Article

Nicotine treatment of mild cognitive impairment: A 6-month double-blind pilot clinical trial

Clinical Neuroscience Research Unit, Department of Psychiatry, University of Vermont College of Medicine, Burlington, USA.
Neurology (Impact Factor: 8.29). 01/2012; 78(2):91-101. DOI: 10.1212/WNL.0b013e31823efcbb
Source: PubMed

ABSTRACT

To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with mild cognitive impairment (MCI).
Nonsmoking subjects with amnestic MCI were randomized to transdermal nicotine (15 mg per day or placebo) for 6 months. Primary outcome variables were attentional improvement assessed with Connors Continuous Performance Test (CPT), clinical improvement as measured by clinical global impression, and safety measures. Secondary measures included computerized cognitive testing and patient and observer ratings.
Of 74 subjects enrolled, 39 were randomized to nicotine and 35 to placebo. 67 subjects completed (34 nicotine, 33 placebo). The primary cognitive outcome measure (CPT) showed a significant nicotine-induced improvement. There was no statistically significant effect on clinician-rated global improvement. The secondary outcome measures showed significant nicotine-associated improvements in attention, memory, and psychomotor speed, and improvements were seen in patient/informant ratings of cognitive impairment. Safety and tolerability for transdermal nicotine were excellent.
This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with MCI over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing, but not in ratings of clinician-rated global impression. We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with MCI; however, whether these effects are clinically important will require larger studies. Classification of evidence: This study provides Class I evidence that 6 months of transdermal nicotine (15 mg/day) improves cognitive test performance, but not clinical global impression of change, in nonsmoking subjects with amnestic MCI.

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    • "Currently, the only nicotinic ligands available either by prescription or over the counter (and thus potentially available for repurposing) are nicotine itself (as a gum or transdermal patch) and the α4β2 nAChR partial agonist/α7 nAChR full agonist, varenicline, both currently used to improve smoking cessation. Despite prior concerns regarding potential side effects of nicotine, there have been several encouraging (albeit small) clinical trials with nicotine for AD (Newhouse et al. 1988; Sahakian and Jones 1991; Jones et al. 1992; Wilson et al. 1995; White and Levin 1999) and one encouraging study in mild cognitive impairment (MCI, Newhouse et al. 2012). There is also some preclinical and clinical evidence to suggest that varenicline might be worth evaluating for repurposing in conditions where cognitive function is impaired . "
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    ABSTRACT: Rationale Due to the rising costs of drug development especially in the field of neuropsychiatry, there is increasing interest in efforts to identify new clinical uses for existing approved drugs (i.e., drug repurposing). Objectives The purpose of this work was to evaluate in animals the smoking cessation agent, varenicline, a partial agonist at α4β2 and full agonist at α7 nicotinic acetylcholine receptors, for its potential as a repurposed drug for disorders of cognition. Methods Oral doses of varenicline ranging from 0.01 to 0.3 mg/kg were evaluated in aged and middle-aged monkeys for effects on the following: working/short-term memory in a delayed match to sample (DMTS) task, distractibility in a distractor version of the DMTS (DMTS-D), and cognitive flexibility in a ketamine-impaired reversal learning task. Results In dose-effect studies in the DMTS and DMTS-D tasks, varenicline was not associated with statistically significant effects on performance. However, individualized “optimal doses” were effective when repeated on a separate occasion (i.e., improving DMTS accuracy at long delays and DMTS-D accuracy at short delays by approximately 13.6 and 19.6 percentage points above baseline, respectively). In reversal learning studies, ketamine impaired accuracy and increased perseverative responding, effects that were attenuated by all three doses of varenicline that were evaluated. Conclusions While the effects of varenicline across the different behavioral tasks were modest, these data suggest that varenicline may have potential as a repurposed drug for disorders of cognition associated with aging (e.g., Alzheimer’s disease), as well as those not necessarily associated with advanced age (e.g., schizophrenia).
    Full-text · Article · Nov 2015 · Psychopharmacology
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    • "However, few studies have investigated the impact of NIC exposure on METH-induced memory deficits. Among these, in clinical trials, NIC patch application improved recognition memory or attention in patients with schizophrenia or mild cognitive impairment compared with placebo-treated patients (Jubelt et al., 2008; Newhouse et al., 2012). Activation of α4β2 subtypes of nAChRs also improved working memory in rhesus monkeys that self-administered cocaine (Gould et al., 2013). "
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    ABSTRACT: Previous studies have demonstrated that methamphetamine (METH) abuse leads to memory deficits and these are associated with relapse. Furthermore, extensive evidence indicates that nicotine (NIC) prevents and/or improves memory deficits in different models of cognitive dysfunction and these nicotinic effects might be mediated by hippocampal or cortical nicotinic acetylcholine receptors (nAChRs). The present study investigated whether NIC attenuates METH-induced novel object recognition (NOR) deficits in rats and explored potential underlying mechanisms. Adolescent or adult male Sprague-Dawley rats received either NIC water (10-75 μg/ml) or tap water for several weeks. METH (4 x 7.5 mg/kg/injection) or saline was administered either before or after chronic NIC exposure. Novel object recognition was evaluated 6 d after METH or saline. Serotonin transporter function and density, and α4β2 nAChR density were assessed on the following day. Chronic NIC intake via drinking water beginning during either adolescence or adulthood attenuated the NOR deficits caused by a high-dose METH administration. Similarly, NIC attenuated METH-induced deficits in NOR when administered after METH treatment. However, NIC did not attenuate the serotonergic deficits caused by METH in adults. Conversely, NIC attenuated METH-induced deficits in α4β2 nAChR density in the hippocampal CA1 region. Furthermore, NIC increased α4β2 nAChR density in the hippocampal CA3, dentate gyrus and perirhinal cortex (PRh) in both saline- and METH-treated rats. Overall, these findings suggest that NIC-induced increases in α4β2 nAChRs in the hippocampus and PRh might be one mechanism by which NOR deficits are attenuated by NIC in METH-treated rats. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Jul 2015 · The International Journal of Neuropsychopharmacology
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    • "A good number of NR products have been developed and licensed as effective treatments for tobacco dependence . However, nicotine isolated from tobacco has been tried as a treatment for many conditions and disorders and some positive effects have been observed in preliminary studies in the following conditions: ulcerative colitis (Sandborn, 1999), major depression (McClernon, Hiott, Westman, Rosse, & Levin, 2006), Tourettes's syndrome (Silver et al., 2001), neuroleptic-induced akathisia (Anfang & Pope, 1997), cognition in schizophrenia (Barr et al., 2008), attention deficit hyperactivity disorder (Gehricke Hong, Whalen, Steinhoff & Wigal, 2009), Parkinsons disease (Thiriez et al., 2011) and mild cognitive impairment (Newhouse et al., 2012). The best evidence is available for Parkinson's disease (Fagerström & Pomerleau, 1994; Thiriez et al., 2011) and ulcerative colitis (Green et al., 1997; Sandborn, 1999). "

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