Targeting alpha-7 nicotinic neurotransmission in schizophrenia: A novel agonist strategy

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Abstract

Alpha7 nicotinic acetylcholine receptor7 nAChR) agonists may be valuable treatments for negative symptoms and cognitive impairment in schizophrenia. Unfortunately, chronic exposure to an agonist may reduce the receptor's sensitivity. Therefore, we combined CDP-choline, a dietary source of the direct agonist choline, with galantamine, a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors, to improve the efficiency of transducing the choline signal and, possibly, preserve the receptor in a sensitive state. We conducted a single-site, double-blind randomized clinical trial comparing galantamine/CDP-choline to placebos in schizophrenia patients with negative symptoms who were receiving second generation antipsychotics. Forty-three subjects received galantamine and CDP-choline or matching placebos for 16 weeks. The primary outcome measure was the 5-item Marder negative-symptoms factor of the Positive and Negative Syndrome Scale (PANSS). Cognition and functioning were also assessed. Trial completion was high; 79%. There was no significant treatment effect on negative symptoms, other PANSS symptom factors, or the MATRICS Cognitive Consensus Battery. There were significant treatment effects in overall functioning and a test of free verbal recall. Three subjects discontinued treatment in the active treatment group for gastro-intestinal adverse events (AE). The most common AE for galantamine/CDP-choline was abdominal pain; for placebo it was headache and sweating. Although there was no significant treatment effect on negative symptoms, the direction of effect mirrored the effects on a cognitive measure and overall functioning. Further study of α7 nAChR agonist/PAMs is warranted in larger studies that will have greater power.

Introduction

Current medications for the treatment of schizophrenia are only partially effective; therefore, many people living with schizophrenia do not achieve full functional recovery. In particular, negative symptoms such as social withdrawal and blunted affect, as well as disturbances of memory and attention still persist. These signs and symptoms contribute to poor social and vocational outcomes leading to chronic disability (Green et al., 2000). In this study, we examined whether a selective α7 nicotinic agonist intervention would improve negative symptoms and cognitive impairment associated with schizophrenia.

Preclinical and clinical findings support the hypothesis of deficient α7 nicotinic acetylcholine receptor (α7 nAChR)-mediated neurotransmission in schizophrenia (Deutsch et al., 2005, Martin and Freedman, 2007, Jones et al., 2011). Schizophrenia patients and their biological relatives display a sensory gating deficit that shows genetic linkage to the locus on chromosome 15, which codes the gene for the α7 nAChR subunit (i.e., CHRNA7) (Freedman et al., 1997). Moreover, decreased expression of the α7 nAChR in the frontal cortex (Guan et al., 1999), interneurons of the hippocampus (Freedman et al., 1995), and reticular nucleus of the thalamus (Court et al., 1999) of postmortem brains obtained from patients with schizophrenia may reflect single nucleotide changes within promoter regions of the gene (Leonard et al., 2002). Thus, promoter variants could account for diminished rates and amount of expression of structurally intact α7 nAChRs, which would support strategies for improving the efficiency of transduction of the acetylcholine signal by functional receptors.

The hypothesis of α7 nAChR “hypofunction” in schizophrenia has stimulated the development of selective α7 nicotinic receptor agonists as putative treatments for negative symptoms and cognitive dysfunction. An early study showed that a partial α7 nicotinic agonist, 3-(2,4-dimethoxy-benzylidene) anabaseine (DMXB-A), co-administered with neuroleptics, reduced auditory sensory gating deficits and improved cognition in the Repeatable Battery of Assessment of Neuropsychological Status (RBANS) in 12 schizophrenia patients in a single-day administration trial (Olincy et al., 2006). In another study, DMXB-A administered over four weeks to 31 patients reduced negative symptoms on the Scale for the Assessment of Negative Symptoms, but did not improve performance on the MATRICS Consensus Cognitive Battery, the primary outcome in the study (Freedman et al., 2008). More recently, another α7 nicotinic receptor partial agonist, TC-5619, was tested in a 12-week randomized, placebo-controlled trial in 185 persons with schizophrenia, and significantly reduced negative symptoms and improved a cognitive measure of executive functioning (Lieberman et al., 2013). Together, these findings suggest that selective α7 nicotinic receptor partial agonists can both reduce residual negative symptoms and improve cognition in trials of up to 12-weeks in duration.

We have proposed a parallel avenue of facilitating α7 nAChR-mediated neurotransmission in schizophrenia (Deutsch et al., 2008). Positive allosteric modulators (PAM) – agents that act at sites distinct from the orthosteric or agonist binding sites – have the capacity to improve the efficiency of coupling the binding of agonists to their biological effects while maintaining the receptor in a responsive, as opposed to refractory, state. Theoretically, allosteric modulatory strategies are very attractive because they preserve the spatial and temporal characteristics of endogenous neurotransmitter release; that is, although they lack intrinsic activity of their own, they are effective where and when neurotransmitters are released in the brain (Dani and Bertrand, 2007, Lightfoot et al., 2008, Gregory et al., 2011).

Thus, we combined galantamine, a PAM at the α7 nAChR and a cholinesterase inhibitor, and CDP-choline, a dietary source of exogenous choline; choline mimics electrophysiological and pharmacological effects of ACh at the α7 nAChR (Albuquerque et al., 1997, Alkondon et al., 1997, Albuquerque et al., 1998). We hypothesized that galantamine would improve the efficiency of coupling between the binding of choline and channel opening and, perhaps, maintain the receptor in a sensitive configuration over time. The dose of CDP-choline used in this trial was adopted from published literature in healthy volunteers, patients with acute ischemic stroke, and those with cognitive impairment due to chronic cerebral disorders (Clark et al., 1997, Clark et al., 1999, Wurtman et al., 2000, Wurtman et al., 2001, Davalos et al., 2002, Fioravanti and Yanagi, 2004). Results show that CDP-choline is safe and well tolerated in dosages of up to 2000 mg/day. In addition, the persistence of elevated plasma levels for up to 8 h after the administration of the 2000 mg oral dose suggested that, at steady state, daily administration of 2000 mg, in two divided doses, would maintain elevated levels throughout much of the day (Wurtman et al., 2000). Theoretically, combining CDP-choline with galantamine might mitigate the potential of α7 nAChRs, like nAChRs in general, to desensitize rapidly upon exposure to an agonist, whereby a full selective agonist, such as choline derived from dietary CDP-choline, becomes a functional antagonist. We predicted that the effect of the combination treatment would be long-term and therefore of potential clinical value.

This trial was designed as a “proof of concept” that selective and sustained stimulation of α7 nAChRs, using a combination of galantamine and CDP-choline, would provide therapeutic advantages to schizophrenia patients maintained on their stable regimens of second-generation antipsychotic medications. The study was a 16-week randomized, double-blind trial, comparing the combination of galantamine/CDP-choline to matching placebos for both agents (“double-dummy”) in schizophrenia patients with predominantly negative symptoms. The primary hypothesis was that galantamine/CDP-choline would reduce negative symptoms measured by the Positive and Negative Syndrome Scale (Kay et al., 1989). Secondary hypotheses were that combination treatment would improve overall functioning assessed by the Scale of Functioning (Rapaport et al., 1996), cognition, and clinical symptoms (e.g., PANSS total).

The α7 nAChR has been identified by the MATRICS working group as a promising target for medication development to improve cognitive impairment in schizophrenia (Geyer and Tamminga, 2004). We expected that the domains of attention and memory in particular would be sensitive to the effects of α7 nicotinic stimulation based on prior research on nicotinic receptor function and cognition (Martin and Freedman, 2007, Jones et al., 2011, for review). Therefore, the neurocognitive battery in this study included selected measures of attention and memory from the MATRICS Consensus Cognitive Battery (MCCB) (Nuechterlein et al., 2008) and additional measures of verbal learning, free recall, and recognition memory from the University of Southern California-Repeatable Episodic Memory Test (USC-REMT; Parker et al., 2004, Schwartz et al., 2009).

Section snippets

Summary of design and study procedures

This study was conducted at the Washington DC VA Medical Center and was approved by the Institutional Review Boards of the VA Medical Center and Georgetown University Medical Center. Interested veterans provided written informed consent for study participation and were randomly assigned to either galantamine/CDP-choline or placebo condition. Consenting participants who met inclusion exclusion criteria and completed baseline assessment entered the 16-week trial. Study participants were

Sample description

As shown in Fig. 1, 74 participants consented and were randomized to treatment. Fig. 1 also shows the numbers who did not meet inclusion exclusion criteria or who failed to validate consent by completing baseline assessments or taking at least one dose of medicine. Forty-three participants received medication; 19 (17 M, 2 F) received galantamine/CDP-choline and 24 (22 M, 2 F) received placebos. Of those 79% in both groups completed the 16-week trial. The mean age of the sample was 53.3 years,

Discussion

This study tested the feasibility of combining a PAM and a cholinergic agonist to treat negative symptoms and cognitive impairment in schizophrenia. We did not find a significant effect on the primary outcome of negative symptoms or on other secondary measures of clinical symptoms. However, there was a significant treatment effect on the secondary outcome of functioning measured by the Scale of Functioning global item. Given the high threshold of negative symptoms that we selected this may be a

Role of funding source

The research was supported by NIMH grant R34MH077849 (SID, principal investigator).

Contributors

Stephen Deutsch developed the pharmacological model. Stephen Deutsch, Nina Schooler, and Barbara Schwartz designed the study and wrote the first draft of the manuscript. Clayton Brown developed the statistical approach and performed the statistical analysis. Richard Rosse managed adverse event assessment and analysis. Stephanie Rosse managed the literature search and helped with data analysis. All authors contributed to and have approved the final manuscript.

Conflict of interest

Stephen Deutsch, M.D., Ph.D. has served as Consultant to Merck and on the Speaker Bureau for AstraZeneca. Nina Schooler, Ph.D. has received grant/research support from the following companies over the past 24 months: Neurocrine and Otsuka and she has served as Consultant or on Advisory Boards for the following companies over the past 24 months: Eli Lilly & Company, Abbott Laboratories, Hoffman LaRoche, H. Lundbeck, Merck Inc., Janssen Psychiatry, Johnson & Johnson, Shire, NuPATHE, Amgen. Barbara

Acknowledgments

Janssen Scientific Affairs LLC donated the galantamine and galantamine placebo. LifeLink and Mr. David Blanco supplied the CDP-choline and CDP-choline placebo.

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    Location of work: Mental Health Service, Washington DC Veterans Affairs Medical Center, Washington DC.

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