clinical Report Varenicline CLINICAL report Mental health stability in veterans with posttraumatic stress disorder receiving varenicline Austin R. Campbell and Keith D. Anderson Purpose. The effects of varenicline treatment for smoking cessation on mental health (MH) stability in veterans with posttraumatic stress disorder (PTSD) was studied. Methods. Data were collected by retrospective chart review at a Veterans Affairs medical center. Patients with PTSD who were prescribed varenicline for smoking cessation between May 2006 and July 2008 were included; all patients had failed previous attempts to quit using nicotine replacement therapy, bupropion, or both. The average numbers of encounters per month with MH professionals in a six-month baseline period before varenicline, during treatment, and after treatment were compared. The numbers of MH encounters were compared for patients with multiple MH disorders including major depressive disorder, schizophrenia, or bipolar disorder and those with PTSD alone. Patients who had completed a full course of varenicline therapy (4 12 weeks) without MH decompensation were surveyed to determine the rate of smoking cessation. Posttraumatic stress disorder (PTSD) is a chronic anxiety disorder of increasing concern among the veteran population. Like most mental health (MH) disorders, PTSD has demonstrated a strong correlation with tobacco dependence. An estimated 40 86% of this population is considered tobacco dependent. 1-3 Numerous studies have shown that patients with MH disorders have significantly higher rates of smoking than the general population. 1-8 This circumstance is made worse by the fact that only 10 26% of MH patients are able to achieve prolonged smoking cessation, a rate less than half that for the general population. 4-8 Considering the detrimental health effects associated with smoking, newer and more effective treatments for tobacco dependence need to be explored in this population. Varenicline, a novel medication for the treatment of tobacco dependence, was approved for marketing by the Food and Drug Administration (FDA) in May 2006. Its unique mechanism of action decreases mesolimbic dopamine release through partial agonism of the a4b2 nicotinic acetylcholine receptor, which reduces nicotine cravings and positive reinforcement of smoking. 9,10 Early clinical trials with varenicline reported smoking cessation rates greater than 40% in patients receiving 12 weeks of therapy. 11-15 Further studies have shown varenicline to be more effective than bupropion or the transdermal nicotine patch and equally Results. Data were analyzed for 78 patients. MH encounters during varenicline therapy increased 29% over baseline. There was no significant difference in the numbers of encounters in the baseline and postvarenicline periods. MH decompensations were documented for 4 patients during varenicline therapy and 2 after completion of therapy. Before, during, and after varenicline, patients with multiple MH disorders had significantly more MH encounters than those with PTSD alone. Of the 42 patients in the follow-up survey, 19 (45%) said they refrained from smoking for 30 days and 13 (31%) for 90 days. Conclusion. Varenicline appeared to have destabilizing effects on MH in veterans with PTSD. Index terms: Department of Veterans Affairs; Nicotinic agonists; Smoking; Stress disorders; Toxicity; Varenicline Am J Health-Syst Pharm. 2010; 67:1832-7 effective as combination therapy. 16-21 The most common adverse effects recorded in these trials were nausea, headache, insomnia, and abnormal dreams. Varenicline is still considered first-line therapy in the treatment of tobacco dependence, despite numerous postmarketing case reports as- Austin R. Campbell, Pharm.D., is Psychiatric Pharmacy Practice Resident, Center for Behavioral Medicine, Kansas City, MO. Keith D. Anderson, Pharm.D., BCPP, is Clinical Pharmacy Specialist, Kansas City Veterans Affairs Medical Center, Kansas City, MO. Address correspondence to Dr. Campbell at the Center for Behavioral Medicine, 1845 Southeast Timbercreek Court, Blue Springs, MO 64014 (austinrcampbell@gmail.com). The assistance of Richard S. Schaefer, Pharm.D., BCPS, Kansas City Veterans Affairs Medical Center, is acknowledged. The authors have declared no potential conflicts of interest. DOI 10.2146/ajhp100196 1832 Am J Health-Syst Pharm Vol 67 Nov 1, 2010
clinical Report Varenicline sociating the drug with serious neuropsychiatric adverse effects. 22-27 FDA safety information has been added to varenicline s labeling, warning of the medication s potential to cause agitation, hostility, depressed mood, changes in behavior or thinking, suicidal ideation, and suicidal behavior. The prevalence of and risk factors for the neuropsychiatric symptoms associated with varenicline have yet to be determined in clinical trials. Safety data on varenicline have indicated no definitive mechanism of action for these effects and are largely derived from the available case reports, which have all involved patients with MH disorders. 23-27 Initial clinical trials of varenicline excluded patients suffering from psychiatric conditions. To date, only two studies have evaluated the safety of varenicline in this population. Stapleton et al. 28 compared varenicline with nicotine replacement therapy in a population that included 111 patients with mental illness. The results indicated no difference in the frequency of adverse effects experienced by patients with mental illness versus those without. Purvis et al. 29 evaluated the safety and effectiveness of varenicline in a population including 24 MH patients at a Veterans Affairs medical center (VAMC). The prevalence of underlying mental illness in patients who successfully quit smoking (4 of 15, 27%) was significantly lower than in patients who were not successful (20 of 35, 57%) (p < 0.001). In addition, 13 patients (26%) dropped out because of adverse effects, 4 of whom experienced aggression, agitation, mood changes, or major depressive state. Currently, there is no evidence to support the use of varenicline in patients suffering from PTSD. Given this population s high prevalence of tobacco dependence and low cessation rates, alternative therapies need to be explored. The primary objective of this study was to determine the effects of varenicline on MH stability in a veteran population suffering from PTSD. This study also investigated whether patients suffering from axis I MH disorders (e.g., major depressive disorders, schizophrenia, bipolar disorder) 30 in addition to PTSD are more susceptible to the neuropsychiatric adverse effects of varenicline. In addition, the sustained smoking cessation rate after treatment with varenicline in this population was investigated. Methods Design. This was a retrospective cohort study conducted at a single VAMC in Kansas City, Missouri, in patients with a diagnosis of PTSD receiving smoking cessation therapy with varenicline between May 2006 and July 2008. The study received approval from the facility s institutional review board and was conducted in two phases: (1) a retrospective chart review comparing the average number of MH encounters required by patients before, during, and after treatment with varenicline and (2) a follow-up telephone survey of all patients completing a full 4 12-week course of varenicline without a decompensation in their MH stability to determine the rate of smoking cessation. For both phases, data were extracted through use of the computerized patient record system (CPRS). For the first phase of the study, the number of MH encounters per month was collected for all patients beginning six months before starting varenicline and continuing for three months after varenicline discontinuation. The study defined a MH encounter as any documented interaction, either in person or by telephone, between a patient and a provider for the treatment or followup of an axis I MH disorder. The providers included psychiatrists, psychologists, and nurse practitioners working in the MH department. Any MH encounter specifically related to smoking cessation therapy for a patient was excluded from evaluation. Information was divided into three time periods for comparison. The first period included all MHencounter data for the six months prior to treatment with varenicline; this information was used to establish a baseline for MH encounters. The second period consisted of MHencounter data for patients actively receiving treatment with varenicline. Data gathered for this period would be compared with the baseline data. This period extended from the date varenicline was issued to five days after the last expected dose of medication; the additional five days allowed for washout of varenicline. Unless otherwise documented in the CPRS, patients filling a prescription for varenicline were assumed, for the purposes of this study, to have taken a full 4 weeks of medication. Patients ordering one or two refills were assumed to have taken varenicline for 8 or 12 weeks, respectively. The third, and final, period included MHencounter data for the three months after the medication washout. Data gathered for this period would be compared with baseline to determine any prolonged neuropsychiatric effects of varenicline. Patient data in all three periods were also evaluated for concomitant axis I MH disorders. This information was used to further divide the study population into two groups: (1) patients diagnosed with PTSD and a concomitant axis I MH disorder and (2) patients with a diagnosis of PTSD only. The data for the two groups would be compared. Finally, a follow-up telephone survey of patients who successfully completed a full course of varenicline therapy (4 12 weeks) without an acute decompensation in MH stability warranting early termination of the drug was conducted. All patients were surveyed in April 2009. An automated messaging system with touchtone answering capabilities was used for the survey. After listening to a brief consent statement, patients were given the option to participate or decline the survey. Patients agree- Am J Health-Syst Pharm Vol 67 Nov 1, 2010 1833
clinical Report Varenicline ing to take part in the survey were asked a series of yes-or-no questions regarding their smoking cessation therapy with varenicline. The purpose of the survey was to determine the effectiveness of varenicline for initial and sustained smoking cessation in the study population. Patients. Patients included in the study were 18 years of age or older with a diagnosis code for PTSD as specified in the Diagnostic and Statistical Manual of Mental Disorders. 30 In order to receive varenicline, patients needed to have at least one previous smoking cessation failure using nicotine replacement therapy, bupropion, or both. Patients were required to have a minimum of one MH encounter per year for treatment or monitoring of PTSD. A MH encounter was considered to be any outpatient or telephone contact with a provider for which the primary or secondary reason was reported as PTSD, schizophrenia, major depressive disorder, or bipolar disorder. Patients were excluded from the study if they experienced a decompensation in MH stability or MH-related hospitalization in the 12 weeks prior to initiating varenicline. Decompensations in MH stability were defined as increased presence of auditory or visual hallucinations; paranoid delusions; suicidal or homicidal ideation; or manic, hypomanic, depressive, or major depressive episodes. MH hospitalizations were any emergency department or inpatient hospitalization in which the primary or secondary reason for admission was related to a decompensation in MH stability. In addition, patients receiving prescriptions for varenicline or being followed for their MH disorders at an outside facility were excluded. Any patient completing a full 4 12-week course of varenicline without a reported decompensation in MH stability was eligible for the follow-up telephone survey. Outcome measures. The primary outcome measure for this study was the average number of MH encounters per month required by patients while taking varenicline. Secondary outcome measures included (1) the number of MH hospitalizations or decompensations experienced by patients while taking varenicline, (2) the average number of MH encounters per month for patients with multiple axis I MH disorders compared with encounters for patients with PTSD alone, and (3) sustained smoking cessation rates at one and three months after completion of varenicline. Statistical analysis. To eliminate interrater variability, study charts were reviewed by a single investigator. Data for the primary outcome measure was analyzed using a onetailed paired Student s t test comparing the average number of MH encounters per month in the baseline and varenicline treatment periods. The same statistical method was used to compare the postvarenicline period with the baseline. A t test was also used in comparing data for patients with multiple axis I MH disorders and patients with PTSD only. For all data analyzed, the a priori level of significance was 0.05. Results MH stability. A total of 87 patients met initial criteria for the study. Nine patients were excluded because of provider-documented decompensation of their MH stability or MH hospitalization within 12 weeks of initiating varenicline. This resulted in 78 patients for inclusion in the final data analysis of the primary efficacy measure. These patients were principally Caucasian men with an average age of 55 years (Table 1). Compared with the baseline period, the mean ± S.D. number of MH encounters per month increased by 29% during the varenicline treatment period (0.84 ± 0.54 and 1.08 ± 0.77 encounters per month, respectively; p = 0.005). However, no difference in the number of encounters was seen between the postvarenicline period and the baseline (0.84 ± 0.54 and 0.82 ± 0.73 encounter per month, respectively; p = 0.4). Overall, six patients experienced provider-documented decompensations in MH stability during either the varenicline treatment period or the postvarenicline period. Two of these patients reported suicidal ideation within the first 2 weeks of taking varenicline. One patient was taken to a local emergency department for observation, and the other was monitored on an outpatient basis. In both cases, varenicline was not documented by the MH provider as a potential contributor to the suicidal ideation, and the medication was continued. Two additional patients were hospitalized for MH-related reasons other than suicidal ideation after completion of varenicline. One of them was hospitalized at the end of the medication washout period, and the other nearly 10 weeks after varenicline was discontinued. Again, varenicline was not documented as a potential contributor to either hospitalization. In two separate instances, patients experienced depressive episodes shortly after initiating treatment with varenicline. In both cases, the cause of the episodes was attributed by providers to varenicline and the medication was promptly discontinued. Neither patient required hospitalization. Of the 78 patients included in the final data analysis, 55% (n = 43) had a concomitant axis I MH disorder, the most common of which was major depressive disorder (n = 33, Table 1). When compared with patients with a MH diagnosis of PTSD alone (n = 35), those with multiple MH disorders required significantly more encounters per month during the baseline, varenicline treatment, and postvarenicline study periods (Table 2). Smoking cessation. A total of 72 patients were eligible for the followup telephone survey after exclusion of any patients experiencing MH decompensations or MH hospitaliza- 1834 Am J Health-Syst Pharm Vol 67 Nov 1, 2010
clinical Report Varenicline tions. Of these, only 42 (58%) gave informed consent and participated in the telephone survey. Nineteen of these patients (45%) reportedly were able to refrain from smoking tobacco products for 30 days after completing treatment with varenicline. Overall, 13 surveyed patients (31%) reported complete abstinence from smoking for 90 days after completing treatment with varenicline (Table 3). Discussion The results of this study suggest that patients diagnosed with PTSD require significantly more MH-related encounters while taking varenicline for smoking cessation therapy. Compared with the baseline period, there was nearly a 30% increase in MH encounters during varenicline therapy. This marked increase suggests that varenicline had some destabilizing effects in this study population. Almost as noteworthy is the finding of no difference between the baseline and postvarenicline periods. The nearly identical MH encounter requirement in these two periods further implies that varenicline may cause some degree of MH instability. The apparent return to baseline of MH encounters after treatment with varenicline was discontinued also demonstrates a lack of persistent destabilization. Also, during this study serious adverse effects, including suicidal ideation, occurred in 6 of 78 patients (8%). This rate is consistent with the findings of Purvis et al. 29 ; 8% of their study population experienced neuropsychiatric effects ranging from agitation and anxiety to a depressive episode in 1 individual. To date, serious adverse effects such as found in that study and this study have been documented only in case reports and not in other clinical trials. 23-27 Thus, the actual rate at which patients may experience neuropsychiatric effects from varenicline has not been consistently elucidated in the literature. Another important finding of this study was that patients with Table 1. Characteristics of Study Patients (n = 78) Variable Mean ± S.D. age (yr) Mean ± S.D. creatinine clearance (ml/min) No. (%) male Race (no. [%]) Caucasian African American Not reported Concomitant MH disorder Depression Bipolar disorder Schizophrenia Duration of varenicline treatment (wk) 4 8 12 multiple axis I disorders required nearly double the number of MH encounters as patients with PTSD only. Although this finding was statistically significant, the lack of a control group containing patients without a MH history makes interpreting the clinical relevance difficult. Furthermore, since the argument can be made that having multiple MH disorders alone necessitates an increase in provider follow-up, this finding does not necessarily mean that this subpopulation is more susceptible to neuropsychiatric effects of varenicline. Although data for both the multiple axis I and PTSD only groups indicated that patients required more MH encounters during the varenicline treatment period, statistical testing to substantiate the significance was not included in the study protocol and thus was not performed. The sustained smoking cessation rate at 90 days after treatment was 31% (n = 13) in this population as determined in the automated telephone survey. Although this is less than the roughly 40% cessation rates reported with varenicline in other clinical trials, several factors may account for this. 11-15 Traditionally, the MH population is more difficult to Value 54.9 ± 8.7 82.5 ± 14.6 65 (83) 61 (78) 5 (6) 12 (15) 33 (42) 9 (11) 1 (1) 11 (14) 44 (56) 23 (29) treat in regard to smoking cessation, with long-term quit rates of only 10 26% reported in the literature. 4-8 Another consideration is that patients in this study were required to have failed at least one previous smoking cessation attempt with nicotine replacement therapy, bupropion, or both, so they may have been more treatment refractory. It is also important to note that self-reported data on smoking cessation are greatly limited by patients recall ability and personal biases. This study had several major limitations related to its retrospective design. The first concerns establishing a causal relationship between varenicline and the primary outcome measure. The retrospective nature of this study required provider documentation to be relied on exclusively in attributing MH effects to varenicline; it also limited the ability to evaluate other possible causes of MH decompensation (e.g., psychosocial stressors) and the increased need for provider follow-up. Another major limitation concerns determining the actual length of treatment with varenicline. Unless directly documented by providers upon follow-up, the last dose of medication for each patient was Am J Health-Syst Pharm Vol 67 Nov 1, 2010 1835
clinical Report Varenicline Table 2. Comparison of Patients With Posttraumatic Stress Disorder (PTSD) Only and With Multiple Axis I Disorders Variable No. (%) male Race (no. [%]) Caucasian African American Mean ± S.D. age (yr) Mean ± S.D. MH a encounters/mo Baseline period During varenicline therapy After varenicline therapy a MH = mental health. Table 3. Responses to Telephone Survey Patients With PTSD Only (n = 35) Patients With Multiple Axis I Disorders (n = 43) p 32 (91) 33 (77) 0.043 0.18 26 (74) 2 (6) 54.4 ± 8.9 35 (81) 3 (7) 55.4 ± 8.6 0.300 0.59 ± 0.33 0.78 ± 0.58 0.52 ± 0.42 Question Did you set a quit date prior to starting varenicline to help you quit smoking? If you chose a quit date, were you able to stop smoking on that date? Were you able to refrain from smoking while taking varenicline? Were you able to refrain from smoking 30 days after treatment with varenicline? Were you able to refrain from smoking 90 days after treatment with varenicline? 1.05 ± 0.65 1.32 ± 0.90 1.07 ± 0.90 0.017 0.034 0.018 Proportion (%) Respondents Answering Yes 23 of 42 (55) 12 of 23 (52) 19 of 42 (45) 19 of 42 (45) 13 of 42 (31) assumed to occur at the end of a four-week course of treatment. This could skew the data if numerous patients discontinued therapy before completing the full varenicline prescription. One other limitation concerns the chart review method. Using a single reviewer eliminates the possibility of interrater variability, but it also introduces potential for bias. The use of multiple reviewers could have minimized this, but resources for that were not available at the time. One other limitation of this study concerns patient follow-up by providers after initiation of a new medication. In response to reports of neuropsychiatric adverse effects with varenicline, the Veterans Health Administration has implemented a new policy regarding use of the medication. The policy mandates that patients with a psychiatric disorder be evaluated by a MH provider before initiation of smoking cessation therapy with varenicline. It also requires providers to follow up with newly initiated patients within 30 days to monitor for neuropsychiatric effects. However, this policy was introduced after the time period for this study (May 2006 through July 2008). In addition, any MH encounters specifically for follow-up of smoking cessation were excluded from the data. On the basis of individual chart review, the possibility of bias resulting from this exclusion appears to be minimal. Conclusion Varenicline appeared to have destabilizing effects on MH in veterans with PTSD. References 1. Fu S, McFall M, Saxon A et al. Posttraumatic stress disorder and smoking: a systematic review. Nicotine Tob Res. 2007; 9:1071-84. 2. Hapke U, Schumann A, Rumpf HJ et al. Association of smoking and nicotine dependence with trauma and posttraumatic stress disorder in a general population sample. J Nerv Ment Dis. 2005; 193:843-6. 3. McFall M, Saxon A, Thaneemit-Chen S et al. Integrated smoking cessation into mental health care for post-traumatic stress disorder. Clin Trials. 2007; 4:178-89. 4. Dixon L, Medoff D, Wohlheiter K et al. Correlates of severity of smoking among persons with severe mental illness. Am J Addict. 2007; 16:101-10. 5. Gelenberg A, de Leon J, Evins A et al. Smoking cessation in patients with psychiatric disorders. J Clin Psychiatry. 2007; 68:1404-10. 6. Lasser K, Boyd JW, Woolhandler S et al. Smoking and mental illness: a population-based prevalence study. JAMA. 2000; 284:2606-10. 7. Snyder M, McDevitt J, Painter S. Smoking cessation and serious mental illness. Arch Psychiatr Nurs. 2008; 22:297-304. 8. Chou K, Chen R, Lee JF et al. The effectiveness of nicotine-patch therapy for smoking cessation in patients with schizophrenia. Int J Nurs Stud. 2004; 41:321-30. 9. Chantix (varenicline) product information sheet. New York: Pfizer Labs, Division of Pfizer Inc.; 2009 Jul. 10. Stack N. Smoking cessation: an overview of treatment options with a focus on varenicline. Pharmacotherapy. 2007; 27:1550-7. 11. Gonzales D, Rennard SI, Nides M et al. Varenicline, an a4b2 nicotinic acetylcholine receptor partial agonist, vs sustainedrelease bupropion and placebo for smoking cessation. JAMA. 2006; 296:47-55. 12. Jorenby DE, Hays JT, Rigotti NA et al. Efficacy of varenicline, an a4b2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation. JAMA. 2006; 296:56-63. 13. Oncken C, Gonzales D, Nides M et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med. 2006; 166:1571-7. 14. Nides M, Oncken C, Gonzales D et al. Smoking cessation with varenicline, a selective a4b2 nicotinic receptor partial agonist. Arch Intern Med. 2006; 166:1561-8. 15. Tonstad S, Tonnesen P, Hajek P et al. Effect of maintenance therapy with vareni- 1836 Am J Health-Syst Pharm Vol 67 Nov 1, 2010
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