Modulation of "Protective" Nicotine Perception and Use Profile by Flavorants: Preliminary Findings in E-cigarettes.

INTRODUCTION: Characterizing flavors are widely available in e-cigarettes and motivate initiation and continued use. Flavors may enhance appeal and facilitate development of addiction to tobacco products through modulation of tobacco products' reinforcing or aversive actions. Palatable flavors (eg, fruit) may increase appeal through primary reinforcing properties. Menthol's cooling and anesthetic effects may increase appeal by counteracting nicotine's aversive effects. Genetics provide a method for modeling individual differences in sensitivity to nicotine's effects. A common polymorphism, rs16969968, encoded in the α5 nicotinic acetylcholine receptor subunit gene (CHRNA5), is a well-recognized marker for smoking risk and reduces sensitivity to nicotine aversiveness. METHODS: This pilot study tested how flavors impacted e-cigarette appeal and self-administration. In a single testing day, cigarette smokers (N = 32; 94% menthol-smokers) self-administered e-cigarettes containing e-liquids differing in nicotine level (0 mg/mL, 24 mg/mL) and flavor (unflavored, menthol, fruit-flavored) within directed and ad libitum e-cigarette paradigms. Subjective drug effects, number of puffs, rs16969968 genotype, plasma nicotine, and menthol glucuronide levels were collected. RESULTS: Menthol partially ameliorated nicotine aversiveness; fruit did not. In nicotine's absence, fruit flavor increased self-reported preference and ad libitum use relative to menthol-containing or unflavored e-liquids. Individuals with high-smoking-risk rs16969968 genotype (N = 7) reported greater craving alleviation following directed administration of nicotine-containing e-liquids, showed a trend rating nicotine-containing e-liquids as less harsh, and self-administered more nicotine during ad libitum compared to individuals with low-smoking-risk genotype (N = 23). CONCLUSIONS: While menthol countered aversiveness of nicotine-containing e-liquids, fruit flavor increased appeal of nicotine-free e-liquids. These preliminary findings suggest menthol and fruit flavor increase e-cigarettes' appeal through distinct mechanisms. IMPLICATIONS: This study provides a detailed characterization of the effects of flavors (unflavored, menthol, fruit), nicotine (0 mg/mL, 24 mg/mL) and their interactions on the subjective drug effects and ad libitum self-administration of e-cigarettes. Genetics were used to assess these effects in higher-smoking-risk (diminished sensitivity to nicotine aversiveness) and lower-risk groups. Findings could inform impact of regulation of flavors or nicotine in e-cigarettes, and their impacts on vulnerable sub-populations.

Impact of E-cigarettes on Smoking and Related Outcomes in Veteran Smokers With Psychiatric Comorbidity.

OBJECTIVE: Compared to the general U.S. population, smokers with comorbid psychiatric and/or substance use disorders have lower quit rates after evidence-based treatments and disproportionately high smoking-related deaths. Improved modalities for reducing tobacco-related harm in this subpopulation are needed. Because electronic cigarettes (e-cigarettes) can now deliver physiologically relevant levels of nicotine to consumers, they represent an additional nicotine delivery system that could be used in cessation interventions. While current data suggest that the use of e-cigarettes by smokers promotes a reduction in combustible cigarette use, smoking quit rates through use of e-cigarettes appears to be low. The goal of this study was to examine impact of e-cigarette use on combustible tobacco use as well as on the readiness to quit smoking and changes in nicotine dependence in a multimorbid population. METHODS: We conducted a 4-week, open-label study in 43 military veteran smokers who had no immediate intention to stop smoking and were currently receiving psychiatric services from the Department of Veterans Affairs health care system. Participants were provided with a study e-cigarette they could use ad libitum along with other tobacco products and were encouraged to attend weekly laboratory visits and a one-month follow-up visit. Main outcome measures were number of cigarettes smoked per day (CPD), the frequency of e-cigarette use, the amount of money spent on combustible cigarettes (U.S. dollars/week), alveolar carbon monoxide (CO) levels, and urine cotinine levels. RESULTS: Mean e-cigarette use was 5.7 days per week and only 9% of participants used the e-cigarette for fewer than 4 days per week. Significant reductions in breath CO (9.3 ppm to 7.3 ppm, p < .02) and CPD (from 16.6 to 5.7, p < .001) were observed across study weeks, and no serious adverse events were reported. Three participants (10% of completers) reported smoking cessation that was corroborated biochemically. At one-month follow-up, motivation to quit smoking remained significantly higher and the level of nicotine dependence was significantly lower than at baseline. CONCLUSIONS: E-cigarettes are acceptable to smokers with psychiatric comorbidities, as indicated by sustained and frequent e-cigarette use by 90% of participants, and may promote reduction and/or cessation of combustible cigarette use. E-cigarettes appear to be a viable harm reduction modality in smokers with psychiatric comorbidities.

Inhalation of Alcohol Vapor: Measurement and Implications.

Decades of alcohol research have established the health risks and pharmacodynamic profile of oral alcohol consumption. Despite isolated periods of public health concern, comparatively less research has evaluated exposure to alcohol vapor. Inhaled alcohol initially bypasses first-pass metabolism and rapidly reaches the arterial circulation and the brain, suggesting that this route of administration may be associated with pharmacological effects that increase the risk of addiction. However, detailed reviews assessing the possible effects of inhaled alcohol in humans are lacking. A comprehensive, systematic literature review was conducted using Google Scholar and PubMed to examine manuscripts studying exposure to inhaled alcohol and measurement of biomarkers (biochemical or functional) associated with alcohol consumption in human participants. Twenty-one publications reported on alcohol inhalation. Fourteen studies examined inhalation of alcohol vapor associated with occupational exposure (e.g., hand sanitizer) in a variety of settings (e.g., naturalistic, laboratory). Six publications measured inhalation of alcohol in a controlled laboratory chamber, and 1 evaluated direct inhalation of an e-cigarette with ethanol-containing "e-liquid." Some studies have reported that inhalation of alcohol vapor results in measurable biomarkers of acute alcohol exposure, most notably ethyl glucuronide. Despite the lack of significantly elevated blood alcohol concentrations, the behavioral consequences and subjective effects associated with repeated use of devices capable of delivering alcohol vapor are yet to be determined. No studies have focused on vulnerable populations, such as adolescents or individuals with alcohol use disorder, who may be most at risk of problems associated with alcohol inhalation.

Ethyl glucuronide and ethyl sulfate assays in clinical trials, interpretation, and limitations: results of a dose ranging alcohol challenge study and 2 clinical trials.

BACKGROUND: The ethanol metabolites, ethyl glucuronide (EtG) and ethyl sulfate (EtS), are biomarkers of recent alcohol consumption that provide objective measures of abstinence. Our goals are to better understand the impact of cutoff concentration on test interpretation, the need for measuring both metabolites, and how best to integrate test results with self-reports in clinical trials. METHODS: Subjects (n = 18) were administered, 1 week apart, 3 alcohol doses calibrated to achieve blood concentrations of 20, 80, and 120 mg/dl, respectively. Urinary EtG/EtS was measured at timed intervals during a 24-hour hospitalization and twice daily thereafter. In addition, participants from 2 clinical trials provided samples for EtG/EtS and drinking histories. Cutoffs for EtG/EtS of 100/50, 200/100, and 500/250 ng/ml were evaluated. RESULTS: Twelve hours following each challenge, EtG was always positive at the 100 and 200 cutoffs, but at 24 hours sensitivity was poor at all cutoffs following the low dose, and poor after 48 hours regardless of dose or cutoff. Similarly, in the clinical trials EtG sensitivity was good for detecting any drinking during the last 24 hours at the 2 lowest cutoffs, but under 40% during the last 24 to 48 hours. Sensitivity was reduced at the 500 ng/ml cutoff. Discrepancies between EtG and EtS were few. Comparison of self-reports of abstinence and EtG-confirmed abstinence indicated underreporting of drinking. CONCLUSIONS: Any drinking the night before should be detectable the following morning with EtG cutoffs of 100 or 200 ng/ml. Twenty-four hours after drinking, sensitivity is poor for light drinking, but good for heavier consumption. At 48 hours, sensitivity is low following 6 drinks or less. Increasing the cutoff to 500 ng/ml leads to substantially reduced sensitivity. Monitoring both EtG and EtS should usually be unnecessary. We recommend EtG-confirmed self-reports of abstinence for evaluation of outcomes in clinical trials.

Smoking cessation is followed by increases in serum bilirubin, an endogenous antioxidant associated with lower risk of lung cancer and cardiovascular disease.

INTRODUCTION: Lower concentrations of serum bilirubin, an endogenous antioxidant, have been associated with risk of many smoking-related diseases, including lung cancer and cardiovascular disease, and current smokers are reported to have lower bilirubin levels than nonsmokers and past smokers. This study evaluates the effects of smoking cessation on bilirubin levels. METHODS: In a secondary analysis of a 6-week placebo-controlled trial of naltrexone for smoking cessation, indirect and total bilirubin concentrations were evaluated at baseline and following smoking cessation. Individuals who were continuously abstinent for 6 weeks (n = 155) were compared to those who were not (n = 193). Participants reported smoking ≥ 20 cigarettes daily at baseline and received smoking cessation counseling, 21 mg nicotine patch daily, and either placebo or 1 of 3 doses of naltrexone (25, 50, or 100mg) for 6 weeks. Change in indirect and total bilirubin following the quit date was measured at Weeks 1, 4, and 6 compared to baseline. RESULTS: Individuals who were continuously abstinent from smoking, independent of naltrexone condition, showed a significantly greater mean increase in indirect (~unconjugated) bilirubin (0.06 mg/dl, SD = 0.165) compared to those who did not (mean = 0.02, SD = 0.148, p = .015). Similar results were obtained for total bilirubin (p = .037). CONCLUSIONS: Smoking cessation is followed by increases in bilirubin concentration that have been associated with lower risk of lung cancer and cardiovascular disease.

Acute effects of inhaled menthol on the rewarding effects of intravenous nicotine in smokers.

OBJECTIVE: This double-blind, placebo controlled study examined whether menthol inhaled from an electronic cigarette (e-cigarette) would change subjective and withdrawal alleviating effects of intravenous nicotine in young adult smokers. METHODS: A total of 32 menthol-preferring smokers and 25 non-menthol-preferring smokers participated in the study that consisted of a random sequence of three different inhaled menthol conditions (0.0%, 0.5%, and 3.2%) across three test sessions (a single menthol condition per session). In each test session (performed at least 24 hours apart), a random order of saline, and two different nicotine infusions of 0.25 mg and 0.5 mg/70 kg of bodyweight were administered, one hour apart, concurrent with menthol inhalation. RESULTS: While menthol did not alter the positive subjective effects of nicotine, menthol significantly enhanced aversive effects of nicotine in non-menthol-preferring smokers and reduced smoking urges in menthol-preferring smokers. In addition, menthol-preferring smokers reported blunted positive subjective responses to nicotine and less severe nicotine withdrawal after overnight nicotine deprivation. Finally, compared to non-menthol-preferring smokers, menthol-preferring smokers had a significantly lower baseline nicotine metabolite ratio indicating slower nicotine metabolism within our sample of menthol-preferring smokers. CONCLUSIONS: Our findings did not support an enhancement of nicotine's positive subjective effects from inhaled menthol. However, as compared to non-menthol-preferring smokers, menthol-preferring smokers had blunted positive subjective responses to nicotine and reduced overnight withdrawal severity that may be partly due to inhibition of nicotine metabolism from chronic exposure to inhaled menthol. Collectively, these results reveal a more complex and nuanced role of inhaled menthol in smokers than previously recognized.

Effects of acute abstinence, reinstatement, and mecamylamine on biochemical and behavioral measures of cigarette smoking in schizophrenia.

BACKGROUND: Schizophrenics have higher rates of smoking than the general population, and more difficulty with smoking cessation. However, there has been little study of differences between schizophrenics and controls with respect to biochemical and behavioral indices of smoking. We compared smokers with schizophrenia (SS; n=27) and control smokers (CS; n=26) on smoking and psychiatric outcomes at baseline, during acute smoking abstinence and reinstatement, and with pre-treatment using the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MEC) in a human laboratory setting. METHODS: Biochemical (e.g., plasma nicotine) and behavioral (e.g., craving, withdrawal) outcomes were assessed at baseline, after overnight abstinence, and after smoking reinstatement during three consecutive test weeks. Each week, participants received one of three doses of MEC (0.0, 5.0, or 10.0 mg/dayx3 days) in a randomized, counterbalanced manner. RESULTS: Compared to CS, SS displayed similar levels of craving and withdrawal, but higher plasma nicotine and cotinine levels, and cotinine/CPD ratio. During reinstatement, SS consumed significantly more cigarettes than CS, but MEC did not significantly alter indices of smoking, psychiatric symptoms, or cigarette consumption during reinstatement. CONCLUSIONS: 1) The reinforcing effects of smoking may be increased in SS versus CS after overnight abstinence; 2) the lack of effects of nAChR antagonism may suggest that non-nicotinic components of cigarettes may contribute to the behavioral effects of smoking in both SS and CS; and 3) consistent with previous studies, SS may exhibit higher baseline levels of nicotine and cotinine, and greater extraction of nicotine per cigarette than CS.

Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms.

BACKGROUND: Cigarette smoking rates in schizophrenia are higher than in the general population. OBJECTIVES: To determine whether cigarette smoking modifies cognitive deficits in schizophrenia and to establish the role of nicotinic acetylcholine receptors (nAChRs) in mediating cigarette smoking-related cognitive enhancement. DESIGN: Neuropsychological assessments were performed at smoking baseline, after overnight abstinence, and after smoking reinstatement across 3 separate test weeks during which subjects were pretreated in a counterbalanced manner with the nonselective nAChR antagonist mecamylamine hydrochloride (0, 5, or 10 mg/d). PARTICIPANTS: Twenty-five smokers with schizophrenia and 25 control smokers. SETTING: Outpatient mental health center. MAIN OUTCOME MEASURES: Visuospatial working memory (VSWM) and Continuous Performance Test (CPT) scores. RESULTS: In smokers with schizophrenia and control smokers, overnight abstinence led to undetectable plasma nicotine levels and an increase in tobacco craving. While abstinence reduced CPT hit rate in both groups, VSWM was only impaired in smokers with schizophrenia. Smoking reinstatement reversed abstinence-induced cognitive impairment. Enhancement of VSWM and CPT performance by smoking reinstatement in smokers with schizophrenia, but not the subjective effects of smoking, was blocked by mecamylamine treatment. CONCLUSIONS: Cigarette smoking may selectively enhance VSWM and attentional deficits in smokers with schizophrenia, which may depend on nAChR stimulation. These findings may have implications for understanding the high rates of smoking in schizophrenia and for developing pharmacotherapies for cognitive deficits and nicotine dependence in schizophrenia.

The effects of alcohol-containing e-cigarettes on young adult smokers.

BACKGROUND: The liquids (e-liquids) used in an electronic cigarette (e-cigarette) contain myriad chemicals without adequate human inhalation safety data. Furthermore, the absence of e-liquid labeling requirements poses a formidable challenge to understanding how e-liquid constituents may promote nicotine addiction and/or have independent or synergistic biological effects when combined with nicotine. Ethyl alcohol is such a constituent, but has received little scientific interest in this context. METHODS: Using a randomized, double blind, crossover design, acute changes in subjective drug effects, motor performance and biochemical measures of alcohol and nicotine intake were evaluated after directed and ad lib puffing from two commercially available e-liquids containing nicotine (8 mg/ml), vanilla flavor and either 23.5% (high) or 0.4% (trace) alcohol. RESULTS: While no differences in subjective drug effects were observed between alcohol conditions, performance on the Purdue Pegboard Dexterity Test (PPDT) improved under the trace, but not under the 23.5% alcohol condition. Although plasma alcohol levels remained undetectable during testing, urine ethyl glucuronide (EtG), an alcohol metabolite, became measurable in three participants after puffing from the 23.5% alcohol e-cigarette. CONCLUSIONS: Brief use of a widely available type of e-cigarette containing an e-liquid purchased from an internet vendor can negatively impact psychomotor performance and in some instances, produce detectable levels of a urine alcohol metabolite. Given the widespread and unregulated use of e-cigarettes, especially by youth and other vulnerable populations, further studies are needed to evaluate both the acute safety and long-term health risks of using alcohol-containing e-cigarettes.

Neonatal isolation alters the estrous cycle interactions on the acute behavioral effects of cocaine.

We demonstrated that neonatal isolation (ISO) increases acquisition of cocaine self-administration and alters psychostimulant-induced ventral striatal dopamine and serotonin levels in female rats. Both dopamine and serotonin modulate the behavioral effects of cocaine and these effects can vary across estrous stages. We now test whether ISO modifies the manner in which estrous stage affects the acute behavioral responses to cocaine. Litters were assigned to ISO (1 h/day isolation; post-natal days 2-9) or non-handled (NH) conditions. In Experiment 1, the ability of cocaine (0.3-30 mg/kg; IP) to disrupt schedule-controlled responding for food was assessed in proestrus, estrus, and diestrus stages. Diestrus and proestrus NH females showed increased response rates at low cocaine doses and decreased rates at higher doses relative to baseline. In contrast, estrus NH females showed decreased responding across all doses. ISO eliminated this estrous stage distinction; only decreased responding to high cocaine doses were seen. Yet, estrous cyclicity during food restriction (Experiment 2) did not differ by group. To confirm this ISO effect, proestrus or estrus rats were administered cocaine (0, 5, 10 mg/kg; IP) and activity monitored in Experiment 3. Locomotor activity differed by estrous stage in NH but not ISO rats. Cocaine plasma levels (Experiment 4) at the time of peak behavioral activity did not differ by group or estrous stage. Results extend prior studies to show estrous stage alters the behavioral effects of cocaine. Neonatal isolation eliminates these effects perhaps reflecting alterations in accumbens monoamine levels or the effects of estrogen on this system.

Acute alcohol consumption elevates serum bilirubin: an endogenous antioxidant.

BACKGROUND: Moderate alcohol consumption has been associated with both negative and favorable effects on health. The mechanisms responsible for reported favorable effects remain unclear. Higher (not necessarily elevated) concentrations of serum bilirubin, an antioxidant, have also been associated with reduced risk of cardiovascular disease and all-cause mortality. This study tests the hypothesis that single dose alcohol consumption elevates bilirubin providing a potential link between these observations. METHODS: 18 healthy individuals (eight cigarette smokers) were administered alcohol, calibrated to achieve blood concentrations of 20, 80 and 120 mg/dL, in random order in three laboratory sessions separated by a week. Each session was preceded by and followed by 5-7 days of alcohol abstinence. Serum bilirubin was measured at 7:45 a.m. prior to drinking, at 2p.m., and at 7:45 the next morning. Mixed effects regression models compared baseline and 24h post-drinking bilirubin concentrations. RESULTS: Total serum bilirubin (sum of indirect and direct) concentration increased significantly after drinking from baseline to 24h in non-smokers (from M = 0.38, SD = 0.24 to M = 0.51, SD = 0.30, F(1,32.2) = 24.24, p<.0001) but not in smokers (from M = 0.25, SD = 0.12 to M = 0.26, SD = 0.15, F(1,31.1) = 0.04, p = 0.84). In nonsmokers the indirect bilirubin concentration and the ratio of indirect (unconjugated) to direct (conjugated) bilirubin also increased significantly. CONCLUSIONS: Alcohol consumption leads to increases in serum bilirubin in nonsmokers. Considering the antioxidant properties of bilirubin, our findings suggest one possible mechanism for the reported association between alcohol consumption and reduced risk of some disorders that could be tested in future longitudinal studies.

Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study.

BACKGROUND: Although several antidepressants are now available, all have limited efficacy and a delayed onset of action. The current study was undertaken as a proof of the concept that combining norepinephrine and serotonin reuptake inhibition would be more effective and act more rapidly than either drug alone. METHODS: Inpatients with nonpsychotic unipolar major depression and a Hamilton Depression Rating Scale (HAMD) score of at least 18 after 1 week of hospitalization without antidepressant medication were randomized to 6 weeks of treatment with fluoxetine (FLX) 20 mg/day, desipramine (DMI) adjusted to an adequate plasma level, or the combination of FLX 20 mg/day and DMI, given under double-blind conditions. Twenty-four-hour DMI levels were used to rapidly adjust DMI dose to achieve a therapeutic level and to anticipate the enzyme-inhibiting effects of FLX. Treatment-resistant patients were stratified. Patients were rated with the HAMD and the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Thirty-nine patients began treatment. One patient withdrew consent. The DMI-FLX combination was significantly more likely to result in remission on the MADRS than either FLX or DMI alone [53.8% vs. 7.1% and 0%, respectively; chi(2)(2) = 13.49, p =.001]. The advantage for combined treatment was not explained by history of treatment resistance or by drug plasma concentrations. Rapid response, at 1 or 2 weeks, was neither statistically nor meaningfully greater with combined treatment. CONCLUSIONS: This study supports the hypothesis that the combination of a noradrenergic and serotonergic agent is more likely to result in remission than either selective agent alone during a 6-week treatment period.

Disulfiram facilitates the development and expression of locomotor sensitization to cocaine in rats.

BACKGROUND: Disulfiram (DS; Antabuse) inhibits dopamine-beta-hydroxylase leading to increased brain dopamine levels and shows treatment efficacy for cocaine addiction. Yet few preclinical studies have been performed. This study establishes the effects of DS on locomotor sensitization to cocaine in rats. METHODS: Rats were administered vehicle, cocaine (10 mg/kg; intraperitoneally [IP]), or DS (50 or 100 mg/kg; IP) alone or in combination for 5 days (development phase). Locomotor activity was measured for 60-min each day. After a 10-day drug washout, rats were administered cocaine, and locomotor activity was measured (expression phase). Plasma cocaine levels were assessed in separate groups of rats administered one of two cocaine doses (0 or 10 mg/kg) and one of two DS doses (0 or 100 mg/kg) for 5 days. Ten days later, blood was collected 60-min postcocaine injection. RESULTS: The development of cocaine locomotor sensitization was facilitated by DS even though DS alone had minimal effect on activity levels. Furthermore, expression of sensitization was greatest in rats previously administered DS, an effect that cannot be attributed to altered plasma cocaine levels. CONCLUSIONS: Because DS shows treatment efficacy for cocaine addiction, results from this study suggest potential treatment agents should enhance, not attenuate, locomotor sensitization in rats.

A preliminary placebo-controlled trial of selegiline hydrochloride for smoking cessation.

BACKGROUND: Since dopaminergic mechanisms appear to be involved in nicotine dependence, we studied the safety and efficacy of the monoamine oxidase B inhibitor selegiline hydrochloride compared with placebo for smoking cessation in nicotine-dependent cigarette smokers. METHODS: Forty subjects with DSM-IV nicotine dependence were randomized to: 1) selegiline hydrochloride (5 mg p.o. twice daily) or 2) placebo in an 8-week trial. Outcome measures included smoking cessation rates, treatment retention, and medication side effects. RESULTS: Selegiline hydrochloride increased trial end point (week 8) 7-day point prevalence smoking cessation rates (selegiline hydrochloride, 9/20 [45.0%]; placebo, 3/20 [15.0%], odds ratio = 4.64, 95% CI, 1.02-21.00, p <.05), and smoking cessation rates during the last 4 weeks of the trial (selegiline hydrochloride, 6/20 [30.0%]; placebo, 1/20 [5.0%], odds ratio = 8.14, 95% CI, 0.88-75.48, p =.07) in comparison with placebo. Six-month follow-up 7-day point prevalence smoking cessation rates were reduced compared with trial end point (selegiline hydrochloride, 4/20 [20.0%]; placebo, 1/20 [5.0%], odds ratio = 4.75, 95% CI, 0.48-46.91, p =.18). Treatment retention was similar between drug and placebo groups (p =.13), and selegiline hydrochloride was well tolerated in cigarette smokers. CONCLUSION: This preliminary study suggests that selegiline (10 mg/day) is safe for use and enhances smoking cessation rates compared with placebo in nicotine-dependent cigarette smokers.

A double-blind, placebo-controlled, randomized clinical trial of oral selegiline hydrochloride for smoking cessation in nicotine-dependent cigarette smokers.

AIM: The primary aim of this study was to determine the safety and efficacy of the monoamine oxidase-B (MAO-B) inhibitor selegiline hydrochloride (SEL, l-Deprenyl; Eldepryl) as an aid for smoking cessation in cigarette smokers. METHODS: One hundred and one nicotine-dependent adult cigarette smokers without current psychiatric or substance use disorders participated in this 8-week randomized, double-blind, placebo-controlled trial. Participants received either SEL (5mg bid, n=51) or placebo (PLO, n=50), in combination with brief (<10 min) manualized smoking cessation counseling. The main smoking outcome measures were 7-day point prevalence abstinence at end of trial (EOT), 4-week continuous smoking abstinence at end of trial (CA), and 7-day point prevalence abstinence at 6-month follow-up (6MFU). Abstinence was determined by an absence of self-reported cigarette smoking and biochemically verified by expired breath carbon monoxide and plasma cotinine levels. RESULTS: Rates of smoking abstinence did not differ by medication group (EOT: SEL=16%, PLO=20%, p=0.57; CA: SEL=14%, PLO=18%, p=0.56; 6MFU: SEL=12%, PLO=16%, p=0.54). Adverse events were modest and comparable between medication groups. Participants receiving SEL were more likely than those receiving PLO to report dry mouth (25.5% versus 8.2%, p<0.05). CONCLUSIONS: Our results suggest that SEL was safe and well-tolerated by adult cigarette smokers, but did not improve smoking abstinence rates compared to PLO.

A placebo-controlled trial of bupropion combined with nicotine patch for smoking cessation in schizophrenia.

BACKGROUND: Individuals with schizophrenia smoke at higher rates (58%-88%) than the general population (approximately 22%), and have difficulty quitting. We determined whether the combination of sustained-release (SR) bupropion (BUP) with the transdermal nicotine patch (TNP) was well-tolerated and superior to placebo (PLO)+TNP for smoking cessation in schizophrenia. METHODS: A 10-week, double-blind, placebo-controlled trial of BUP (300 mg/day) in combination with TNP (21 mg/24h) for 58 outpatient smokers with schizophrenia was conducted. Primary outcome measures were continuous smoking abstinence in the last 4 weeks of the trial (Days 43-70) and 7-day point prevalence abstinence at 6 months post-target quit date (TQD) (week 26). RESULTS: Smokers assigned to the BUP+TNP group (n = 29) were more likely to achieve continuous smoking abstinence (8/29, 27.6%) than the PLO+TNP group (n = 29, 1/29, 3.4%) [Fisher's Exact Test, p < .05]; at 6-months post-TQD, 4/29 (13.8%) versus 0/29 (0.0%) achieved 7-day point prevalence smoking abstinence (p = .11). Neither bupropion SR nor smoking abstinence significantly altered the positive or negative symptoms of schizophrenia. The combination was well-tolerated in smokers with schizophrenia. CONCLUSIONS: Combination therapy with bupropion SR+TNP versus placebo+TNP is well-tolerated and significantly improved short-term smoking abstinence in smokers with schizophrenia.

Maternal fluoxetine treatment in the postpartum period: effects on platelet serotonin and plasma drug levels in breastfeeding mother-infant pairs.

OBJECTIVE: Postpartum major depression, a frequently (10%) occurring complication of childbirth, adversely affects the mother's functioning, the mother-infant relationship, and the child's subsequent development and propensity for later psychopathology. Although selective serotonin reuptake inhibitors (SSRIs) are effective in treating postpartum depression, concerns have been raised regarding their use in lactating women. Although plasma drug levels of infants who are exposed to SSRIs through breast milk are low compared with those typically seen in patients, infant levels in some reports do seem to be at or near the drugs' reported affinities (K(D)s) and IC(50)s for inhibition at the serotonin (5-hydroxytryptamine [5-HT]) transporter. The impact of central serotonin 5-HT modulation by SSRIs during critical periods of brain development is unknown. These concerns have led our group to examine whether exposure through breast milk has a discernible effect on platelet 5-HT uptake. Taking advantage of the similarities between platelet and neuronal serotonin transporters, we previously used measurements of platelet 5-HT before and during maternal sertraline treatment to determine the degree of 5-HT transporter blockade in breastfed infants. We found that infants who were exposed to sertraline through their mothers' breast milk experienced little to no change in platelet 5-HT levels, suggestive of minimal effects on peripheral and central 5-HT transporter blockade. Compared with sertraline and most other SSRIs, fluoxetine and its active metabolite, norfluoxetine, have substantially longer plasma half-lives, and both compounds have been found in measurable quantities in plasma of nursing infants. Thus, to extend our previous work in this area, we measured platelet 5-HT levels and plasma drug levels in breastfeeding mother-infant pairs before and during maternal treatment with fluoxetine. METHODS: Maternal and infant transporter blockade was assessed by measurement of platelet 5-HT in 11 breastfeeding mother-infant pairs before and after 4 to 12 weeks of maternal fluoxetine (20-40 mg/d) treatment for postpartum depression. The study was approved by the Human Investigation Committee of Yale University School of Medicine, and each mother (mean age: 34.5 years; standard deviation [SD]: 5.3) gave written informed consent. Whole-blood 5-HT levels and plasma fluoxetine and norfluoxetine levels were determined by high-performance liquid chromatography. RESULTS: Five mothers were taking 20 mg of fluoxetine daily, 4 were taking 30 mg daily, and 2 were taking 40 mg daily. Mean infant age at the start of the study was 16.8 (SD: 8.8) weeks. All infants except 1 were <6 months of age and 4 were <3 months of age when their mothers began treatment. Six infants were breastfed exclusively; the remaining were breastfed between 3 and 8 times daily and were given supplemental feedings. Mean maternal postexposure 5-HT levels of 22.9 ng/mL (SD: 12.5) were markedly lower than mean preexposure (baseline) levels of 156.6 ng/mL (SD: 71.4; paired t = 6.9, df = 10). In contrast, the mean infant pre- and postexposure 5-HT concentrations of 217.1 (SD: 66.5) and 229.9 (SD: 83.5) ng/mL, respectively, were similar (paired t = -0.24, df = 10). However, the 1 infant with measurable plasma fluoxetine had a substantial decline in 5-HT to 40% of baseline. In samples obtained from the same infant 4 months later, plasma drug levels were undetectable (<1 ng/mL) and the platelet serotonin levels were no longer reduced (12% increase from baseline). CONCLUSIONS: The marked declines (to 9%-28% of baseline) in platelet 5-HT concentrations seen in mothers who were treated with the SSRI fluoxetine were similar to those observed in our study of sertraline in breastfeeding and other previous studies. In contrast, all but 1 infant experienced little or no decline in whole-blood (platelet) 5-HT concentrations after exposure to fluoxetine through breast milk. The substantial drop in platelet 5-HT seen in 1 infant and the coupling of this drop with measurable plasma fluoxetine leves drop with measurable plasma fluoxetine level raises some concern. Possible reasons for the infant's measurable plasma fluoxetine level include his mother's high plasma drug level and his being breastfed exclusively. However, the observations may be coincidental, and the infant experienced no discernible adverse effects. These data suggest that most infants may continue to breastfeed without experiencing meaningful changes in platelet 5-HT transport while their mothers are treated with 20 to 40 mg of fluoxetine daily. Given the limited data regarding occurrence and extent of SSRI exposure and the uncertainties concerning the possible effects of exposure, it is premature to propose treatment guidelines. Our own advice to women who are thinking of combining breastfeeding and SSRI treatment will weigh a range of factors, including severity of postpartum depression, any demonstrated preferential response to a specific SSRI, and the mother's commitment to breastfeeding. Additional research is needed to establish more definitively the frequency of physiologically meaningful infant SSRI exposure during breastfeeding and to determine the behavioral consequences of such exposure.