Lighting Up Nicotinic Receptors
15 December 2011. Two new papers, by teams at Yale School of Medicine* and at the University of Maryland School of Medicine, join a growing body of research on the role of nicotinic acetylcholine receptors (nAChRs) in schizophrenia. In an imaging study of cigarette smokers with schizophrenia published online in the American Journal of Psychiatry, the Yale team, headed by the late Julie Staley, reports that the availability of nAChRs in several brain regions was markedly lower in patients than in smokers without mental illness, as well as a significant negative correlation in the patient group between nAChR availability and negative symptoms. In a controlled trial of the nAChR agonist varenicline published in the December issue of the Archives of General Psychiatry, the Maryland group led by L. Elliot Hong found that a moderate dose of the drug significantly improved measures on three well-validated schizophrenia biomarkers.
Some studies of nAChRs by schizophrenia researchers are aimed at finding treatments for the severe and damaging nicotine addiction seen in numerous patients (see SRF related news story; Wing et al., 2011), while others see patients’ conspicuous consumption of tobacco as reflecting important aspects of schizophrenia pathophysiology that could lead to novel, nAChR-based treatments for the disease itself. The newly published papers take this latter perspective.
Nicotine and negative symptoms
Chronic exposure to acetylcholine or nicotine causes a desensitization of nAChRs that is offset in smokers by receptor upregulation, which increases the availability of nicotinic binding sites (Marks et al., 2011). However, a postmortem study of smokers with schizophrenia (Breese et al., 2000) noted a deficit in nAChR upregulation, which added to suspicions that nAChR dysfunction may contribute to the pathophysiology of the illness. This view has been bolstered by genetic studies of schizophrenia that implicate the nAChR-related genes CHRNA7 (Freedman et al., 1997), CHRNA4, and CHRNB2 (De Luca et al., 2006).
First author Deepak Cyril D’Souza and colleagues at Yale focused on so-called β2* receptors, a subcategory of the nAChR superfamily that includes any such receptors containing β2 subunits. These receptors, particularly the α4β2 subtype, are widely expressed in the brain, and play a major role in tobacco addiction by modulating dopamine release in midbrain reward regions (McGranahan et al., 2011).
Based on SPECT (single-photon emission computed tomography) assessments of β2* availability in 11 smokers with schizophrenia and in age- and gender-matched comparison smokers, the team reported that the subjects with schizophrenia had 21 to 26 percent fewer binding sites than the comparison smokers in the frontal and parietal cortices and in the thalamus (no significant differences were seen in the hippocampus or striatum).
Moreover, among the smokers with schizophrenia, there was a “specific and robust” negative correlation between β2* availability and negative symptoms scores, as measured by both the SANS and PANSS scales, a pattern that held for all brain regions examined. This means that individuals with less β2* availability had more severe negative symptoms than individuals with greater β2* availability.
These findings are not likely to be due to differences in antipsychotic treatment, say the authors, but would be strengthened by expanded studies that include nonsmoking individuals with schizophrenia as comparison subjects, to determine whether reduced upregulation of nAChRs is a general characteristic of schizophrenia. Nonetheless, they write, given the paucity of effective medications for negative symptoms, the data argue for further testing of drugs targeting nAChRs, a strategy that has been given priority by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project (Buchanan et al., 2007).
One such compound, varenicline, is an nAChR partial agonist with high affinity for the α4β2 subtype that has been used successfully in smoking cessation programs under the trade names Chantix and Champix. In the new study from the University of Maryland, first author Elliot Hong and colleagues measured the effects of a moderate, long-term dose of varenicline on several sensory and cognitive biomarkers associated with schizophrenia that have also been used in previous studies testing effects of smoking or nicotine.
A range of biomarkers was chosen because, in addition to modulating dopaminergic systems, nAChRs also regulate GABAergic and glutamatergic circuits in the striatum, prefrontal cortex, and hippocampus, and hence affect many sensory and cognitive functions. Previous trials of varenicline in smokers with schizophrenia have been unblinded (Smith et al., 2009) or non-randomized (Liu et al., 2011), but the Maryland group chose a double-blind, randomized, placebo-controlled study design in which both smokers and nonsmokers with schizophrenia or schizoaffective disorder (N = 69) were given placebo or varenicline on four parallel tracks.
No significant treatment effects were seen after two weeks on varenicline, but at eight weeks the treatment groups (N = 32) showed significant improvements in startle reactivity; P50 sensory gating; and antisaccade performance, a measure of executive function. No improvements were seen in prepulse inhibition; spatial working memory; maintenance or predictive smooth-pursuit eye movement; cognitive processing speed; sustained attention; or scores on the MATRICS Consensus Cognitive Battery (MCCB; August et al., 2011).
Improvements in cognitive measures have been seen in previous studies employing nicotine or varenicline, but the Maryland group attributes these discrepancies to the limitations of short-term challenge studies, open-label study designs, and crucial pharmacological differences between nicotine and varenicline. Nicotine, a full agonist at nAChRs, robustly stimulates midbrain dopamine release, while varenicline is “a 30 percent to 60 percent partial agonist (of the nicotinic effect on dopamine turnover) and also a partial antagonist [via competitive binding] of α4β2” receptors. “[O]ur study suggests that the α4β2 partial agonist-antagonist is modest…. Instead, it reduces selected biomarker deficits, particularly P50 gating and antisaccadic deficits.”—Pete Farley.*
*Contributor Pete Farley is an employee of Yale University, where he serves as managing editor of Medicine@Yale.
D'Souza DC, Esterlis I, Carbuto M, Krasenics M, Seibyl J, Bois F, Pittman B, Ranganathan M, Cosgrove K, Staley J. Lower β2*-nicotinic acetylcholine receptor availability in smokers with schizophrenia. Am J Psychiatry. Abstract
Hong LE, Thaker GK, McMahon RP, Summerfelt A, Rachbeisel J, Fuller RL, Wonodi I, Buchanan RW, Myers C, Heishman SJ, Yang J, Nye A. Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 2011 Dec;68(12):1195-206. Abstract
Comments on Related News
Related News: Cholinergic Drug Improves Cognition in Nonsmokers With SchizophreniaComment by: Britta Hahn
Submitted 7 October 2012
Posted 7 October 2012
The study by Zhang et al. (2012) provides further evidence for the therapeutic potential of partial α7 nicotinic acetylcholine receptor (nAChR) agonists in the treatment of the cognitive deficits associated with schizophrenia. Given the impact of this symptom group on psychosocial functioning (Green et al., 2004; Tan, 2009) and the current absence of effective treatments, the importance of such findings is easily seen. Tropisetron administered over 10 days improved immediate and delayed memory subscales of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and improved P50 auditory gating deficits in 40 non-smoking inpatients with schizophrenia.
The evidence for enhanced auditory gating was strong, with the reduction in the S2/S1 ratio being entirely due to a decrease in S2 amplitude with no change in S1. By limiting the study sample to patients who displayed P50 gating deficits at baseline (~40 percent of all screened patients), the authors may have selected a subpopulation of patients particularly prone to showing benefits from α7 nAChR agonist treatment, possibly due to a larger incidence of genetic mutations reducing α7 nAChR subunit expression (Leonard et al., 2002) in this subsample. This type of pre-screening may indeed be a clinical approach to be considered prior to α7 agonist treatment. However, the measurement reliability of the P50 S2/S1 ratio tends to be low, and the degree to which P50 gating deficits predict treatment success with α7 agonists remains to be determined. Despite the large role that this ERP has played as an endophenotype of schizophrenia guiding drug development, evidence that P50 gating deficits are related to higher cognitive functions is still sparse (Potter et al., 2006). Zhang et al. found that changes in P50 gating from baseline to day 10 were correlated with changes in RBANS scores, collapsing data across all four treatment groups (including placebo). However, such correlations may be based on day-to-day fluctuations in cognitive state that could affect both measures in the same manner. More evidence is needed to clarify the clinical significance of improvements in P50 gating.
The finding that effects of tropisetron were seen mostly on memory indices differs from studies with the partial α7 agonist DMXB-A (Olincy et al., 2006; Freedman et al., 2008) and a previous study with tropisetron (Shiina et al., 2010), which reported effects predominantly on attention/vigilance indices. Larger trials may be able to determine more conclusively the cognitive domains beneficially affected by α7 agonists. Relatively flat dose-response curves were observed with tropisetron, consistent with a partial agonist mode of action. The finding that the largest dose (20 mg) produced no added benefits but tended to be associated with more side effects argues for the choice of lower doses.
Caution is warranted to not let positive findings with α7 agonists convey the impression that non-α7 nAChR subtypes are irrelevant for the treatment of cognitive deficits in schizophrenia. Indeed, non-α7 subtypes such as α4β2 mediate beneficial effects of nAChR agonists on cognitive performance (e.g., Dunbar et al., 2007; Grottick et al., 2003; Hahn et al., 2003; Levin, 2002), including improvements in sensory gating (Radek et al., 2006). The advantage of targeting α7 over other nAChR subtypes remains to be established by direct comparison. There is also a need for direct comparisons of α7-selective agonists with broader acting nAChR agonists to determine whether this subtype captures all cognitive benefit to be harvested from nAChR modulation in the treatment of schizophrenia.
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Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR. (2008) Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165: 1040-7. Abstract
Green MF, Kern RS, Heaton RK (2004) Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res 72: 41-51. Abstract
Grottick AJ, Haman M, Wyler R, Higgins GA (2003) Reversal of a vigilance decrement in the aged rat by subtype-selective nicotinic ligands. Neuropsychopharmacology 28: 880-7. Abstract
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Levin ED (2002) Nicotinic receptor subtypes and cognitive function. J Neurobiol 53: 633-640. Abstract
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. (2006) Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 63: 630-8. Abstract
Potter D, Summerfelt A, Gold J, Buchanan RW (2006) Review of clinical correlates of P50 sensory gating abnormalities in patients with schizophrenia. Schiz Bull 32: 692-700. Abstract
Radek RJ, Miner HM, Bratcher NA, Decker MW, Gopalakrishnan M, Bitner RS (2006) Alpha4beta2 nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating. Psychopharmacology 187: 47-55. Abstract
Shiina A, Shirayama Y, Niitsu T, Hashimoto T, Yoshida T, Hasegawa T, Haraguchi T, Kanahara N, Shiraishi T, Fujisaki M, Fukami G, Nakazato M, Iyo M, Hashimoto K (2010) A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann Gen Psychiatry 9: 27. Abstract
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View all comments by Britta Hahn
Related News: Cholinergic Drug Improves Cognition in Nonsmokers With Schizophrenia
Comment by: Georg Winterer (Disclosure)
Submitted 30 October 2012
Posted 30 October 2012
The paper of Zhang et al. once more presents promising findings suggesting that nicotinic α7 (partial) agonists may eventually be used as cognition enhancers in schizophrenia. Since several completed studies about the effect of nicotinic agonists on P50 gating and cognitive parameters are now around, we should try to figure out what distinguishes the negative and positive studies.
In the particular case of tropisetron, it certainly needs to be acknowledged that this drug also is a serotonin 5-HT3 antagonist. Previous studies (e.g., Adler et al., 2005) have already suggested that drugs that act as antagonists at this receptor improve P50 gating. Since antagonism of 5-HT3 increases release of acetylcholine, this may add to the direct partial agonist effect of tropisetron at the (low affinity) α7 nicotinic receptor as well as other nicotinic receptors, including high-affinity α4β2 receptors. In this regard, we should also acknowledge that agonists that act at other nicotinic receptors (α4β2) are now under investigation and show promising results when it comes to cognition enhancement in schizophrenia (e.g., varenicline).
Varenicline is primarily a partial agonist of the α4β2 subtype (although agonism at α7 has also been reported). Notably, other than tropisetron, varenicline is an agonist of 5-HT3 receptors. This is puzzling, adding to the confusion about the true cognition-enhancing effect in cholinergic drugs. It might be (exclusively) α7, but it is too early to jump to this conclusion. For instance, we recently published a negative proof-of-mechanism study on allosteric α7 nicotinic receptor modulation and P50 sensory gating in schizophrenia (Winterer et al., 2013).
In my opinion, what we need now is to go back to healthy probands (Phase 1) and select a range of drugs with different receptor profiles, but which have in common that they all act directly or indirectly at nicotinic receptors. These drugs then should be systematically tested for their effects on electrophysiological surrogate measures, including P50 gating, as well as cognitive measures, followed by corresponding investigations (using a preselected subset of compounds) in schizophrenia patients. Of course, this would require collaboration between R&D of different pharmaceutical companies—in other words: an industrial network approach is the unmet need!
Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A, Waldo MC. Improved p50 auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry . 2005 Feb ; 162(2):386-8. Abstract
Winterer G, Gallinat J, Brinkmeyer J, Musso F, Kornhuber J, Thuerauf N, Rujescu D, Favis R, Sun Y, Franc MA, Ouwerkerk-Mahadevan S, Janssens L, Timmers M, Streffer JR. Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: A proof-of-mechanism study. Neuropharmacology . 2013 Jan ; 64(1):197-204. Abstract
View all comments by Georg Winterer