Dr. Lorenz is assistant clinical professor in the Department of Pharmacy Practice at Auburn University Harrison School of Pharmacy in Auburn, Alabama and adjunct assistant professor in the Department of Psychiatry at the University of South Alabama College of Medicine in Mobile. Dr. Whitley is assistant clinical professor in the Department of Pharmacy Practice at Auburn University Harrison School of Pharmacy and in the Department of Community and Rural Medicine at the University of Alabama School of Medicine in Tuscaloosa. Dr. McCoy is assistant clinical professor in the Department of Pharmacy Practice at Auburn University Harrison School of Pharmacy.
Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Off-label disclosure: This article includes discussion of the unapproved use of varenicline for the adjunct treatment of depression and cognitive enhancement in depressed patients.
Acknowledgments: The authors thank Cory Wiggins, PharmD, a fourth-year student pharmacist during the writing of this article, for helping in preparing the article.
Please direct all correspondence to: Raymond Lorenz, PharmD, BCPP, University of South Alabama, Technology & Research Park Bldg. 3 Suite 2100, Mobile, AL 36688; Tel: 251-445-9316; Fax: 251-445-9341; E-mail: firstname.lastname@example.org.
• This article reviews literature regarding the safety of smoking-cessation aid varenicline for patients with mental illness.
• Although the relationship between varenicline and psychiatric adverse events (AEs) is not clear, there appears to be a greater likelihood of event development in those with baseline mental illness.
• Many confounding factors may contribute to psychiatric AEs in mentally ill patients who receive varenicline.
• Caution should be exercised when considering prescribing varenicline in patients with mental illness.
• Any patient receiving varenicline who develops new or exacerbated psychiatric symptoms should discontinue therapy immediately.
This article reviews literature regarding safety of smoking-cessation aid varenicline for patients with mental illness. Although clinical trials with varenicline showed improved efficacy for smoking cessation and relatively low adverse events (AE) rates, many case reports suggest an increased risk of psychiatric AEs, particularly in patients with baseline mental illness. The Institute for Safe Medication Practices (ISMP) published a review of the serious AEs associated with varenicline obtained from Food and Drug Administration-submitted reports. The ISMP report specifically mentions psychiatric AEs in patients with preexisting psychiatric conditions. While varenicline use among patients without mental illness is likely safe, appropriate use in mentally ill patients is controversial; the paucity of data currently precludes drawing definite conclusions. While further prospective trials evaluating the use of varenicline in mental illness may be inappropriate, the information currently available does little to fully elucidate the effects of varenicline in patients with mental illness. As such, cautious use in this population is warranted. Varenicline discontinuation is recommended in any patient reporting new-onset psychiatric symptoms.
Approximately 440,000 of the 45 million American smokers die annually from the leading preventable cause of death: tobacco use. This percentage accounts for 20% of deaths in the United States.1-2 Patients with mental illness are more likely to smoke cigarettes than patients without mental illness (59.0% vs. 39.1%).3 These data highlight the need for safe and effective smoking cessation aids, especially in patients with mental illness. Tobacco users are more likely to initiate a smoking cessation plan when encouraged by a healthcare professional and are more successful when aided by a pharmaceutical agent.1,4-8 Varenicline, the most recent Food and Drug Administration-approved smoking cessation aid, and the first in a class of α4β2 nicotinic acetylcholine receptor (nAChR) partial agonists, came to market in 2006.
Since FDA approval, varenicline has been cited by mainstream media reports as an impetus for several suicides and suicide attempts. Case reports, an Institute for Safe Medication Practices (ISMP) report, and new FDA warnings have been published regarding the safety of varenicline. This new information may cause concern for its use in patients with a history of mental illness despite its improved efficacy and cost benefits over previous therapies. This article analyzes these newly reported risks of varenicline therapy and provides specific recommendations regarding the role of varenicline in smoking cessation among patients with mental illness.
Clinical trials that brought varenicline to market demonstrate greater benefit compared to placebo and bupropion sustained release (SR) in terms of patients achieving smoke-free status.4-8 In addition, a meta-analysis comparing abstinence rates for six first-line pharmacotherapies and placebo over 6 months demonstrated varenicline to have the highest estimated abstinence rate (33.2% for varenicline vs. 19.0% to 26.7% for other active treatments vs. 13.8% for placebo).9 Due to the documented efficacy of varenicline, the Health and Human Services guidelines on Treating Tobacco Use and Dependence has recommended the product as a first-line treatment option.9
Although data support varenicline as the most effective smoking cessation aid on the US market, some may argue that the cost of therapy is prohibitive and outweighs its benefits when considering use of generic alternatives.10 A recent pharmacoeconomic analysis considered this financial aspect and demonstrated varenicline as the most cost-effective smoking cessation option.11 The analysis used a hypothetical cohort of US adult smokers who make one attempt at smoking cessation. For the purposes of the analysis, efficacy was estimated using two head-to-head trials of varenicline, bupropion SR, and placebo, along with a meta-analysis of nicotine replacement therapy. Costs analyzed included the lifetime direct (medication cost plus smoking-related morbidity) but not indirect costs. Varenicline decreased direct costs compared to unaided smoking cessation, traditional nicotine replacement therapy, and bupropion SR by $4.7 billion, $4.1 billion, and $2.4 billion respectively.11 These cost savings were a direct result of the increased efficacy of varenicline in the models used. Additionally, if 25% of smokers initiated a quit attempt with the use of varenicline, 144,000 more smoking-related deaths would be prevented compared with unaided smoking cessation. Further, having a quit attempt with varenicline over unaided smoking cessation would produce 261,000 fewer incidences of asthma exacerbations, chronic obstructive pulmonary disease, coronary heart disease, stroke, and lung cancer. A follow-up cost-effectiveness study using an additional 12 weeks of varenicline after the initial 12-week treatment period (for a total of 24 weeks of treatment) showed similar results, even with the increased expenditure of obtaining varenicline.12
Phase II and III clinical trials showed varenicline to have a mild side-effect profile. Nausea (30%) was the most commonly reported adverse drug reaction (ADR), although it was generally mild to moderate and resolved over time. A lower incidence of nausea is seen when varenicline is initiated at a low dose (0.5 mg/day) and titrated slowly to the target dose (1 mg BID), as recommended in the product information.13 Headache (15%), insomnia (18%), and abnormal dreams (13%) were the next most commonly reported ADRs. Discontinuation rates due to ADRs were similar between varenicline (11.2% to 14.3%) bupropion SR (15.9%), and placebo (9.8%) in the phase III trials, with the main cause for discontinuation of varenicline being nausea. One episode of atrial fibrillation in one patient8 and one episode of worsening vertigo, increased blood pressure, and chest pain in a second patient4 were attributed to varenicline during the trials. Although weight gain was observed in two clinical trials,3,7 patients taking placebo averaged more weight gain (2.92 kg) compared to varenicline (2.37 kg); therefore, this event is considered a common effect of smoking cessation. Laboratory parameters, electrocardiogram recordings, incidence of seizures, and vital signs showed no clinically significant differences between placebo and varenicline.14 No neuropsychiatric adverse events (AEs) or deaths were reported in these clinical trials.
Clinical trials are not always able to identify rare, serious ADRs, defined as occurring once out of every 3,000 exposures, due to inclusion of relatively small sample sizes. In order to detect such events, studies must include a minimum of 3,000 patients per treatment arm. Phase III varenicline studies exposed >4,500 patients to varenicline,13 thus making detection of such events unlikely. Therefore, the FDA must rely on post-marketing reports, such as those reported to the ISMP to evaluate the true overall safety of any new medication. The ISMP is a nonprofit organization that monitors medication safety and recommends ways to prevent medication errors. This organization plays a major role in documenting and reporting AEs from medications once they are approved by the FDA. Reporting AEs to the ISMP is voluntary and information collected about AEs is limited.
Approximately 3.5 million people have taken varenicline since its FDA-approval in May 2006.15 Since that time, 6,363 cases of AEs have been submitted to the FDA; 3,063 were deemed as serious. The ISMP has compiled these cases into a single report to better collectively document risks of varenicline therapy (Table 1).15 According to the ISMP, risks of varenicline use have been underestimated. Neuropsychiatric AEs, such as agitation, mood and behavioral changes, and suicidal ideation, are most concerning.15 Also included in the ISMP report are 78 deaths in which varenicline was the principal suspect drug. Suicide contributed to 28 of these deaths and the majority of the other deaths were due to cardiovascular, arrhythmic, or thrombotic events. The report also specifically mentioned the increased rate of accidental injuries such as traffic accidents in users of varenicline, which was attributed to loss of consciousness, muscle spasms, dizziness, and mental confusion.15 As a result, the Federal Aviation Administration banned varenicline use in pilots.16
Furthermore, determining the strength of the relationship between varenicline and the proposed associated events noted in the ISMP report is complicated by confounding factors inherent in an analysis of this type. Certain facets of information, such as previous medications, medical history, and patient demographics, are lacking in the report. In fact, the ISMP states that “these reports do not establish causality; almost two-thirds of patients were taking multiple drugs; the event classification tool is limited to identifying potential cases and is not definitive. Reporting is voluntary for consumers and health professionals and little is known about reporting rates.”15
While the FDA acknowledges that there are many confounding factors affecting the development of neuropsychiatric symptoms,17 subsequent to the ISMP report, the FDA published early communication warnings in November 2007 about isolated reports of neuropsychiatric events including suicidal ideation as well as aggressive and erratic behavior following treatment with varenicline.18 The FDA alert notes that some of these events could be caused by withdrawal symptoms from nicotine, but in some cases the patients had yet to discontinue smoking.18 Later, in February 2008, the FDA requested the manufacturer of varenicline, Pfizer Inc., to develop a public health advisory and add warnings to the package labeling educating users about the possible risk of neuropsychiatric events.19 Pfizer heeded these requests in May 2008. The FDA released a second public health advisory in July 2009 which highlighted the addition of a boxed warning to the package labeling of varenicline. The advisory required this new boxed warning because of “…the risk of serious neuropsychiatric symptoms in patients receiving [varenicline].”17 The advisory included that the same black box warning be added to bupropion SR (Zyban) as well; other forms of bupropion SR (Wellbutrin SR), used for depression, already carried a similar warning.
Because patients with mental illness were excluded from the initial clinical trials of varenicline,4-8 it is important to seriously consider the information detailed in the ISMP report. Although the ISMP does not specify details regarding the patients reporting these neuropsychiatric AEs, it documents the time course between varenicline initiation and development of the precipitating events. While some patients began exhibiting hostility, aggression, psychosis, or suicidal ideation, or performing self injury, only days after initiation of varenicline therapy, others did not develop these side effects until weeks after initiation. Furthermore, other patients did not develop psychiatric AEs until after varenicline was discontinued. As such, the time to development of psychiatric AEs from varenicline initiation or discontinuation remains unclear. Unfortunately, the ISMP did not specify any underlying medical or psychiatric conditions in these patients. This information may have elucidated causes or risk factors for developing psychiatric AEs from varenicline. In addition to the ISMP, one case report20 has documented the onset of psychiatric symptoms in a patient without a preexisting mental illness, and a second case report21 describes the onset of hallucinations upon varenicline withdrawal.
The United Kingdom (UK) also released results from similar AE surveillance data. This retrospective cohort study22 included 2,682 varenicline users in the interim analysis. Psychiatric AEs, which developed in <2% of the study population, included sleep disturbances, depression, anxiety, abnormal dreams, and changes in mood. In patients who experienced the psychiatric AEs (n=142), ~65% had no prior history of mental illness; however, 31% did have a preexisting mental illness. There were six episodes of suicidal ideation or attempts in five patients. Of these five patients, four had preexisting depression. The remaining patient had no history of mental illness.
Since the release of the FDA warnings, several studies have been conducted to examine the event rate of these psychiatric AEs comparing varenicline to other smoking cessation aids. One large cohort study (n=80,660)23 conducted in the UK examined the risk of suicide and suicidal behavior between patients using varenicline (n=10,973), nicotine replacement therapy (NRT; n=63,265), and bupropion SR (n=6,422). Approximately 48.5% of patients who received varenicline were current or past users of antidepressants. Other medications such as hypnotics and antipsychotics (37.8% and 17.6%, respectively) were less common, as was a past suicide event (9.5%). While varenicline was associated with a 43% increased risk of suicidal thoughts compared with NRT, it was not significant (95% CI –47%-285%). Hazard ratios comparing varenicline to NRT [1.12(0.68–0.88)] and bupropion to NRT for self harm were similar [1.17 (0.59-2.32)]. The authors23 concluded that varenicline had no increased risk of psychiatric AEs compared to other first-line cessation aids.
Although psychiatric AEs may be uncommon in the general population, patients with preexisting mental illness or who use psychoactive medications might be at an increased risk of developing psychiatric AEs when taking varenicline. In fact, the ISMP report stated that many patients experiencing psychiatric AEs were concomitantly taking varenicline along with other psychoactive agents such as antidepressants, benzodiazepines, and antipsychotics.15 To date, there have been no reports of drug interactions between varenicline and antidepressants, benzodiazepines, and antipsychotics. These medications treat common mental illnesses, such as depression, anxiety, and schizophrenia, which may be exacerbated by varenicline.
Ten case reports (Table 2)20,21,24-33 have been published linking psychiatric AEs to varenicline use in patients with various mental illnesses including depression,24-27 bipolar disorder,28-31 schizoaffective disorder,32 and schizophrenia.33
A 2007 retrospective chart review34 evaluated 50 veterans who received varenicline for smoking cessation. Patients in this study had a high prevalence of preexisting mental illness (48%), including four patients who discontinued varenicline for worsening mood and behavioral changes. Interestingly, those subjects achieving a smoke-free status was significantly lower (P<.001) in mentally ill patients (27%) versus those without mental illness (57%). The small sample size precludes extrapolation to a larger population, but these results lay a foundation for further study.
In contrast, some post-marketing studies have not found varenicline to cause an exacerbation of psychiatric symptoms in patients with mental illness. A small (n=53) retrospective study35 conducted in the UK showed presence of mental illness had no impact on development of psychiatric AEs with varenicline use. In another case series,36 none of 19 patients with schizophrenia developed psychiatric AEs during a course of varenicline use. Two separate case reports also showed no development of psychiatric AEs with varenicline in a patient with schizophrenia37 and a patient with bipolar disorder.38 Although the data suggest preexisting mental illness has no impact on the likelihood of experiencing a psychiatric AE caused by varenicline, the small sample size within each of these publications prevents a definitive conclusion from being made regarding the safety of varenicline in patients with mental illness.
Another study (n=1,117)39 compared differences in psychiatric AE rates between patients with and without a history of depression taking varenicline. No differences in smoking cessation rates or overall AE rates were found between the two groups. However, those previously diagnosed with depression were more likely to experience a psychiatric AE (P<.01), including depression, anxiety, and irritability. Although statistically significant, the authors considered the difference to have no clinical significance.
An open-label study40 evaluated the addition of varenicline (up to 1 mg BID) to depressed tobacco users’ (n=18) current antidepressant to determine effects on depression rating scale scores. After 8 weeks, depression rating scale scores improved significantly (P<.001) and 44% of patients achieved abstinence. One patient discontinued treatment due to worsening mood; others experienced various common psychiatric AEs (eg, irritability, nightmares, insomnia).
The effect of varenicline therapy on improving cognitive functioning in the face of nicotine withdrawal was also examined through a prospective trial.41 In this study (n=67), varenicline showed positive results for improving mood, cognitive performance, and withdrawal symptoms compared to placebo. Insomnia, abnormal dreams, and fatigue were common AEs within both treatment arms; no other psychiatric AEs were reported.
Varenicline has shown improved efficacy over other smoking cessation aids, but since the time of its approval it has also been associated with an increased risk of serious AEs. The FDA now requires a boxed warning in the package labeling and a patient medication guide dispensed with varenicline detailing the increased risk of psychiatric AEs.17 Studies22,23 have found that, for the general population, the risk of developing psychiatric AEs, while serious, is relatively rare. According to the data presented here, it appears that the risk for developing psychiatric AEs is greater for those with pre-existing mental illness. Patients with psychiatric conditions were excluded from the phase III clinical trials, which forced discovery of these rare ADRs into the post-marketing period. Since a large proportion of smokers may also have a mental illness,3 this seems to be a glaring oversight in the conduction of these trials.
One possible explanation for these increased risks could be the drug’s unique mechanism of action. Nicotinic receptors are selectively distributed throughout the central nervous system (CNS). While there are many subtypes of nicotinic receptors in the CNS, nicotine displays the highest affinity for the α4β2 nAChR subtype which causes dopamine release within the nucleus accumbens. The surge of dopamine release caused by α4β2 nAChR activation is responsible for the pleasurable feelings caused by nicotine. A selective partial agonist for this receptor, such as varenicline, decreases withdrawal symptoms and cravings without causing dependence. Combining this property with a long half-life (24 hours), varenicline blocks nicotine from binding to the receptor and prevents nicotine-induced dopamine release.12 This partial agonistic activity at nicotinic receptors, which increases dopamine transmission throughout the cortex, could cause the increased incidence of psychiatric AEs.42 Dopamine is hypothesized to be involved in the development and continuation of various psychiatric illnesses such as schizophrenia,43 bipolar disorder,44 and depression.45 Varenicline also binds to serotonin (5-HT)3 receptors, which may contribute to the high incidence of nausea experienced by patients when initiating therapy.13 Preclinical studies46 in mice using models of depression have shown that affinity at 5-HT3 receptors may help augment traditional antidepressant therapy. Therefore, this 5-HT3 agonistic activity of varenicline may also contribute to psychiatric AEs by disrupting the brain’s serotonin homeostasis.
Nicotine withdrawal alone may contribute to psychiatric AEs as well. Agitation, irritability, and decreased concentration are all possible withdrawal symptoms that may mimic certain aspects of psychiatric illnesses. The causal mechanism behind these psychiatric symptoms remains unclear, but may be the result of a lack of stimulation of the nAchR leading to decreased activation of dopamine receptors in the nucleus accumbens, ventral tegmental area, and prefrontal cortex. It is this decreased activation of the dopamine receptors in the prefrontal cortex that may lead to psychiatric AEs. Although the mechanism of varenicline’s action mutes the intensity of nicotine withdrawal symptoms, one study47 reported an increased incidence of depression after smoking cessation. Concomitant use of psychiatric medication may also heighten these AEs. One case report48 demonstrated amphetamine, commonly used for the treatment of attention-deficit/hyperactivity disorder, blocks the effects of varenicline, thus increasing the severity of nicotine withdrawal symptoms. Furthermore, patients with an underlying mental illness (diagnosed or undiagnosed) often exhibit neuropsychiatric symptoms, identical to those reported by the ISMP, as a result of their illness. In addition, patients who are noncompliant with their psychiatric medications may have symptoms similar to those seen with varenicline use. Collectively, these aspects of stress induced through the challenge of smoking cessation, including nicotine withdrawal, concomitant use of psychiatric medications, underlying mental illness, potential noncompliance with medication, and other unidentified factors, confound and complicate identifying the cause of psychiatric AEs in patients with mental illness.
The ISMP does not adequately evaluate the role these various factors may play in the development of psychiatric AEs. Additional factors such as comcomitant medications, previous psychiatric history including suicidality, and previous quit attempt methods need to be investigated further. The authors agree with the ISMP which states that some risks with varenicline may have been underestimated, specifically in patients with mental illness. However, while the number of AEs identified by the ISMP is striking, they constitute a very low percentage of the total number of patients who have received varenicline (3,063 out of 3.5 million exposures, ~.08%). In addition, the ISMP reports 78 deaths in which the principle suspect drug was varenicline. This number equates to a .002% death rate in the varenicline-exposed population, and when compared to the annual age-adjusted death rate in the general population (776.4 per 100,000), gives some perspective to the deaths attributed to varenicline.49 Further, the percentage of deaths due to suicide in the general and depressed populations are 1.3%49 and between 2% and 9%,50 respectively. Comparing these suicide rates with that of the varenicline-exposed population (.0008%) places the low incidence of suicide caused by varenicline into perspective. At first glance, comparison of these percentages may make it appear that varenicline actually prevents patients from committing suicide; however, the suicide rates for varenicline cannot be extrapolated to the general population as the amount of patients who have taken varenicline is low compared to the total US population. The calculation of suicide rates with varenicline is for illustrative purposes only and serves to frame the deaths due to varenicline in light of the recent ISMP and mass media reports. Still, it is unknown whether varenicline increases the risk of suicide further in patients with mental illness. Although the rates of death for varenicline presented here may be skewed due to under-reporting of AEs to the FDA, the difference in rates is noteworthy.
It is exceedingly difficult, given the relatively weak body of evidence, to come to a firm conclusion about the role varenicline plays in causing psychiatric AEs. Many of the articles incorporated in this review are case reports, case series, and retrospective chart reviews which include a small number of patients. This limits the ability to extrapolate results to the population at large. Further, four publications35-38 do not support an increased incidence of psychiatric AEs among varenicline users. However, a large prospective trial39 did show an increased risk of psychiatric AEs in patients with depression. While the absolute numbers of psychiatric AEs may be small and a large body of literature is lacking, their seriousness belies any lackadaisical approach, especially in patients with mental illness.
Patients desiring a pharmacotherapy smoking cessation aid have many available options. Selection of smoking cessation aids should be individualized to each patient’s needs.9 Presence of psychiatric conditions should be included in this decision-making process and may steer selection away from varenicline. Patients without a history of mental illness using varenicline should be monitored closely for psychiatric AEs, although the likelihood appears infrequent. Caution should be exercised and close monitoring implemented when varenicline is used by patients with preexisting psychiatric conditions to enable discovery of serious AEs. The authors echo the FDA’s statement from a recent Public Health Advisory:
“Healthcare providers should monitor all patients taking [varenicline] for symptoms of serious neuropsychiatric symptoms….Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder, may experience worsening of their pre-existing psychiatric illness while taking [varenicline].”51
It is prudent to engage patients in the product selection and discussion about common adverse reactions, serious AEs, and how to manage these occurrences. Discontinuation of varenicline is recommended in all patients reporting new-onset psychiatric symptoms or exacerbations of underlying psychiatric diseases.51 Practitioners should reevaluate the risks, benefits, and smoking cessation strategy when varenicline is used for extended periods of time.
Varenicline has proven efficacy for aiding in smoking cessation, but appears to carry some serious risks, particularly for patients with preexisting mental illness. While further prospective trials on the use of varenicline in mental illness may be inappropriate, the information currently available does little to fully elucidate the effects of varenicline in patients with mental illness. At a minimum, the data reviewed here validate cautious use of varenicline in patients with mental illness. PP
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