Experimental Schizophrenia Drug Shows Encouraging Results

For a few years now, Robert Freedman, M.D., chair of psychiatry at the University of Colorado Health Sciences Center, and colleagues have been undertaking a valiant quest to find a drug that improves cognition and eradicates negative symptoms in individuals with schizophrenia—something that available medications for schizophrenia generally fail to do.

Specifically Freedman and his team have been trying to determine whether drugs that soup up the action of the alpha 7 nicotinic acetylcholine receptors in the brain—the so-called alpha 7 receptor agonists—might be the answer.

Two years ago, they reported very preliminary, but heartening results for an alpha 7 receptor agonist called DMXB-A. Eleven subjects with schizophrenia were found to experience significantly better cognition a day after receiving DMXB-A than a day after getting a placebo. Improvement in attention was especially notable. Results were published in the June 2006 Archives of General Psychiatry (Psychiatric News, July 21, 2006).

Now Freedman and his group report more encouraging results regarding DMXB-A. The results, which first appeared online in AJP in Advance on April 1, will be published in the August print edition of the American Journal of Psychiatry. Freedman is editor in chief of the journal.

This time, 29 subjects with schizophrenia were studied. They were assessed for cognitive abilities with the MATRICS Consensus Cognitive Battery (MATRICS), for negative symptoms with the Scale for Assessment of Negative Symptoms (SANS), and for clinical effects with the Brief Psychiatric Rating Scale (BPRS). After that, they received daily, for four weeks each, a 75 mg dose of DMXB-A, a 150 mg dose of DMXB-A, or a placebo in this three-arm, double-blind, crossover phase 2 trial. Throughout the study, they also continued to take whatever dopamine-antagonist antipsychotic drugs they had already been taking.

At the end of each four-week arm, the researchers used the same instruments as at baseline to evaluate the subjects' cognition, negative symptoms, and clinical effects. After that, the researchers compared the subjects' cognition, negative symptoms, and clinical effects at baseline with their cognition, negative symptoms, and clinical effects after getting 75 mg of DMXB-A daily, 150 mg of DMXB-A daily, or a placebo daily. Finally, the researchers compared all of the subjects' outcomes while on 75 mg of DMXB-A daily, 150 mg of DMXB-A daily, or a placebo daily.

Subjects showed no significant improvement in cognition on the MATRICS test after receiving either 75 mg or 150 mg of DMXB-A daily than they had after getting a placebo daily. The reason why no significant improvement was found, the investigators suspected, may have been because the subjects' cognition tended to improve with testing throughout the three arms of the study. So they decided to examine cognitive outcome for subjects only in the first arm of the study to see whether they could find any significant differences. And they could: subjects on either 75 mg of DMXB-A daily or on 150 mg of DMXB-A daily showed significant improvement in attention over baseline and in working memory over baseline, whereas subjects on a daily placebo did not.

Moreover, when the researchers examined negative-symptom outcomes and clinical-effects outcomes for all three arms of the study, they found a significant lessening of negative symptoms and a trend toward improvement in clinical effects when subjects received 150 mg of DMXB-A daily versus a placebo daily. Improvements were most notable on two negative symptoms—anhedonia (inability to experience pleasure from normally pleasurable life events) and alogia (difficulty in conversing fluently). Also, numerous subjects reported that they were markedly more organized in their thinking and behavior than they had been before getting DMXB-A.

“The results, although still preliminary, are important for two reasons,” Freedman told Psychiatric News. “First, when a new intervention enhances the brain performance of patients with schizophrenia beyond what it is currently, the results are encouraging for patients and their families, and they tell psychiatrists that their patients' brain deficits are not immutable. Second, the results suggest that... this specific intervention... should be further developed.”

Ann Olincy, M.D., associate professor of psychiatry at the University of Colorado Health Sciences Center and one of the study investigators, was“ a bit disappointed” by the three-arm cognition test results, she told Psychiatric News. But on the whole, she said, she was gratified by the results, “primarily because they replicated our results from the phase 1 study with findings of enhanced attention, though with a longer duration of dosing... [and because] patients reported they wanted to continue the drug after the trial because it helped them function.”

Freedman's team also plans to explore the possible value of some other alpha-7 receptor agonists besides DMXB-A in enhancing cognition and/or in abolishing negative symptoms, he said.

The study was funded by the VA Biomedical Laboratory and Clinical Science Research and Development Service, the National Association for Research in Schizophrenia and Affective Disorders, and the Institute for Children's Mental Disorders.

“Initial Phase 2 Trial of a Nicotinic Agonist in Schizophrenia” is posted at<http://ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2008.07071135v1>.▪