Pharmacokinetic Limitations on Effects of an Alpha7-Nicotinic Receptor Agonist in Schizophrenia: Randomized Trial with an Extended-Release Formulation.

The aim of the trial was to assess whether extending plasma levels of the alpha7-nicotinic acetylcholine receptor (nAChR) agonist 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) over time enhances its cognitive effects in schizophrenia. Both smoking and non-smoking patients were studied, to determine whether effects differ between these two groups. Forty-three smokers and thirty-seven non-smokers who met DSM-IV criteria for schizophrenia were enrolled in a double-blind, randomized, placebo-controlled 1 month trial. DMXB-A 150 mg was formulated with hypromellose to produce extended release over 4 h and administered four times daily. The primary outcome (the Neurocognitive Composite of the MATRICS Consensus Cognitive Battery) and secondary outcomes (the MATRICS Attention-Vigilance Domain and P50 gating), showed no significant effect. Plasma levels were obtained 2.5 h post administration. In non-smokers, levels were similar to those reached transiently with 75-150 mg DMXB-A immediate-release formulations twice daily, which were earlier shown to be effective doses. However, the extended-release formulation produced no cognitive or clinical effect either in non-smokers or smokers. The 10-fold lower DMXB-A plasma levels in smokers suggest that chronic smoking enhances DMXB-A metabolism. Pro-cognitive effects of DMXB-A may result from transient increases in cell signaling that are limited by receptor tachyphylaxis. Future efforts to improve cognition in schizophrenia by enhancing alpha7 nAChR function may require consideration of these pharmacokinetic limitations.

First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288.

Type I positive allosteric modulators (PAMs) of the alpha7-nicotinic receptor enhance its cholinergic activation while preserving the spatiotemporal features of synaptic transmission and the receptor's characteristic rapid desensitization kinetics. Alpha7-nicotinic receptor agonists have shown promise for improving cognition in schizophrenia, but longer-term trials have been disappointing. Therefore, the type I PAM AVL-3288 was evaluated for safety and preliminary evidence of neurocognitive effect in healthy human subjects. Single-dose oral administration in ascending doses was conducted in a double-blind, placebo-controlled Phase I trial in non-smokers. The trial found indication of positive but non-significant effects on neurocognition at 10 and 30 mg, two doses that produced overlapping peak levels. There was also some evidence for effects on inhibition of the P50 auditory evoked potential to repeated stimuli, a biomarker that responds to alpha7-nicotinic receptor activation. The pharmacokinetic characteristics were consistent between subjects, and there were no safety concerns. The effects and safety profile were also assessed at 3 mg in a cohort of smokers, in whom concurrent nicotine administration did not alter either effects or safety. The trial demonstrates that a type I PAM can be safely administered to humans and that it has potential positive neurocognitive effects in central nervous system (CNS) disorders.

Schizophrenia, smoking status, and performance on the matrics Cognitive Consensus Battery.

Cognitive deficits and high rates of nicotine dependence are consistently documented in the schizophrenia literature. However, there is currently no consensus about how regular smoking influences cognition in schizophrenia or which cognitive domains are most affected by chronic smoking. Previous studies have also failed to disambiguate the effects of chronic nicotine from those of acute exposure. The current study uses a novel approach to testing nicotine addicted patients at a time-point between acute enhancement and withdrawal and implements the MATRICS Cognitive Consensus Battery (MCCB) to compare the overall cognitive performance of regular smokers (n=40) and nonsmokers (n=36) with schizophrenia. Controlling for age, gender, and education, smokers with schizophrenia were significantly more impaired on a visual learning task, the Brief Visuospatial Memory Test-Revised (BVMT-R), than their nonsmoking peers. Among smokers, smoking behavior (i.e., exhaled carbon monoxide levels of smokers) predicted BVMT-R T score; greater smoking was associated with more impaired visual learning. Negative symptom severity was not predictive of greater visual learning deficits in smokers or nonsmokers. Future longitudinal research will be required to determine if there is a dose-response relationship between chronic nicotine and visual learning impairment in patients at various stages of psychotic illness.

Initial phase 2 trial of a nicotinic agonist in schizophrenia.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Effects of nicotine on cognitive deficits in schizophrenia.

Several lines of evidence suggest a pathophysiological role for nicotinic receptors in schizophrenia. Activation by nicotine alters physiological dysfunctions, such as eye movement and sensory gating abnormalities, but effects on neuropsychological performance are just beginning to be investigated. Nicotine-induced desensitization and the well-known tachyphylaxis of nicotinic receptors may confound such efforts. In all, 20 schizophrenics, 10 smokers, and 10 nonsmokers were assessed following the administration of nicotine gum and placebo gum. The Repeatable Battery for the Assessment of Neuropsychological Status was administered. Nicotine affected only the Attention Index; there were no effects on learning and memory, language, or visuospatial/constructional abilities. Attentional function was increased in nonsmokers, but decreased in nicotine-abstinent smokers after nicotine administration. The effects of nicotine in schizophrenia do not extend to all areas of cognition. Effects on attention may be severely limited by tachyphylaxis, such that decremented performance occurs in smokers, while modest effects may be achieved in nonsmokers.

Gliomatosis cerebri: neurobehavioral and neuropathological observations.

BACKGROUND: Gliomatosis cerebri is a rare neoplasm in which individual neoplastic cells diffusely permeate the brain; a cohesive tumor mass may appear late in the disease course, or not at all. The diagnosis can be made either at autopsy or premortem by combining biopsy and neuroimaging findings to demonstrate involvement of more than two lobes of the brain. Extensive hemispheric white matter and corpus callosum infiltration is characteristic, with lesser spread to subcortical and cortical gray matter. Whereas this pattern of localization can be predicted to cause significant disturbances of higher function, the neurobehavioral profile of gliomatosis cerebri patients has not been well described. METHOD: Three patients with gliomatosis cerebri had detailed neurobehavioral assessment, and one had neuropsychological testing early in the disease. Neuropathological investigation focused on the localization of the neoplasm, the correlation between extent of myelin and axon damage with tumor cell density, and the histogenesis of the tumor. RESULTS: The patient with neuropsychological testing had impaired executive function and verbal memory retrieval that reflected bifrontal and left temporal white matter tumor involvement seen on neuroimaging. In the other cases, apathy and fatigue progressed to severe dementia in association with bihemispheric white matter infiltration. Myelin and axon stains and myelin stains showed relative preservation of white matter architecture with severity of damage paralleling increased tumor cell density. Immunostaining for TP53 was found in a high percentage of tumor nuclei in two of three cases, suggesting overlapping features between gliomatosis cerebri and diffuse astrocytomas. CONCLUSIONS: Subtle cognitive and emotional alterations antedate the florid dementia that develops later in the course of gliomatosis cerebri. Clinical, neuroimaging, and neuropathological data suggest that white matter is damaged directly by the tumor and its associated mild edema, although infiltration of subcortical and cortical gray matter also occurs to a variable extent. Strong TP53 immunostaining in gliomatosis cerebri suggests a commonality with diffuse fibrillary astrocytomas that also often show TP53 staining. Gliomatosis cerebri can be considered a cause of white matter dementia resulting from preferential neoplastic disruption of white matter tracts.