Effector membrane translocation biosensors reveal G protein and ßarrestin coupling profiles of 100 therapeutically relevant GPCRs.

The recognition that individual GPCRs can activate multiple signaling pathways has raised the possibility of developing drugs selectively targeting therapeutically relevant ones. This requires tools to determine which G proteins and ßarrestins are activated by a given receptor. Here, we present a set of BRET sensors monitoring the activation of the 12 G protein subtypes based on the translocation of their effectors to the plasma membrane (EMTA). Unlike most of the existing detection systems, EMTA does not require modification of receptors or G proteins (except for Gs). EMTA was found to be suitable for the detection of constitutive activity, inverse agonism, biased signaling and polypharmacology. Profiling of 100 therapeutically relevant human GPCRs resulted in 1500 pathway-specific concentration-response curves and revealed a great diversity of coupling profiles ranging from exquisite selectivity to broad promiscuity. Overall, this work describes unique resources for studying the complexities underlying GPCR signaling and pharmacology.

Tobacco and alcohol use among firefighters during their first 3 years of service.

Firefighters constitute an understudied occupational group that are exposed to a great deal of occupational stress including potentially traumatic stress. As such, higher prevalence rates of posttraumatic stress disorder (PTSD) and substance use disorders have been observed within this population; however, very little is known about the trajectories of health-risk behaviors among firefighters in response to occupational stress over time. The present study enrolled 322 fire service recruits from 7 urban U.S. professional fire departments and followed them through the first 3 years of service. All enrollees were free of Axis I psychopathology at the time of baseline assessments, which were conducted while participants were still enrolled in the fire academy. We hypothesized that: (a) firefighters who used tobacco would have higher levels of alcohol use over time; and (b) firefighters with higher levels of traumatic exposure and mental health symptoms would evidence a stronger multisubstance risk pattern. Analyses provided support for our first hypothesis and revealed that depressive symptoms (but neither trauma exposure nor PTSD symptoms) moderated the alcohol-tobacco relationship. The clinical and public safety implications of these results are discussed. (PsycINFO Database Record

Posttransplantation Outcomes in Veterans With Serious Mental Illness.

BACKGROUND: Anticipating poor recovery due to impaired self-management and appointment-keeping, clinicians may consider serious mental illness (SMI) a significant concern in organ transplantation. However, little empirical evidence exists regarding posttransplantation outcomes for patients with SMI. METHODS: This study analyzed health services data to evaluate posttransplantation 3-year survival by SMI status in a nationwide cohort of patients in the Veterans Health Administration (VHA). RESULTS: A total of 960 recipients of solid organ or bone marrow transplants were identified from Veterans Health Administration administrative data extracts for fiscal years 2006 to 2009. Of these, 164 (17%) had an SMI diagnosis before transplantation (schizophrenia, posttraumatic stress, major depressive, and bipolar disorders); 301 (31%) had some other mental illness diagnosis (such as anxiety, adjustment reactions, or substance abuse); and 495 (52%) had no mental health diagnosis. Twenty-two patients (2%) required retransplantation and 208 patients (22%) died during follow-up. Data on whether these were primary or repeat transplantations were unavailable. Rates of attendance at postoperative outpatient visits and number of months for which immunosuppressive drugs fills were recorded were similar among mental illness groups, as were rates of diagnosed immunological rejection. Three-year mortality was equivalent among mental health groups: no mental health (19%) versus other mental illness (23%) versus SMI (27%; χ(2) = 5.11; df = 2; P = .08). In adjusted survival models, no effect of mental health status was observed. CONCLUSIONS: Serious mental illness diagnosis does not appear to be associated with adverse transplantation outcomes over the first 3 years; however, a potentially diverging survival curve may portend higher mortality at 5 years.

Polypharmacy with antipsychotic drugs in patients with schizophrenia: trends in multiple health care systems.

PURPOSE: Patterns of pharmacologic treatment in U.S. outpatients with schizophrenia across multiple health care settings were investigated. METHODS: Antipsychotic drug utilization by patients with schizophrenia and related disorders was analyzed using data on 119,662 patients served by the Veterans Affairs (VA) health care system in fiscal years 2005-09, data on 5,440 enrollees in two health maintenance organizations (HMOs) in 2002-09, and National Ambulatory Medical Care Survey (NAMCS) data reflecting the experience of 17.6 million U.S. residents seeking care outside federal systems during the same eight-year period. Polypharmacy was defined as the use of more than one antipsychotic agent during one year (in the VA sample) or one week (in the HMO and NAMCS samples). The association of polypharmacy with hospital admissions was assessed via multivariable logistic regression. RESULTS: Rates of antipsychotic use in the VA sample ranged from 74% to 78%, with lower and more variable rates in the NAMCS sample (69-84%) and the HMO sample (22-67%). VA patients were found to have lower polypharmacy rates (20-22%) than patients in the HMO and NAMCS samples (19-31%). In all samples evaluated, polypharmacy was associated with an increased likelihood of hospital admission (odds ratio range, 1.4-2.4). CONCLUSION: A multisystem study revealed that antipsychotic use among patients with schizophrenia varied substantially among health care systems and that nearly one fifth of patients with schizophrenia or other psychotic disorders in most of the health care systems experienced antipsychotic polypharmacy.

The effect of social anxiety on urge and craving among smokers with and without anxiety disorders.

BACKGROUND: Despite the often social nature of smoking, relatively little research has been conducted on the relationship between smoking and social anxiety disorder (SAD). METHOD: Participants (N=99) included 34 smokers without current mental health disorders, 37 smokers with SAD, and 28 smokers who met criteria for other anxiety disorder diagnoses (e.g., panic disorder or generalized anxiety disorder, but not SAD). Nicotine and placebo patches were administered to participants in a counterbalanced manner across two assessment days. Urge and craving were assessed before and after a 5-h nicotine absorption/deprivation period. RESULTS: Compared to smokers without current mental health disorders, smokers with SAD did not report greater nicotine dependence, but did endorse greater motivation to use nicotine to avoid negative outcomes. In addition, after controlling for demographic variables, smoking characteristics, pre-deprivation urge and craving, and other anxiety/depression symptoms, social anxiety symptoms uniquely predicted urge and craving in the placebo patch condition; however, social anxiety had no influence on urge and craving in the nicotine patch condition. CONCLUSIONS: These findings suggest that one potential reason that smokers with SAD may have worse cessation outcomes is that they may experience higher levels of craving and urge to smoke during quit attempts. Thus, during a quit attempt, particularly in the absence of nicotine replacement therapy, smokers with SAD are likely to benefit from additional treatment aimed at managing or reducing their social anxiety symptoms.

Differences in drinking patterns, occupational stress, and exposure to potentially traumatic events among firefighters: predictors of smoking relapse.

BACKGROUND AND OBJECTIVES: Despite the increased awareness regarding the risks of cigarette smoking, this behavior continues to be a serious public health concern. As such, the goal of the current study was to examine risk factors for smoking relapse among individuals employed through fire service. METHODS: In this report, drinking changes, trauma exposure, and occupational stress were compared among firefighters (N = 81) who reported a relapse to cigarette smoking (n = 27), a lifetime former history of smoking (n = 27), or no history of smoking (n = 27). Mechanisms behind tobacco relapse occurring after employment in fire service were explored. RESULTS: Firefighters who relapsed to smoking, when compared to their nonsmoking peers, had higher rates of weekly alcohol consumption throughout their first year of fire service and had greater increases in drinking from preacademy to postacademy. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Gaining a better understanding of these behaviors within this understudied and high-risk population may provide valuable information that can be used in designing future relapse prevention strategies as well as smoking cessation interventions.

Transdermal nicotine during cue reactivity in adult smokers with and without anxiety disorders.

Transdermal nicotine almost doubles tobacco cessation rates; however, little is known about what happens to smokers during the quit process when they are wearing the nicotine patch and are confronted with high-risk smoking triggers. This is particularly important for smokers with psychological disorders who disproportionately represent today's smokers and have more trouble quitting. Using a mixed between- and within-subjects design, smokers with anxiety disorders (n=61) and smokers without any current Axis I disorders (n=38) received transdermal nicotine (21 mg) or a placebo patch over two assessment days separated by 48 hr. Urge to smoke was evaluated during a 5-hr patch absorption period (reflecting general smoking deprivation) and during imaginal exposure to theoretically high-risk triggers containing smoking cues, anxiety cues, both, or neutral cues. No differences were observed between smokers with and without anxiety disorders. Significant Patch×Time and Patch×Cue Content interactions were found. Both patch conditions experienced an increase in urge during the deprivation period, but postabsorption urge was significantly higher in the placebo condition, suggesting that transdermal nicotine attenuated the degree to which urge to smoke increased over time. During the cue reactivity trials, when participants received the nicotine patch, they experienced significantly lower urge in response to both smoking-only and neutral cues, but not when anxiety cues were present (alone or in combination with smoking cues). These data suggest that transdermal nicotine alleviates urge only under certain circumstances and that adjunctive interventions are likely necessary to address smoking urges in response to spikes in distress among smokers trying to quit.

Measuring smoking-related preoccupation and compulsive drive: evaluation of the obsessive compulsive smoking scale.

RATIONALE: Tobacco use for many people is compulsive in nature. Compelling theories of how smoking becomes compulsive exist but are largely based on extrapolation from neuroscience findings. Research on smokers is impeded, in part, by a lack of instruments that specifically measure compulsive smoking. OBJECTIVE: This study evaluated the measurement structure and validity of the Obsessive Compulsive Smoking Scale (OCSS), a ten-item questionnaire designed to measure compulsive smoking. METHODS: Participants were 239 daily smokers (>/=1 cigarette/day), including 142 students at a public university in Chicago and 97 veterans treated at the VA Boston Healthcare System. The OCSS and questionnaires measuring current and past smoking, cigarette craving, automatic smoking, and nicotine dependence were administered. RESULTS: Factor analysis with maximum likelihood extraction and oblique rotation revealed two correlated underlying factors, interpreted as "Preoccupation with Smoking" and "Compulsive Drive." The measurement structure was consistent across students and veterans, and confirmed in an independent sample of adults (n = 95). Veterans exhibited higher OCSS scores (full scale and subscales) than students. Across groups, higher OCSS scores were positively correlated with smoking intensity, craving, and nicotine dependence. OCSS full-scale and compulsive drive scores, but not smoking preoccupation scores, were inversely correlated with past month smoking reduction and minutes since last cigarette. CONCLUSIONS: The OCSS is a valid and reliable inventory for measuring the degree to which daily smokers are preoccupied with smoking and engage in compulsive tobacco use, and may be useful for advancing understanding of core smoking phenotypes or for tailoring cessation therapies.

Implications of participant self-selection for generalizability: who participates in smoking laboratory research?

The generalizability of data from laboratory smoking studies using volunteer samples is debatable. We tracked potential participants from first contact with research staff through screening to study completion. We found that a minority of individuals were ultimately enrolled in the study. Failure to enroll was as often a function of participant lack of attendance at the laboratory as a function of ineligibility. With some exceptions, groups of potential participants were similar regarding demographic characteristics and substance use history. These findings support the generalizability of the sample and highlight the importance of documenting details of study eligibility and participation. The study's limitations are noted.

Differences between daily smokers, chippers, and nonsmokers with co-occurring anxiety and alcohol-use disorders.

Tobacco use is disproportionately represented among both alcohol-use disorders (AUDs) and anxiety disorders (ANX) compared to the general population [Kalman, D. A., Morissette, S. B., & George, T. P. (2005). Co-morbidity of nicotine and tobacco use in psychiatric and substance use disorders. The American Journal on Addictions, 14, 1-18]. Despite this common overlap, little is known about how smokers with co-occurring AUD-ANX differ from their nonsmoking counterparts. Seventy-two patients participated in a larger clinical trial evaluating the efficacy of venlafaxine and cognitive-behavioral therapy for AUD-ANX. Differences between daily smokers (n=23), chippers (n=12) and nonsmokers (n=37) with AUD-ANX were examined with respect to intensity and frequency of alcohol use, anxiety symptoms, depressed mood, and stress. Point prevalence of current daily smoking was 31.9%, which is considerably lower than traditionally reported in AUD studies. Consistent with predictions, daily smokers reported higher levels of alcohol dependence, average drinks per drinking occasion, and peak blood concentration levels in a day than nonsmokers during the 90 days prior to assessment. Chippers were nonsignificantly different from either smokers or nonsmokers. Smokers and nonsmokers did not differ with respect to percent heavy drinking days or emotional symptoms.

Anxiety sensitivity and perceived control over anxiety-related events: associations with smoking outcome expectancies and perceived cessation barriers among daily smokers.

The present investigation examined the extent to which the cognitive factors of anxiety sensitivity (AS) and perceived control over anxiety-related events are independently related to smoking outcome expectancies and perceived barriers to quitting. Participants were 125 community-recruited adult, daily smokers. Consistent with hypotheses, AS and perceived control over anxiety-related events independently and significantly predicted smokers' expectancies for negative affect reduction from smoking, whereas only AS predicted expectancies for negative personal consequences from smoking. Also as hypothesized, AS and perceived control over anxiety-related events each independently and significantly predicted level of general perceived barriers to quitting smoking. All of the observed significant effects were evident above and beyond the variance accounted for by gender, alcohol consumption, number of cigarettes smoked per day, and negative affectivity. Together, these findings further the literature on the relation between anxiety-relevant cognitive factors and psychological smoking processes.

Anxiety, anxiety disorders, tobacco use, and nicotine: a critical review of interrelationships.

Smoking is highly prevalent across most anxiety disorders. Tobacco use increases risk for the later development of certain anxiety disorders, and smokers with anxiety disorders have more severe withdrawal symptoms during smoking cessation than smokers without anxiety disorders. The authors critically examined the relationships among anxiety, anxiety disorders, tobacco use, and nicotine dependence and reviewed the existing empirical literature. Future research is needed to better understand the interrelationships among these variables, including predictors, moderators, and mechanisms of action. Increased knowledge in these areas should inform prevention efforts as well as the development and improvement of smoking cessation programs for those with anxiety and other psychiatric disorders.

Differences between smokers and nonsmokers with anxiety disorders.

Epidemiological data suggest that early smoking increases the risk for emergence of certain anxiety disorders (e.g., panic disorder, generalized anxiety disorder (GAD)), and that presence of certain anxiety disorders (e.g., social anxiety) increases the risk for later development of nicotine dependence. Although some studies report a high prevalence of smoking among anxiety disorders, the extent to which smokers with anxiety disorders differ from their nonsmoking counterparts remains uncertain. Differences between smokers and nonsmokers with anxiety disorders (N=527) were examined with respect to multiple measures of theoretical and clinical interest. Compared to nonsmokers, smokers with anxiety disorders reported greater anxiety sensitivity, anxiety symptoms, agoraphobic avoidance, depressed mood, negative affect, stress and life interference; however, these differences were largely accounted for by panic disorder. No differences were found between smokers and nonsmokers regarding social anxiety, worry, obsessive-compulsive symptoms or positive affect. Differential patterns were observed when evaluating constructs within anxiety disorder diagnoses.

A psychometric evaluation of the Smoking Consequences Questionnaire-Adult in smokers with psychiatric conditions.

Rates of smoking among individuals with psychiatric conditions are much greater than those seen in the general population, yet little is known about the psychometric properties of commonly used instruments that assess smoking-related variables among smokers with psychiatric conditions. The present study examined the factor structure and psychometric characteristics of the Smoking Consequences Questionnaire-Adult (SCQ-A; Copeland, Brandon, & Quinn, 1995, Psychological Assessment, 7, 484-494) among smokers with psychiatric conditions. A confirmatory factor analysis of the instrument indicated that the factor structure derived by the instrument's authors provided an adequate fit to the data. In addition, many of the 10 subscales of the SCQ-A demonstrated adequate internal consistency as assessed by Cronbach's alpha as well as adequate test-retest reliability over the course of 1 week. Based on the data derived from this sample, the SCQ-A has adequate psychometric properties for applications involving smokers with psychiatric conditions.

Co-morbidity of smoking in patients with psychiatric and substance use disorders.

This article reviews cigarette smoking in patients with psychiatric disorders (PD) and substance use disorders (SUD). Rates of smoking are approximately 23% in the U.S. population but approximately two- to four-fold higher in patients with PD and SUD. Many remaining smokers have had repeated smoking cessation failures, possibly due to the presence of co-morbid PD and SUDs. There is modest, evidence-based support for effective treatment interventions for nicotine addiction in PD and SUD. Further research is needed to increase our understanding of nicotine addiction in PD and SUD and develop more effective treatment interventions.

Effects of transdermal nicotine during imaginal exposure to anxiety and smoking cues in college smokers.

In a 2 (patch) x 2 (smoking) x 2 (anxiety) mixed design, 52 undergraduate smokers randomly received a nicotine (21 mg) or placebo patch. After a 4-hr nicotine absorption/deprivation period, participants imagined several scenarios varying in cue content: (a) anxiety plus smoking, (b) anxiety, (c) smoking, and (d) neutral. Although smoking urge increased in both the nicotine and placebo conditions after the absorption/deprivation period, those who received the placebo reported significantly greater urge. During the cue reactivity trials, a significant Patch x Smoking x Anxiety interaction effect was observed for urge. However, participants who received nicotine still experienced moderate urges, indicating that nicotine did not attenuate cue-elicited urge. Transdermal nicotine did not diminish anxiety during the absorption/deprivation period or in response to the cues.