mg, BID group (in other words: very small effect sizes). To be fair, the effect seen was only at the tail end of treatment, so it is possible that after more time, the effect would be larger. Adverse effects are always hard to gauge, as things happen to people whether or not they are taking medication—or think they are. However, three patients had serious adverse events: vasovagal syncope, myocardial infarction, and gallstones. While the investigators did not feel that these were related to drug (and the patients were on the lower doses of medication), the compound does modulate cholinergic activity, so you never can tell. Irritability was the most frequent “non-serious” adverse event. In the pediatric paper (Wilens TE et al, J Am Acad Child Adolesc Psychiatry 2011;50(1):73–84.e1), two similar studies were reported together. Both enrolled subjects between ages six and 12 with ADHD (per the KSADS-PL). One study used doses equivalent, in mg/kg, to the first four adult doses. The second study used the equivalent of the 80 mg dose. Rather than a cross-over design, the subjects were given six weeks of drug or placebo or atomoxetine (Strattera). There were about 40 subjects per group. Using the outcome of Attention-Deficit/Hyperactivity Disorder Rating Scale-IV: Home Version, and the secondary outcome of Clinical Global Impression–Attention-Deficit/Hyperactivity Disorder-Severity Scale, the study found no statistical difference in ABT-089 vs placebo, but the atomoxetine group did improve.

TCPR's Take:
In comparison to the Apostol et al adult study, the Wilens et al pediatric study suggests that ABT-089 is really not effective in children. The authors remind us that the blood-brain barrier differs in permeability from children to adults, and offer this as one possible explanation. It will be interesting to see if, like atomoxetine, ABT-089 goes on to achieve FDA approval in adults despite poor early trials. If so, it is likely that less well informed practitioners will use it in kids. Fortunately, you don’t have to be one of them.