Initial Phase 2 Trial of a Nicotinic Agonist in Schizophrenia

Department of Psychiatry, Denver VA Medical Center and University of Colorado, Denver, CO 80262, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 05/2008; 165(8):1040-7. DOI: 10.1176/appi.ajp.2008.07071135
Source: PubMed


Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of alpha(7)-nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial alpha(7)-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia.
Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers.
There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A.
DMXB-A, a nicotinic agonist that activates alpha(7)-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined.

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Available from: James Gold, Oct 01, 2015
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    • "However, α7-PAMs appear to have a broader spectrum of therapeutic activity as compared to α4β2-PAMs, possibly, because they appear to be able to convert endogenous choline into a potent therapeutic agent. DMXB-A is a selective α7 nicotinic receptor agonist that has been extensively tested at various phases of pre-clinical and clinical trials as a potential therapy for a number of neurological conditions, including Alzheimer's disease (Kem, 2000) and most recently, schizophrenia (Freedman et al., 2008; Olincy et al., 2006) (see As a novel therapeutic opportunity, nicotinic-PAMs that could recruit endogenous cholinergic pathways and enhance pathology-activated auto-therapies would hold significant translational potential. "
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