5 July 2006. A small phase 1 trial has yielded encouraging results for the use of an α7 nicotinic acetylcholine receptor agonist in the treatment of schizophrenia. In the study, Robert Freedman and colleagues at the University of Colorado School of Medicine in Denver evaluated 12 schizophrenia patients after 1-day dosing of the partial α7 agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXB-A), and saw a significant improvement in neurocognitive test scores. Treatment also reversed the P50 auditory-evoked potential defect observed in schizophrenia and mediated by α7 receptors. The results, published in the June issue of the Archives of General Psychiatry, support the clinical use of α7 receptor agonists, a proposition that will be put to the test in a larger and longer phase 2 study of DMXB-A now underway.
With their work and that of others in recent years, Freedman and colleagues have built the case for targeting the α7 nicotinic acetylcholine receptor for treatment of schizophrenia (see review by Martin et al., 2004). They established that people with schizophrenia have an impaired physiological response to repeated auditory stimuli—the P50 evoked response does not diminish after a second stimulus as it does in cognitively normal people. The lack of P50 inhibition correlates with attentional problems, and the theory is that an inability to properly gate sensory inputs could contribute to symptoms such as disorganized thought. Appropriate P50 inhibition requires α7 receptor activity in animals, and several drugs already in clinical use modulate α7 receptor function. Both the α7 receptor agonist tropisetron and clozapine, which stimulates release of acetylcholine in the hippocampus, increase inhibition of the p50 auditory response. (Early on, cigarette smoking was shown to improve P50 inhibition [Adler et al., 1993], leading to the suggestion that the reason 80 percent of people with schizophrenia smoke is that they are self-medicating. As a therapy, though, nicotine is not useful because the receptors very rapidly desensitize to its effects.)
More recently, genetic studies have linked the α7 receptor locus (CHRNα7) at 15q14 to a heritable P50 gating defect and cognitive dysfunction. Several studies have linked this region to schizophrenia as well. Postmortem brain from schizophrenia patients show lower levels of α7 receptor, all adding up to α7 receptors as a promising therapeutic target for cognitive symptoms of the disease.
The alkaloid derivative DMXB-A is a partial α7 agonist first discovered by coauthor William Kem at the University of Florida. DMXB-A has been shown to improve memory in humans and animals, and to normalize P50 auditory inhibition in animals, with significantly less tachyphylaxis than nicotine. To test DMXB-A in a pilot study in humans, the researchers, led by first author Ann Olincy, treated non-smokers with schizophrenia with placebo, or one of two drug doses. In each 1-day session, the subjects were evaluated before and after dosing with the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) and for P50-evoked auditory potential in response to two stimuli.
Even brief drug treatment resulted in an increase in RBANS scores that was just significant (p = 0.05). There was a measurable practice effect, causing scores to rise from baseline over the study, and adjusting for this made the p value rise to 0.08. The cognitive effects of DMXB-A were similar to those of nicotine (Harris et al., 2004), but stronger. Just as with nicotine, of the six individual indices within RBANS, the attention index showed the greatest improvement. Overall, five subjects increased their RBANS scores between 12 and 18 points, a change that might be clinically significant, as a 15-point score difference was found to separate unemployed and employed patients in a previous study (Gold et al., 1999).
The drug showed neurophysiological effects on P50 potentials consistent with an action at nicotinic receptors. When the researchers measured P50 potentials before drug exposure on each day, they consistently found the lack of inhibition characteristic of schizophrenia patients. However, after drug treatment, while the P50 response to a conditioning stimulus was unchanged, the amplitude to the test stimulus was significantly decreased compared to placebo (p = 0.03), as was the ratio of the test amplitude to conditioning amplitude (p = 0.01). In drug-treated patients, the P50 response values were brought into the range of normal.
DMXB-A was well tolerated by subjects—the most common complaint was sleepiness, but this was reported equally in all treatment groups. One patient was withdrawn from the study because of a decreased white blood cell count, but recovered promptly. Some patients remarked on feeling improved powers of concentration on the high-dose treatment.
Longer and larger studies will be required to determine if the short-term effects noted in this trial carry into prolonged treatment. An important question to settle will be whether chronic exposure to nicotine affects the action of DMXB-A in patients who smoke. Nonetheless, the authors conclude that, “The findings with DMXB-A in this study are a direct demonstration of the effects of activation of the α7 nicotinic receptors in schizophrenia, and they suggest that nicotinic cholinergic agonism may be a therapeutic mechanism worthy of further development for schizophrenia,” the authors write. To that end, they report the initiation of a phase 2 double blind, three-arm crossover study with 1-month administration of two different doses of DMXB-A or placebo in both smokers and nonsmokers.—Pat McCaffrey.
Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry. 2006 Jun;63(6):630-8. Abstract