Agonist Varenicline Research Articles

The nicotinic acetylcholine receptor partial agonist varenicline increases the ataxic and sedative-hypnotic effects of acute ethanol administration in C57BL/6J mice.

The costs associated with alcohol abuse are staggering, therefore much effort has been put into developing new pharmacologic strategies to decrease alcohol abuse. Recently, the nicotinic acetylcholine receptor (nAChR) partial agonist varenicline has been shown to decrease ethanol consumption in both humans and animal models. We examined the effects of varenicline on the ataxic and sedative-hypnotic effects of ethanol. First, varenicline was administered prior to placement in a locomotor activity chamber to determine whether varenicline influenced baseline locomotor activity. To determine the effect of nicotinic modulation on ethanol-induced motor incoordination, varenicline was administered 30 minutes prior to an acute ethanol injection and then mice were tested on the balance beam, dowel test, or fixed-speed rotarod. To examine ethanol's sedative-hypnotic effects, varenicline was administered 30 minutes prior to 4 g/kg ethanol and the duration of loss of righting reflex (LORR) was measured. Varenicline markedly reduced baseline locomotor activity in C57BL/6J mice. Varenicline increased ethanol-induced ataxia when measured on the balance beam and dowel test but had no effect when measured on the fixed-speed rotarod. Pretreatment with varenicline increased the duration of LORR. These data provide evidence that nAChRs may be involved in the ataxic and sedative effects of ethanol. It is possible that one mechanism that could contribute to the ability of varenicline to decrease ethanol consumption may be through increasing negative behavioral effects of alcohol.

Nicotinic Partial Agonists Varenicline and Sazetidine-A Have Differential Effects on Affective Behavior

Clinical and preclinical studies suggest that nicotinic acetylcholine receptors are involved in affective disorders; therefore, the potential therapeutic value of nicotinic partial agonists as treatments of these disorders is of growing interest. This study evaluated the effects of acute and chronic administration of nicotine and the alpha4beta2 nicotinic partial agonists varenicline and sazetidine-A in mouse models of anxiety and depression. Acutely, only nicotine and varenicline had anxiolytic effects in the marble-burying test and in the novelty-induced hypophagia (NIH) test. In contrast, in animal models of antidepressant efficacy, such as the forced swim and the tail suspension test, only acute sazetidine-A had significant antidepressant-like effects. The NIH test provides an anxiety-related measure that is sensitive to the effects of chronic but not acute antidepressant treatment. Chronic nicotine and chronic sazetidine-A treatment were effective in this paradigm, but varenicline was ineffective. These results suggest that the partial agonists varenicline and sazetidine-A may have diverse therapeutic benefits in affective disorders.

Mouse model predicts effects of smoking and varenicline on event-related potentials in humans

Nicotine alters auditory event-related potentials (ERPs) in rodents and humans and is an effective treatment for smoking cessation. Less is known about the effects of the partial nicotine agonist varenicline on ERPs. We measured the effects of varenicline and nicotine on the mouse P20 and varenicline and smoking on the human P50 in a paired-click task. Eighteen mice were tested following nicotine, varenicline, and their combination. One hundred and fourteen current smokers enrolled in a placebo-controlled within-subject crossover study to test the effects of varenicline during smoking and abstinence. Thirty-two subjects participated in the ERP study, with half receiving placebo first and half varenicline first (VP). Nicotine and varenicline enhanced mouse P20 amplitude, while nicotine improved P20 habituation by selectively increasing the first-click response. Similar to mice, abstinence reduced P50 habituation relative to smoking by reducing the first-click response. There was no effect of varenicline on P50 amplitude during abstinence across subjects. However, there was a significant effect of medication order on P50 amplitude during abstinence. Subjects in the PV group displayed reduced P50 during abstinence, which was blocked by varenicline. However, subjects in the VP group did not display abstinence-induced P50 reduction. Data suggest that smoking improves sensory processing. Varenicline mimics amplitude changes associated with nicotine and smoking but fails to alter habituation. The effect of medication order suggests a possible carryover effect from the previous arm. This study supports the predictive validity of ERPs in mice as a marker of drug effects in human studies.

Effects of the α4β2 Partial Agonist Varenicline on Brain Activity and Working Memory in Abstinent Smokers

Cognitive alterations are a core symptom of nicotine withdrawal, contributing to smoking relapse. In rodents and humans, cognitive deficits can be reversed by treatment with the alpha4beta2 nicotinic receptor partial agonist varenicline. This neuroimaging study examined the neural mechanisms that underlie these effects. Twenty-two smokers completed 13 days of varenicline and placebo treatment in a double-blind crossover study with two functional magnetic resonance imaging sessions: after 3 days of abstinence while on varenicline and after 3 days of abstinence while on placebo (counterbalanced randomized order, 2-week washout). Blood oxygenation level-dependent (BOLD) data were acquired during performance of a visual N-back working memory task. In a region of interest analysis, significant effects of treatment on mean percent signal change (varenicline > placebo) were observed in the dorsal anterior cingulate/medial frontal cortex, left dorsolateral prefrontal cortex, and right dorsolateral prefrontal cortex. In a cross-region model, there was a significant interaction of treatment by memory load, indicating significant increases in BOLD signal for varenicline versus placebo at the 2-back and 3-back levels but not the 1-back level. Varenicline improved performance (correct response time) in highly dependent smokers with no effect among less dependent smokers. In highly dependent smokers, faster correct response time was associated with increased BOLD signal. This study provides novel evidence that the alpha4beta2 partial agonist varenicline increases working memory-related brain activity after 3 days of nicotine abstinence, particularly at high levels of task difficulty, with associated improvements in cognitive performance among highly dependent smokers.

Modulation of ethanol consumption by genetic and pharmacological manipulation of nicotinic acetylcholine receptors in mice.

Alcohol and nicotine are commonly co-abused. Genetic correlations between responses to these drugs have been reported, providing evidence that common genes underlie the response to alcohol and nicotine. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system are important in mediating nicotine response, and several studies suggest that alcohol may also interact with these nAChRs. The aim of this study was to examine the role of nAChRs containing α7 or β2 subunits in ethanol consumption. A two-bottle choice paradigm was used to determine ethanol consumption in wild-type and nAChR subunit knockout mice. Challenge studies were performed using the α4β2 nAChR partial agonist varenicline. Mice lacking the β2 subunit consumed a similar amount of ethanol compared to their wild-type siblings in an ethanol-drinking paradigm. In contrast, mice lacking the α7 nAChR receptor subunit consumed significantly less ethanol than wild-type mice but consumed comparable amounts of water, saccharin, and quinine. In C57BL/6J mice, varenicline dose-dependently decreased ethanol consumption with a significant effect of 2 mg/kg, without affecting water or saccharin consumption. This effect of varenicline was not reversed in mice lacking either the α7 or β2 subunit, providing evidence that nAChRs containing one of these subunits are not required for this effect of varenicline. This study provides evidence that α7 nAChRs are involved in ethanol consumption and supports the idea that pharmacological manipulation of nAChRs reduces ethanol intake. Additional nAChRs may also be involved in ethanol intake, and there may be functional redundancy in the nicotinic control of alcohol drinking.

The α4β2 nicotinic acetylcholine-receptor partial agonist varenicline inhibits both nicotine self-administration following repeated dosing and reinstatement of nicotine seeking in rats

The alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline has greater efficacy than other pharmacotherapeutic aids for smoking cessation. This presents an opportunity to evaluate the predictive validity of rat models of nicotine taking and relapse. The aim of this study was to evaluate the ability of varenicline to attenuate nicotine self-administration and relapse, as modelled by the reinstatement model of nicotine relapse in rats. Rats were trained to respond for intravenous nicotine under a fixed ratio schedule of reinforcement. The effects of varenicline (0.3-3.0 mg/kg s.c.) on both nicotine and food self-administration and reinstatement of nicotine seeking were evaluated. Varenicline dose-dependently reduced nicotine self-administration and attenuated both nicotine prime and combined nicotine prime plus nicotine-paired cue-induced reinstatement. Varenicline had no effect on cue-induced reinstatement in the absence of a nicotine prime nor did it induce reinstatement when given alone. The effects of varenicline on nicotine-induced reinstatement of drug-seeking are consistent with the demonstrated clinical efficacy of varenicline for smoking cessation.

The nicotinic acetylcholine receptor partial agonist varenicline and the treatment of drug dependence: A review

Drug dependence is a chronic brain disease characterized by recurrent episodes of relapse, even when the person is motivated to quit. Relapse is a major problem and new pharmacotherapies are needed to prevent relapse episodes. The nicotinic acetylcholine receptor (nAChR) plays an important role in nicotine dependence, alcohol consumption and cue-induced cocaine craving. Stimulation of the nAChR has been found to alter and modulate cell firing in brain areas important for the maintenance of drug dependence. Varenicline, an alpha4beta2 nAChR partial agonist and an alpha7 nAChR full agonist registered for the treatment of nicotine dependence, significantly reduces nicotine craving and prevents relapse. In addition, varenicline reduces alcohol consumption in rats. Based on a review of the available literature, we hypothesize a potential role for varenicline in the prevention of relapse in patients recovering from drug dependence other than nicotine dependence.

Effect of the α4β2∗ nicotinic acetylcholine receptor partial agonist varenicline on dopamine release in β2 knock-out mice with selective re-expression of the β2 subunit in the ventral tegmental area

We studied the effects of 1 mg/kg doses of nicotine and the alpha4beta2* nicotinic acetylcholine receptor (nAChR) partial agonist, varenicline, on extracellular dopamine (DA) levels in the nucleus accumbens (NuAcc) of lentivirally vectorized male mice. Three separate experimental groups were injected with a lentiviral vector transducing the ventral tegmental area (VTA): wild-type C57BL/6J mice with a vector expressing eGFP only, beta2 knock-out mice (beta2KO) with the eGFP-only vector, and beta2KO mice with a bicistronic vector reintroducing beta2 and eGFP into the VTA as recently described (Maskos et al., 2005). Our results suggest that the neurochemical effects of varenicline as measured by using microdialysis in awake, freely moving mice are mainly mediated via beta2* nAChR subunits localized in the VTA.

Preclinical pharmacology of the α4β2 nAChR partial agonist varenicline related to effects on reward, mood and cognition

The pharmacological properties and pharmacokinetic profile of the α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline provide an advantageous combination of free brain levels and functional potencies at the target receptor that for a large part explain its efficacy as a smoking cessation aid. Since α4β2 and other nAChR subtypes play important roles in mediating central processes that control reward, mood, cognition and attention, there is interest in examining the effects of selective nAChR ligands such as varenicline in preclinical animal models that assess these behaviors. Here we describe results from studies on varenicline's effects in animal models of addiction, depression, cognition and attention and discuss these in the context of recently published preclinical and preliminary clinical studies that collected data on varenicline's effects on mood, cognition and alcohol abuse disorder. Taken together, the preclinical and the limited clinical data show beneficial effects of varenicline, but further clinical studies are needed to evaluate whether the preclinical effects observed in animal models are translatable to the clinic.

Aktuelle und neue Medikamente in der Tabakentwöhnung

Tobacco smoking is the leading cause of preventable morbidity and mortality in the world. There are nearly 1, 3 billion users of nicotine and tobacco products worldwide while approximately 4, 9 millions of them die from smoking-related disease every year. Cigarette smoking is a highly addictive behavior. Pharmacotherapy can be useful to achieve long-term abstinence. Nicotine replacement products are widely employed and recommended by the World Health Organization. There is strong evidence for the efficacy of the atypical antidepressant Bupropion as therapy for smoking cessation. The partial nicotinic receptor agonist varenicline has recently been approved as treatment for nicotine addiction in Germany. Preliminary data from clinical trials have suggested that varenicline may be an effective therapy for tobacco dependence with minimal side effects. Clonidine and nortriptyline have demonstrated some efficacy but possible side effects may limit their use. Additionally both are not approved for smoking cessation in Germany. Other promising new therapeutic drugs include Rimonabant and nicotine vaccines. They will provide smokers additional options to assist in achieving smoking cessation. Treatment of psychological dependence in addition to physiological dependence, however, is a must for long-term abstinence. For this reason a successful smoking cessation intervention requires besides pharmacological treatments motivational counseling and behavioral interventions.

Reduced affective symptoms during tobacco dependence treatment with varenicline

The nicotinic acetylcholine receptor partial agonist varenicline has been shown to be effective in the treatment of tobacco dependence, but has been reported to induce exacerbations of psychiatric symptoms in subjects with pre-existing psychiatric disorders. We report a tobacco-dependent patient who developed depression and suicidal tendencies during several cessation attempts, but was finally able to stay nicotine-abstinent by taking varenicline. In this case varenicline did not lead to exacerbation but appeared to improve the affective symptoms.

Effects of varenicline on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys

In the CNS, stimulation of nicotinic acetylcholine receptors (nAChR) can directly affect dopaminergic tone and may, therefore, modulate the reinforcing effects of abused drugs. In rhesus monkeys, we examined the nAChR partial agonist varenicline and full agonist nicotine in i.v. drug self‐administration and cocaine discrimination procedures. When substituted for cocaine in monkeys responding under a progressive‐ratio (PR) schedule, nicotine (0.03‐0.3 mg/kg) but not varenicline (0.01‐0.17 mg/kg) functioned as a reinforcer. When administered chronically, varenicline (titrated up to 0.3 mg/kg, BID p.o. by day 30) did not affect cocaine break point under the PR schedule or cocaine intake. In monkeys discriminating 0.3 mg/kg i.v. cocaine from saline, varenicline (0.03‐0.3 mg/kg, i.v.) did not engender cocaine‐like discriminative stimulus effects, but dose‐dependently potentiated the effects of cocaine when administered 60 min prior to testing. These preliminary results indicate low abuse liability for the nAChR partial agonist varenicline but suggest that varenicline may potentiate the subjective effects of cocaine. Future studies will investigate nAChR compounds of varying intrinsic efficacy and subtype specificity to further understand the role of nAChRs in mediating the reinforcing and discriminative stimulus effects of cocaine. All doses are expressed as that of the salt. DA12460.

P01-35 Is varenicline able to prevent smoking cessation induced affective symptoms?

The selective alpha4-beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline has been shown to be effective in the treatment of tobacco dependence by counteracting withdrawal symptoms and reducing smoking reward. However, the need to test safety, especially in smokers with varying co-morbidities and risk patterns is highlighted. There are some publications reporting exacerbation of psychiatric symptoms in subjects with pre-existing psychiatric disorders associated with varenicline treatment.This case-report describes a patient whose several smoking cessation attempts led to enduring nicotine-related symptoms such as depression and suicidal tendencies. All further cessation attempts under medical control with nicotine patches, bupropion and psychotherapy failed. At lest reducing her daily dose by one cigarette already led to suicidal thoughts. We took her into inpatient treatment and started an uptitration with varenicline. Unlike earlier attempts there were no complications during the detoxication and depressive symptoms improved clearly.Affective symptoms like depression are known to develop during nicotine cessation. The improving of affective symptoms in this case might be a result of the partial agonistic effects of varenicline.

Successful Smoking Cessation and Improvement of Negative Symptoms With Varenicline in a Stable Schizophrenia Patient

Back to table of contents Previous article Next article LETTERFull AccessSuccessful Smoking Cessation and Improvement of Negative Symptoms With Varenicline in a Stable Schizophrenia PatientIon Anghelescu M.D.,Ion Anghelescu M.D.Search for more papers by this author,Published Online:1 Jan 2009AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: The selective nicotinic partial agonist varenicline is approved for smoking cessation 1 in more than 30 countries. Freedman 2 has reported a case of a patient with a schizophrenic exacerbation after initiation of varenicline for smoking cessation. Here we present a case of successful smoking cessation and substantial improvement of negative symptoms in a clinically stable patient with schizophrenia. Case ReportMr. A is a 27-year-old former student with the diagnosis of schizophrenia, paranoid subtype for 4 years. His last admission as an inpatient took place 2 years ago and was due to delusions, visual and tactile hallucinations, and ideas of reference. He had no insight into his disorder and ideas of grandiosity (“the creator and guardian of the light”). By then he had also been a cannabis user (on average 0.5 g per day). No somatic disorders had been reported. He was then put on depot medication which he received every 14 days (risperidone, 37.5 mg). He smoked cigarettes for 5 years, increasing to 30 cigarettes a day over the last 6 months. His Positive and Negative Syndrome Scale (PANSS) negative symptoms score fluctuated between 42 and 45 over this period of time, with a PANSS positive symptoms score of only 8 points. Quitting smoking strategies like group counseling and nicotine replacement therapy via patch were altogether unsuccessful. Therefore, a trial with varenicline added to risperidone was started. The drug was titrated to 2 mg per day over a period of 1 week. It was tolerated well, and he experienced no nausea. After 2 weeks, complete abstinence was achieved (that was confirmed via CO measurement in the expiration air) and maintained for 6 months. Moreover, his PANSS negative score decreased from the second week on varenicline to 22 points. Risperidone and 9-hydroxy-risperidone concentrations remained unchanged.Discussion We report for the first time a successful trial of smoking cessation in a patient with very mild positive but marked negative symptoms which substantially improved during the treatment with varenicline without exacerbation of psychotic symptoms. We interpret this clinical observation by the indirect dopamine releasing properties of varenicline. 3 Schizophrenia patients seem to have altered nicotinic acetylcholine receptors and stimulation by nicotine has a positive effect on cognition and other symptoms of schizophrenia, which is thought a transient effect. 4 Nicotine as a full agonist on nicotinic acetylcholine receptors has a very high affinity for these receptors and a tolerance inducing effect that has not been described for varenicline yet. Since the patient still received risperidone he was probably sufficiently protected from the development of new positive symptoms. Systematic controlled studies of schizophrenia patients with different predominant symptoms treated with varenicline seem warranted to evaluate its possible risks and advantages in this population.Department of Psychiatry and Psychotherapy, Charité, University Medicine Berlin, Germany, Campus Benjamin Franklin, GermanyReferences1 . Cahill K, Stead LF, Lancaster T: Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2007; CD00103Google Scholar2 . Freedman R: Exacerbation of schizophrenia by varenicline. Am J Psychiatry 2007; 164:1269Google Scholar3 . Rollema H, Coe JW, Chambers LK, et al: Rationale, pharmacology and clinical efficacy of partial agonists of alpha4beta2 nACh receptors for smoking cessation. Trends Pharmacol Sci 2007; 28:316–325Google Scholar4 . Adams CE, Stevens KE: Evidence for a role of nicotinic acetylcholine receptors in schizophrenia. Front Biosci 2007; 12:4755–4772Google Scholar FiguresReferencesCited byDetailsCited ByFrontiers in Psychiatry, Vol. 9Varenicline disrupts prepulse inhibition only in high-inhibitory ratsProgress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 53EPA Guidance on Tobacco Dependence and Strategies for Smoking Cessation in People with Mental Illness30 January 2014 | European Psychiatry, Vol. 29, No. 2Acta Neuropsychiatrica, Vol. 23, No. 5Expert Opinion on Pharmacotherapy, Vol. 12, No. 11Journal of the Korean Society for Research on Nicotine and Tobacco, Vol. 1, No. 2 Volume 21Issue 1 Winter, 2009Pages 102-103 Metrics PDF download History Published online 1 January 2009 Published in print 1 January 2009

Aktuelle und neue Medikamente in der Tabakentwöhnung

Tobacco smoking is the leading cause of preventable morbidity and mortality in the world. There are nearly 1, 3 billion users of nicotine and tobacco products worldwide while approximately 4, 9 millions of them die from smoking-related disease every year. Cigarette smoking is a highly addictive behavior. Pharmacotherapy can be useful to achieve long-term abstinence. Nicotine replacement products are widely employed and recommended by the World Health Organization. There is strong evidence for the efficacy of the atypical antidepressant Bupropion as therapy for smoking cessation. The partial nicotinic receptor agonist varenicline has recently been approved as treatment for nicotine addiction in Germany. Preliminary data from clinical trials have suggested that varenicline may be an effective therapy for tobacco dependence with minimal side effects. Clonidine and nortriptyline have demonstrated some efficacy but possible side effects may limit their use. Additionally both are not approved for smoking cessation in Germany. Other promising new therapeutic drugs include Rimonabant and nicotine vaccines. They will provide smokers additional options to assist in achieving smoking cessation. Treatment of psychological dependence in addition to physiological dependence, however, is a must for long-term abstinence. For this reason a successful smoking cessation intervention requires besides pharmacological treatments motivational counseling and behavioral interventions.

Effects of the nicotinic receptor partial agonists varenicline and cytisine on the discriminative stimulus effects of nicotine in rats

The nicotinic partial agonist varenicline (VCL) is a recently approved medication for the treatment of tobacco dependence, yet very little preclinical research on this drug has been published. The present experiment examined the nicotinic partial agonist properties of VCL and its parent compound, cytisine (CYT), in a nicotine discrimination assay. Rats were trained to discriminate nicotine (0.4 mg/kg, s.c.) from saline using a two-lever discrimination procedure, followed by generalization and antagonism tests with VCL and CYT. Antagonism was examined across a range of nicotine doses. In generalization tests, VCL produced a maximum of 63% responding on the nicotine-appropriate lever, indicating partial generalization. In antagonism tests, VCL decreased the % responding on the nicotine-appropriate lever at 0.2 and 0.4 mg/kg nicotine, indicating antagonism of nicotine's discriminative stimulus effects. No dose of VCL produced significant effects on response rate. The two highest doses of CYT weakly substituted for nicotine, producing a maximum of 23% nicotine-appropriate responding. CYT produced a weak antagonism of the discrimination of moderate nicotine doses, but not of the training dose. These results demonstrate that VCL and CYT partially generalize to and partially antagonize nicotine's discriminative stimulus effects, consistent with a partial agonist mechanism of action.

The potential of neuronal nicotinic acetylcholine receptor agonists for treating CNS conditions

Background: Nicotine has a variety of effects in humans and in experimental animals that are suggestive of therapeutic potential. However, nicotine has a variety of adverse effects that preclude its development as a therapeutic agent, with the exception of its short-term use as a smoking cessation aide. Objective: In this paper, we describe the clinical evidence supporting the potential of new nicotinic acetylcholine receptor (nAChR) agonists for the treatment of CNS conditions and review discovery strategies for targeting neuronal nAChRs as well as some of the opportunities and challenges still ahead. Method: The scientific literature and company websites are used for this literature review. Conclusion: Advances in the understanding of nAChRs during the past two decades have revealed evidence of considerable subtype diversity and hence the possibility of targeted nAChR ligands as improved therapeutics. Several new nAChR agonists have advanced to Phase II clinical trials and have produced signals of efficacy in Alzheimer's disease, attention deficit hyperactivity disorder, cognitive deficits of schizophrenia and pain. In addition, the neuronal nAChR partial agonist varenicline recently received regulatory approval for use in smoking cessation.

Pharmacological Effects of Nicotine on Norepinephrine Metabolism in Rat Brown Adipose Tissue: Relevance to Nicotinic Therapies for Smoking Cessation

In a two-year carcinogenicity study with administration of high doses of the partial nicotinic agonist varenicline (recently approved for smoking cessation), mediastinal hibernomas occurred in three male rats. To investigate potential mechanisms for partial and full nicotinic agonists to contribute to development of hibernomas, the effects of nicotine on rat brown adipose tissue (BAT) were studied. Male and female rats were administered nicotine at doses of 0, 0.3, and 1 mg/kg subcutaneously for fourteen days. Intrathoracic (mediastinal periaortic and mediastinal perithymic) BAT and interscapular BAT were examined microscopically, and determinations of uncoupling protein-1 (UCP-1) expression and norepinephrine (NE) content were made. Additionally, NE turnover was measured in mediastinal periaortic and perithymic BAT. Nicotine (1 mg/kg) administration resulted in decreased vacuolation only in mediastinal periaortic and mediastinal perithymic BAT of males and elevated UCP-1 in mediastinal periaortic BAT of males and females. Increased NE content occurred only in mediastinal periaortic BAT of males given 0.3 and 1 mg/kg doses, whereas NE turnover was decreased in both males and females given 1 mg/kg. Together, these data demonstrate that nicotine primarily affects mediastinal BAT in male rats, consistent with the gender and location of the hibernomas observed in the two-year carcinogenicity study.

An update on therapeutics for tobacco dependence

The aim of this review is to consider the clinical trial evidence for the efficacy of four classes of pharmacological treatment for nicotine dependence: nicotine replacement, antidepressants, nicotine-receptor partial agonists and drugs blocking cannabinoid receptors. Despite falls in many developed countries, the prevalence of smoking remains high and is increasing in developing countries. Stopping smoking before middle age substantially reduces the mortality associated with tobacco use. Although many people quit without formal help, both non-pharmacological and pharmacological interventions can help people to stop smoking. Drug therapies target neural pathways to reduce withdrawal symptoms associated with psychopharmacological dependence on nicotine. Nicotine replacement therapy and some antidepressants aid smoking cessation and are an established part of therapy. Newer pharmacological approaches include the use of the selective nicotinic partial agonists, varenicline and cytisine, and compounds targeting cannabinoid receptors (rimonabant). Recent evidence suggests that the nicotine-receptor partial agonist varenicline is at least as effective as nicotine replacement therapy and antidepressants.

Exacerbation of Schizophrenia by Varenicline

Back to table of contents Previous article Next article Letters to the EditorFull AccessExacerbation of Schizophrenia by VareniclineROBERT FREEDMAN M.D.,ROBERT FREEDMAN M.D.Search for more papers by this author,Published Online:1 Aug 2007https://doi.org/10.1176/appi.ajp.2007.07020326AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To The Editor: Schizophrenia is associated with heavy smoking. The replacement of tobacco by other forms of nicotine only occasionally achieves abstinence in persons with schizophrenia (1) . The nicotinic agonist varenicline is a new alternative replacement agonist. There are no reports of its use in schizophrenia. We present the case of a patient with schizophrenia who received varenicline and experienced an activated psychotic relapse. A 42-year-old woman with schizophrenia had been treated for 17 years with 1015 mg of thiothixene. She had several brief psychotic episodes per year, which seldom lasted for more than 3 days. She had no overt psychotic symptoms during an office visit one month previously. Her usual symptoms during acute psychotic episodes were voices commenting on her behavior, confusion, and angry outbursts. She smoked one to two packs of cigarettes per day and had made several attempts to discontinue the use of nicotine chewing gum and trandermal nicotine patches. The patient’s mother reported a 5-day psychotic episode that began with increased activity, primarily the discarding of financial statements. At day 4, the patient ordered her daughter out of the house, and she threw away her thiothixene, which her daughter had insisted that she continue to take. She spent the next day screaming in her closet. Her mother administered thiothixene (20 mg) on the fifth evening and fed her because she had stopped eating. She appeared well groomed the next morning, without psychotic symptoms. She had no explanation for her sudden relapse and remission, but she announced with pride that her internist had prescribed a new medication, varenicline (2 mg), to help her stop smoking. The patient had been receiving varenicline for 5 days, and her quit day was the following day. She was advised to continue thiothixene, to avoid varenicline, and to return to nicotine chewing gum as a smoking substitute. She had no further exacerbations, but she continued to smoke cigarettes. Nicotine activates several classes of brain cholinergic receptors. Many are high affinity presynaptic receptors, composed primarily of alpha4 and beta2 subunits, which cause the release of dopamine and other neurotransmitters. Nicotine produces profound tachyphylaxis at doses that are close to its agonist effect, which quickly ends its pleasurable effect. Heavy smokers, including persons with schizophrenia, respond by increasing their smoking to overcome the tachyphylaxis. Varenicline is principally an agonist at high affinity receptors, with a lower propensity to tachyphylaxis than nicotine (2) . The more prolonged agonist effect of the drug was selected to increase its acceptance by smokers as a substitute for the briefer effects of cigarettes. Prolonged release of dopamine and norepinephrine may have resulted in the activated psychotic relapse in our patient. Her relatively low neuroleptic dose likely increased her vulnerability to this effect. In addition to its pleasurable effects, smoking is a possible self-medication for cognitive dysfunction in schizophrenia. We have postulated the involvement of a different class of postsynaptic cholinergic receptors, composed primarily of alpha7 subunits, which activate inhibitory interneurons and thus inhibit response to extraneous sensory response. Pharmacological activation of these receptors by more alpha7-selective agonists improves cognitive performance in schizophrenia (3) . Consideration of the unique neurobiological vulnerabilities of persons with schizophrenia is necessary in the design of cholinergic therapies for psychosis and smoking cessation. Denver, Colo.Dr. Freedman, through the Department of Veterans Affairs, is co-inventor of a patent for genomic sequences for the alpha7 subunit.This letter (doi: 10.1176/appi.ajp.2007.07020326) was accepted for publication in March 2007.