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PURPOSE - Persistent chemotherapy-related cognitive impairment (pCRCI) is commonly reported following cancer treatment and negatively affects quality of life; however, there is currently no pharmacological treatment indicated for pCRCI. This pilot study obtained preliminary data regarding the use of transdermal nicotine patches as a therapeutic strategy for women with pCRCI to (1) reduce subjective cognitive complaints and (2) enhance objective cognitive performance in breast, colon, lymphoma, or ovarian cancer survivors with pCRCI.
METHODS - Participants were randomized to either placebo (n = 11) or transdermal nicotine (n = 11) for 6 weeks, followed by 2 weeks of treatment withdrawal for a total of 8 weeks. Participants were assessed using both subjective and objective measures of cognitive functioning at five visits before, during, and after treatment.
RESULTS - Over the course of the study, women in both groups improved substantially in severity of self-reported cognitive complaints measured by Functional Assessment of Cancer Therapy-Cognitive Function Perceived Cognitive Impairments regardless of treatment arm. Additionally, objective cognitive performance measures improved in both groups; however, there was no significant difference in improvement between groups.
CONCLUSIONS - Due to a large placebo response, we were unable to determine if a drug effect was present. However, we did observe substantial improvement in self-reported cognitive symptoms, likely resulting from factors related to participation in the trial rather than specific drug treatment effects.
TRIAL REGISTRATION - The study was registered with clinicaltrials.gov (trial registration: NCT02312943).
IMPLICATIONS FOR CANCER SURVIVORS - These results suggest that women with pCRCI can exhibit improvement in subjective cognition, with attention paid to symptoms and close follow-up over a short period of time.
OBJECTIVE - Late-life depression (LLD) is characterized by poor antidepressant response and cognitive dysfunction. This study examined whether transdermal nicotine benefits mood symptoms and cognitive performance in LLD.
METHODS - In a 12-week open-label outpatient study conducted between November 2016 and August 2017, transdermal nicotine was given to 15 nonsmoking older adults (≥ 60 years of age). Eligible participants met DSM-IV-TR criteria for major depressive disorder with ≥ 15 on the Montgomery-Asberg Depression Rating scale (MADRS) and endorsed subjective cognitive impairment. Transdermal nicotine patches were applied daily and titrated in a rigid dose escalation strategy to a maximum dose of 21.0 mg/d, allowing dose reductions for tolerability. The primary mood outcome was MADRS change measured every 3 weeks, with response defined as ≥ 50% improvement from baseline and remission as MADRS score ≤ 8. The primary cognitive outcome was the Conners Continuous Performance Test (CPT), a test of attention.
RESULTS - Robust rates of response (86.7%; 13/15 subjects) and remission (53.3%; 8/15 subjects) were observed. There was a significant decrease in MADRS scores over the study (β = -1.51, P < .001), with improvement seen as early as 3 weeks (Bonferroni-adjusted P value = .004). We also observed improvement in apathy and rumination. We did not observe improvement on the CPT but did observe improvement in subjective cognitive performance and signals of potential drug effects on secondary cognitive measures of working memory, episodic memory, and self-referential emotional processing. Overall, transdermal nicotine was well tolerated, although 6 participants could not reach the maximum targeted dose.
CONCLUSIONS - Nicotine may be a promising therapy for depressed mood and cognitive performance in LLD. A definitive placebo-controlled trial and establishment of longer-term safety are necessary before clinical usage.
TRIAL REGISTRATION - ClinicalTrials.gov identifier: NCT02816138.
© Copyright 2018 Physicians Postgraduate Press, Inc.
Late-life depression is characterized by both lower mood and poor cognitive performance, symptoms that often do not fully respond to current antidepressant medications. Nicotinic acetylcholine receptor (nAChR) agonists such as nicotine may serve as a novel therapeutic approach for this population. Both preclinical and preliminary clinical studies suggest that nAChR agonists can improve depressive behavior in animal models and improve mood in depressed individuals. Substantial literature also supports that nAChR agonists benefit cognitive performance, particularly in older populations. These potential benefits may be mediated by the effects of nAChR stimulation on neural network function and connectivity. Functional neuroimaging studies detail effects of nAChR agonists on the default mode network, central-executive network, and salience network that may oppose or reverse network changes seen in depression. We propose that, given the existent literature and the clinical presentation of late-life depression, nicotine or other nAChR agonists may have unique therapeutic benefits in this population and that clinical trials examining nicotine effects on mood, cognition, and network dynamics in late-life depression are justified.
Published by Elsevier Ltd.
Most drugs of abuse easily cross the placenta and can affect fetal brain development. In utero exposures to drugs thus can have long-lasting implications for brain structure and function. These effects on the developing nervous system, before homeostatic regulatory mechanisms are properly calibrated, often differ from their effects on mature systems. In this review, we describe current knowledge on how alcohol, nicotine, cocaine, amphetamine, Ecstasy, and opiates (among other drugs) produce alterations in neurodevelopmental trajectory. We focus both on animal models and available clinical and imaging data from cross-sectional and longitudinal human studies. Early studies of fetal exposures focused on classic teratological methods that are insufficient for revealing more subtle effects that are nevertheless very behaviorally relevant. Modern mechanistic approaches have informed us greatly as to how to potentially ameliorate the induced deficits in brain formation and function, but conclude that better delineation of sensitive periods, dose-response relationships, and long-term longitudinal studies assessing future risk of offspring to exhibit learning disabilities, mental health disorders, and limited neural adaptations are crucial to limit the societal impact of these exposures.
Dopamine (DA) signaling in the central nervous system mediates the addictive capacities of multiple commonly abused substances, including cocaine, amphetamine, heroin and nicotine. The firing of DA neurons residing in the ventral tegmental area (VTA), and the release of DA by the projections of these neurons in the nucleus accumbens (NAc), is under tight control by cholinergic signaling mediated by nicotinic acetylcholine (ACh) receptors (nAChRs). The capacity for cholinergic signaling is dictated by the availability and activity of the presynaptic, high-affinity, choline transporter (CHT, SLC5A7) that acquires choline in an activity-dependent matter to sustain ACh synthesis. Here, we present evidence that a constitutive loss of CHT expression, mediated by genetic elimination of one copy of the Slc5a7 gene in mice (CHT+/-), leads to a significant reduction in basal extracellular DA levels in the NAc, as measured by in vivo microdialysis. Moreover, CHT heterozygosity results in blunted DA elevations following systemic nicotine or cocaine administration. These findings reinforce a critical role of ACh signaling capacity in both tonic and drug-modulated DA signaling and argue that genetically imposed reductions in CHT that lead to diminished DA signaling may lead to poor responses to reinforcing stimuli, possibly contributing to disorders linked to perturbed cholinergic signaling including depression and attention-deficit hyperactivity disorder (ADHD).
Copyright © 2013 Elsevier Inc. All rights reserved.
Depression is associated with impairments to cognition and brain function at any age, but such impairments in the elderly are particularly problematic because of the additional burden of normal cognitive aging and in some cases, structural brain pathology. Individuals with late-life depression exhibit impairments in cognition and brain structural integrity, alongside mood dysfunction. Antidepressant treatment improves symptoms in some but not all patients, and those who benefit may not return to the cognitive and functional level of nondepressed elderly. Thus, for comprehensive treatment of late-life depression, it may be necessary to address both the affective and cognitive deficits. In this review, we propose a model for the treatment of late-life depression in which nicotinic stimulation is used to improve cognitive performance and improve the efficacy of an antidepressant treatment of the syndrome of late-life depression. The cholinergic system is well-established as important to cognition. Although muscarinic stimulation may exacerbate depressive symptoms, nicotinic stimulation may improve cognition and neural functioning without a detriment to mood. While some studies of nicotinic subtype specific receptor agonists have shown promise in improving cognitive performance, less is known regarding how nicotinic receptor stimulation affects cognition in depressed elderly patients. Late-life depression thus represents a new therapeutic target for the development of nicotinic agonist drugs. Parallel treatment of cognitive dysfunction along with medical and psychological approaches to treating mood dysfunction may be necessary to ensure full resolution of depressive illness in aging.
Copyright © 2013 Elsevier Inc. All rights reserved.
Compounds that modulate metabotropic glutamate subtype 2 (mGlu(2)) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu(2) receptor positive allosteric modulators (PAMs). The effects of N-substitution (R(1)) and substitutions on the aryl ring (R(2)) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu(2) receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans.
OBJECTIVE - To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with mild cognitive impairment (MCI).
METHODS - 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.
RESULTS - 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.
CONCLUSION - 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.
In the developing brain, nicotinic acetylcholine receptors (nAChRs) are involved in cell survival, targeting, formation of neural and sensory circuits, and development and maturation of other neurotransmitter systems. This regulatory role is disrupted when the developing brain is exposed to nicotine, which occurs with tobacco use during pregnancy. Prenatal nicotine exposure has been shown to be a strong risk factor for memory deficits and other behavioral aberrations in the offspring. The molecular mechanisms underlying these neurobehavioral outcomes are not clearly elucidated. We used a rodent model to assess behavioral, neurophysiological, and neurochemical consequences of prenatal nicotine exposure in rat offspring with specific emphasis on the hippocampal glutamatergic system. Pregnant dams were infused with nicotine (6 mg/kg/day) subcutaneously from the third day of pregnancy until birth. Results indicate that prenatal nicotine exposure leads to increased anxiety and depressive-like effects and impaired spatial memory. Synaptic plasticity in the form of long-term potentiation (LTP), basal synaptic transmission, and AMPA receptor-mediated synaptic currents were reduced. The deficit in synaptic plasticity was paralleled by declines in protein levels of vesicular glutamate transporter 1 (VGLUT1), synaptophysin, AMPA receptor subunit GluR1, phospho(Ser845) GluR1, and postsynaptic density 95 (PSD-95). These results suggest that prenatal nicotine exposure by maternal smoking could result in alterations in the glutamatergic system in the hippocampus contributing to the abnormal neurobehavioral outcomes.
© Springer Basel AG 2011
RATIONALE - Evidence for a relationship between cigarette smoking and attention-deficit/hyperactivity disorder (ADHD) has prompted investigations into nicotinic treatments for this disorder. Impulsivity is a hallmark of ADHD and is measured in the laboratory as behavioral inhibition (BI) using the stop signal task (SST). Acute nicotine improves SST performance in adolescents and young adults who have both ADHD and impaired baseline SST performance, raising questions about the role of nicotinic acetylcholine receptor function in BI. The specificity of this effect to those with ADHD, the component processes of the SST affected by nicotine, and the effects of nicotinic antagonism are yet unknown.
OBJECTIVES - This study investigated the effects of both a nicotinic receptor agonist and antagonist on the SST and choice reaction time task (CRT) in highly impulsive (HI) and control (CTRL) subjects.
METHODS - This was a within-subjects, double-blind study of: 7 mg transdermal nicotine, 20 mg oral mecamylamine, and placebo. Subjects were recruited into HI (n = 11) and CTRL (n = 14) groups based on both SST and clinical criteria.
RESULTS - BI was significantly improved by nicotine compared with placebo in the HI group and impaired by mecamylamine in the CTRL group. Go signal reaction time on the SST was improved by nicotine compared with placebo in the CTRL group and was unchanged in both groups on the CRT.
CONCLUSIONS - These findings demonstrate nicotinic modulation of BI in subjects with both normal and disordered baseline performance. The effects on BI are consistent with cholinergic enhancement of signal detection processes and/or modulation of noradrenaline by nicotine.