Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence.

Addiction to nicotine and the ability to quit smoking are influenced by genetic factors. We used functional genomic approaches (chromatin immunoprecipitation (ChIP) and whole-genome sequencing) to identify cAMP response element-binding protein (CREB) targets following chronic nicotine administration and withdrawal (WD) in rodents. We found that chronic nicotine and WD differentially modulate CREB binding to the gene for neuregulin 3 (NRG3). Quantitative analysis of saline, nicotine and nicotine WD in two biological replicates corroborate this finding, with NRG3 increases in both mRNA and protein following WD from chronic nicotine treatment. To translate these data for human relevance, single-nucleotide polymorphisms (SNPs) across NRG3 were examined for association with prospective smoking cessation among smokers of European ancestry treated with transdermal nicotine in two independent cohorts. Individual SNP and haplotype analysis support the association of NRG3 SNPs and smoking cessation success. NRG3 is a neural-enriched member of the epidermal growth factor family, and a specific ligand for the receptor tyrosine kinase ErbB4, which is also upregulated following nicotine treatment and WD. Mice with significantly reduced levels of NRG3 or pharmacological inhibition of ErbB4 show similar reductions in anxiety following nicotine WD compared with control animals, suggesting a role for NRG3 in nicotine dependence. Although the function of the SNP in NRG3 in humans is not known, these data suggest that Nrg3/ErbB4 signaling may be an important factor in nicotine dependence.

APOE ɛ4, an Alzheimer's disease susceptibility allele, and smoking cessation.

Possessing an apolipoprotein E (APOE) ɛ4 allele, advanced age and smoking are risk factors for Alzheimer's disease and cognitive decline. Deficits in cognitive function also increase risk for smoking relapse. Data from 917 adult smokers of European ancestry were pooled across three randomized trials of smoking cessation. We examined whether smokers who carry at least one ɛ4 allele (n=252) have more difficulty quitting smoking compared with noncarriers (n=665), and whether age moderated this association. The genotype by age interaction was significant for 7-day point-prevalence abstinence rates (P=0.04) and time to 7-day failure (P=0.03). Among smokers over age 60, ɛ4 carriers were less likely to quit (odds ratio=0.27, P=0.018) and relapsed more quickly (hazard ratio=3.38, P=0.001) compared with noncarriers. The genotype association with relapse was nonsignificant among younger smokers. An increased understanding of the underlying pathophysiological mechanisms of this association could facilitate the development of targeted therapies for smokers with increased risk for cognitive decline.

Gender-stratified gene and gene-treatment interactions in smoking cessation.

We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain-reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P-values for multiple correlated tests, and used a Bonferroni-corrected α-level of 5 × 10(-4) to determine system-wide significance. Four single-nucleotide polymorphisms (rs12021667, rs12027267, rs6702335, rs12039988; r2 > 0.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (odds ratio (OR) = 0.5; 95% confidence interval (CI): 0.3-0.6) at end of treatment (adjusted P < 6 × 10(-5)). rs806365 in cannabinoid receptor 1 (CNR1) had a significant male-specific gene-treatment interaction at 6-month follow-up (adjusted P = 3.9 × 10(-5)); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR = 0.04; 95% CI: 0.01-0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.

Effect of abstinence challenge on brain function and cognition in smokers differs by COMT genotype.

The val allele of the catechol-O-methyltransferase (COMT) val(158)met polymorphism has been linked with nicotine dependence and with cognitive performance in healthy volunteers. We tested the hypothesis that the val allele is a risk factor for altered brain function and cognition during nicotine abstinence as compared with the normal smoking state. Chronic smokers (n=33) were genotyped prospectively for the COMT polymorphism for balanced selection of met/met, val/met and val/val groups. A visual N-back working memory task was performed during two separate blood oxygen level-dependent (BOLD) functional magnetic resonance imaging sessions in counterbalanced order: (1) smoking as usual, and (2)>or=14 h confirmed abstinence. Significant genotype by session interactions were observed for BOLD signal in right dorsolateral prefrontal cortex (DLPFC; (P=0.0005), left DLPFC (P=0.02) and dorsal cingulate/medial prefrontal cortex (P=0.01) as well as for task reaction time (P=0.03). Smokers with val/val genotypes were more sensitive to the abstinence challenge than carriers of the met allele, with the greatest effects on BOLD signal and performance speed at the highest working memory load. These data suggest a novel brain-behavior mechanism that may underlie the increased susceptibility to nicotine dependence and smoking relapse associated with the COMT val allele. Exploration of the effects of COMT inhibitors as a possible smoking cessation aid in this group may be warranted.

Effects of atomoxetine on subjective and neurocognitive symptoms of nicotine abstinence.

Nicotine dependence has been linked to attention-deficit hyperactivity disorder (ADHD) symptoms in both clinical and general populations. This behavioural pharmacology study used a within-subject, double-blind, crossover design to test the effects of atomoxetine, a medication for ADHD, on nicotine abstinence symptoms. Fifty non treatment-seeking smokers (>/=15 cigarettes/day) completed a baseline session when they were smoking as usual and then two laboratory testing sessions after overnight abstinence and treatment with 7 days of either atomoxetine (1.2 mg/kg) or placebo. During each laboratory session, participants completed subjective measures of abstinence symptoms and performed neurocognitive tasks. In mixed effects models, atomoxetine, compared with placebo, was found to be associated with a reduction in abstinence-induced subjective withdrawal symptoms. Atomoxetine was also associated with significant reductions in self-reported smoking urges amongst smokers who scored high on a baseline measure of smoking for stimulation. However, atomoxetine had no effect on any of the cognitive tasks employed in the study. Thus, atomoxetine may reduce cravings to smoke among smokers who use nicotine to increase arousal.

Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment.

We evaluated the cost-effectiveness of a range of smoking cessation drug treatments, including varenicline, transdermal nicotine (TN), bupropion and the use of a genetic test to choose between TN and bupropion. We performed Monte Carlo simulation with sensitivity analysis, informing analyses with published estimates of model parameters and current prices for genetic testing and smoking-cessation therapy. The primary outcomes were discounted life-years (LY) and lifetime tobacco-cessation treatment costs. In the base case, varenicline treatment was optimal with an ICER, compared to bupropion, of $2985/LY saved. In sensitivity analyses, varenicline was in all cases (and bupropion in most cases) admissible; only under favorable assumptions was the genetically tailored approach competitive. Our data suggest that an untailored approach of treatment with either bupropion or varenicline is a cost-effective form of tobacco dependence treatment, but a tailored approach for selecting between TN and bupropion can be cost-effective under plausible assumptions.

Association of OPRM1 A118G variant with the relative reinforcing value of nicotine.

RATIONALE: The endogenous opioid system has been implicated in substance abuse and response to pharmacotherapies for nicotine and alcohol addiction. We examined (1) the association of the functional OPRM1 A118G variant with the relative reinforcing value of nicotine and (2) the main and interacting effects of the mu-opioid receptor antagonist naltrexone on nicotine reinforcement. METHODS: In a within-subject, double-blind human laboratory study, 30 smokers of each OPRM1 genotype (A/A vs. A/G or G/G) participated in two experimental sessions following 4 days of orally administered naltrexone 50 mg or placebo. Participants completed a validated assessment of the relative reinforcing value of nicotine. This cigarette choice paradigm assesses self-administration of 0.6 mg nicotine vs. 0.05 mg (denicotinized) cigarettes after a brief period of nicotine abstinence. RESULTS: The relative reinforcing value of nicotine (number of nicotine cigarette puffs) was predicted by a significant OPRM1 by gender interaction. Among women, the low-activity G allele (A/G and G/G) was associated with a reduced reinforcing value of nicotine; among male smokers, there was no association with genotype. Smokers carrying a G allele were also significantly less likely to differentiate the nicotine vs. denicotinized cigarettes by subjective ratings of satisfaction and strength. No evidence for an effect of naltrexone on nicotine reinforcement was found in the overall sample or in the genotype or gender subgroups. CONCLUSIONS: This study provides initial evidence for an association of the OPRM1 A118G variant with nicotine reinforcement in women.

Effects of individualized breast cancer risk counseling: a randomized trial.

BACKGROUND: Studies have shown that a majority of women with a family history of breast cancer have exaggerated perceptions of their own risk of this disease and experience excessive anxiety. In response to the need to communicate more accurate risk information to these women, specialized programs for breast cancer risk counseling have been initiated in medical centers across the United States. PURPOSE: Our purpose was 1) to evaluate the impact of a standardized protocol for individualized breast cancer risk counseling on comprehension of personal risk among first-degree relatives of index breast cancer patients and 2) to identify women most and least likely to benefit from such counseling. METHODS: This study is a prospective randomized trial comparing individualized breast cancer risk counseling to general health counseling (control). We studied 200 women aged 35 years and older who had a family history of breast cancer in a first-degree relative. Women with a personal history of cancer were excluded. Risk comprehension was assessed as the concordance between perceived "subjective" lifetime breast cancer risk and estimated "objective" lifetime risk. RESULTS: The results of logistic regression analysis showed that women who received risk counseling were significantly more likely to improve their risk comprehension, compared with women in the control condition (odds ratio [OR] = 3.5; 95% confidence interval [CI] = 1.3-9.5; P = .01). However, in both groups, about two thirds of women continued to overestimate their lifetime risks substantially following counseling. Examination of subjects by treatment interaction effects indicated that risk counseling did not produce improved comprehension among the large proportion of women who had high levels of anxious preoccupation with breast cancer at base line (P = .02). In addition, white women were less likely to benefit than African-American women (OR = 0.34; 95% CI = 0.11-0.99; P = .05). CONCLUSION: Efforts to counsel women about their breast cancer risks are not likely to be effective unless their breast cancer anxieties are also addressed. IMPLICATIONS: Attention to the psychological aspects of breast cancer risk will be critical in the development of risk-counseling programs that incorporate testing for the recently cloned breast cancer susceptibility gene, BRCA1 (and BRCA2 when that gene has also been cloned).

Enhancing adherence following abnormal Pap smears among low-income minority women: a preventive telephone counseling strategy.

BACKGROUND: Although the incidence of precancerous conditions of the cervix has recently been increasing, prompt initial and long-term follow-up care can effectively reduce unnecessary morbidity and mortality. For example, the 4-year survival rates among those individuals at greatest risk for cervical cancer (i.e., minority women of low socioeconomic status) approach 95% with early detection. Women who present with advanced disease have a much poorer outlook (0%-39% survival). Yet, high-risk individuals are least likely to adhere to recommended diagnostic regimens. PURPOSE: We tested the effectiveness of a brief telephone counseling intervention directed to low-income, inner-city women after they had received an abnormal Pap smear result. The women were counseled on the importance of having an initial and 6-month repeat follow-up diagnostic procedure (i.e., colposcopic examination of the cervix). METHODS: A randomized trial design was used to compare the effects on these women of telephone counseling with (n = 192) or without (n = 203) a booster counseling telephone call prior to the appointment for a repeat colposcopy 6 months later, with a telephone appointment confirmation/reminder call (n = 216) and with standard care (i.e., no telephone contact) (n = 217). The telephone counseling protocol probed for and addressed three psychologic barriers to adherence (i.e., attendance at appointment for colposcopy examination): 1) encoding/expectancy (e.g., did the patient understand her risk of developing cervical cancer?); 2) affective/emotional (e.g., was the woman worried about the condition and its consequences?); and 3) self-regulatory/practical (e.g., was the woman likely to forget medical appointments?). Logistic regression was used to analyze the effects of the intervention group and the type of psychologic barriers elicited on colposcopy adherence. RESULTS: The results of logistic regression analysis (using those who received an appointment confirmation/reminder telephone call as the comparison group) revealed that telephone counseling produced significantly higher adherence rates to the initial colposcopy visit compared with telephone confirmation (300 [76%] of 395 women versus 147 [68%] of 216; odds ratio [OR] = 1.50; 95% confidence interval [CI] = 1.04-2.17). Additionally, standard care resulted in significantly lower adherence rates than did telephone confirmation (109 [50%] of 217 women versus 147 [68%] of 216; OR = 0.47; 95% CI = 0.32-0.73). Regarding attendance at the 6-month repeat colposcopy appointments, the 80 patients who had received telephone counseling prior to the initial visit (and were recommended for follow-up colposcopy) were significantly more likely to adhere than were the 47 patients who had received telephone confirmation (49 [61%] of 80 women versus 17 [36.2%] of 47; OR = 2.70; 95% CI = 1.15-6.51). The 6-month adherence rates for patients in the telephone confirmation group and the standard care group (n = 30) were low and did not differ significantly (17 [36.2%] of 47 women versus nine [30.0%] of 30; OR = 1.08; 95% CI = 0.40-2.89). Forgetting medical appointments (OR = 0.31; 95% CI = 0.19-0.51) and having scheduling conflicts (OR = 0.45; 95% CI = 0.28-0.72) were also associated with lower rates of adherence. CONCLUSION: The use of telephone counseling appears to be an effective strategy for enhancing initial and long-term adherence to a follow-up cervical diagnostic procedure in a traditionally underserved population. Patients who respond to a positive Pap test result with a particular profile of psychologic barriers may require more intensive and targeted counseling interventions.

Controlled trial of pretest education approaches to enhance informed decision-making for BRCA1 gene testing.

BACKGROUND: In response to the isolation of the BRCA1 gene, a breast-ovarian cancer-susceptibility gene, biotechnology companies are already marketing genetic tests to health care providers and to the public. Initial studies indicate interest in BRCA1 testing in the general public and in populations at high risk. However, the optimal strategies for educating and counseling individuals have yet to be determined. PURPOSE: Our goal was to evaluate the impact of alternate strategies for pretest education and counseling on decision-making regarding BRCA1 testing among women at low to moderate risk who have a family history of breast and/or ovarian cancer. METHODS: A randomized trial design was used to evaluate the effects of education only (educational approach) and education plus counseling (counseling approach), as compared with a waiting-list (control) condition (n = 400 for all groups combined). The educational approach reviewed information about personal risk factors, inheritance of cancer susceptibility, the benefits, limitations, and risks of BRCA1 testing, and cancer screening and prevention options. The counseling approach included this information, as well as a personalized discussion of experiences with cancer in the family and the potential psychological and social impact of testing. Data on knowledge of inherited cancer and BRCA1 test characteristics, perceived risk, perceived benefits, limitations and risks of BRCA1 testing, and testing intentions were collected by use of structured telephone interviews at baseline and at 1-month follow-up. Provision of a blood sample for future testing served as a proxy measure of intention to be tested (in the education and counseling arms of the study). The effects of intervention group on study outcomes were evaluated by use of hierarchical linear regression modeling and logistic regression modeling (for the blood sample outcome). All P values are for two-sided tests. RESULTS: The educational and counseling approaches both led to significant increases in knowledge, relative to the control condition (P < .001 for both). The counseling approach, but not the educational approach, was superior to the control condition in producing significant increases in perceived limitations and risks of BRCA1 testing (P < .01) and decreases in perceived benefits (P < .05). However, neither approach produced changes in intentions to have BRCA1 testing. Prior to and following both education only and education plus counseling, approximately one half of the participants stated that they intended to be tested; after the session, 52% provided a blood sample. CONCLUSIONS: Standard educational approaches may be equally effective as expanded counseling approaches in enhancing knowledge. Since knowledge is a key aspect of medical decision-making, standard education may be adequate in situations where genetic testing must be streamlined. On the other hand, it has been argued that optimal decision-making requires not only knowledge, but also a reasoned evaluation of the positive and negative consequences of alternate decisions. Although the counseling approach is more likely to achieve this goal, it may not diminish interest in testing, even among women at low to moderate risk. Future research should focus on the merits of these alternate approaches for subgroups of individuals with different backgrounds who are being counseled in the variety of settings where BRCA1 testing is likely to be offered.

Mammography adherence and psychological distress among women at risk for breast cancer.

BACKGROUND: Previous studies estimate that first-degree relatives of women with breast cancer have a twofold to 10-fold increased risk of developing breast cancer. Recently, attention has focused on the mammography screening practices of women who are at high risk for breast cancer. PURPOSE: Our purpose was to characterize mammography screening practices in a sample of first-degree relatives of breast cancer patients and to identify variables that may serve as barriers to or facilitators of adherence to mammography. METHODS: Cross-sectional (rather than prospective) data were collected by telephone interviews with 140 women aged 35-79 years who had a family history of breast cancer in at least one first-degree relative (mother, sister, or daughter). Data were recorded on mammography screening patterns, depression, stress impact, and breast cancer worries. RESULTS: Women whose mammography history adhered to age-specific recommendations varied by age: 76% of first-degree relatives aged 35-39 years, 86% aged 40-49 years, and 63% aged 50 years or more. In bivariate analyses, level of education (P = .001), employment (P = .046), and time since diagnosis of the index patient (P = .044) were significantly and positively associated with mammography adherence. Variables associated negatively with adherence included age (P = .019), intrusive thoughts about breast cancer (P = .042), and breast cancer worries that interfered with daily functioning (P = .004). Multivariate analysis by logistic regression indicated that only breast cancer worries (odds ratio [OR] = 2.5; 95% confidence interval [CI] = 1.09-5.9) and education (OR = 4.8; CI = 1.6-14.3) were significant independent predictors of mammography adherence. CONCLUSIONS: This study suggests that most women at high risk for breast cancer adhere to the recommended mammography screening guidelines of the National Cancer Institute. However, rates of adherence among high-risk women aged 50 years and older are suboptimal; only 63% of these women received annual screening mammograms, and 13% had never been screened. Breast cancer worries may pose a barrier to mammography adherence among high-risk women, particularly those with less formal education. IMPLICATIONS: Prospective longitudinal studies are needed to validate the present findings and to evaluate the impact of psychoeducational interventions for women with affected first-degree relatives.

Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes.

BACKGROUND: Smoking has carcinogenic effects, and possibly antiestrogenic effects as well, but it has not been found to be a risk factor for breast cancer in women in the general population. However, hereditary breast cancer is primarily a disease of premenopausal women, and interactions between genes and hormonal and environmental risk factors may be particularly important in this subgroup. METHODS: We conducted a matched case-control study of breast cancer among women who have been identified to be carriers of a deleterious mutation in either the BRCA1 or the BRCA2 gene. These women were assessed for genetic risk at one of several genetic counseling programs for cancer in North America. Information about lifetime smoking history was derived from a questionnaire routinely administered to women who were found to carry a mutation in either gene. Smoking histories of case subjects with breast cancer and age-matched healthy control subjects were compared. Odds ratios for developing breast cancer were determined for smokers versus nonsmokers by use of conditional logistic regression for matched sets after adjustment for other known risk factors. RESULTS: Subjects with BRCA1 or BRCA2 gene mutations and breast cancer were significantly more likely to have been nonsmokers than were subjects with mutations and without breast cancer (two-sided P = .007). In a multivariate analysis, subjects with BRCA1 or BRCA2 mutations who had smoked cigarettes for more than 4 pack-years (i.e., number of packs per day multiplied by the number of years of smoking) were found to have a lower breast cancer risk (odds ratio = 0.46, 95% confidence interval = 0.27-0.80; two-sided P = .006) than subjects with mutations who never smoked. CONCLUSIONS: This study raises the possibility that smoking reduces the risk of breast cancer in carriers of BRCA1 or BRCA2 gene mutations.

Cancer risk notification: psychosocial and ethical implications.

Basic and medical science investigations have identified a growing number of risk factors important in carcinogenesis. By communicating cancer risk information in medical practice, we have the potential to motivate high-risk individuals to adhere to cancer prevention and surveillance protocols. However, cancer screening and risk notification might have adverse psychologic and social consequences as well. In this review, we address the psychosocial and ethical implications of cancer risk notification. The literature on the psychosocial impact of cancer screening programs and programs for notifying workers exposed to occupational carcinogens is reviewed critically. In addition, we examine new concerns and responsibilities raised by the emerging field of cancer genetics. Suggestions for future research and for patient education are addressed.

Attitudes about genetic testing for breast-ovarian cancer susceptibility.

PURPOSE: In anticipation of the availability of genetic testing for a breast-ovarian cancer susceptibility gene (BRCA1), this study examined interest in and expectations about the impact of a potential genetic test. PATIENTS AND METHODS: The subjects were 121 first-degree relatives (FDRs) of ovarian cancer patients. The design was cross-sectional. Subjects completed a structured telephone interview of attitudes about cancer and genetic testing, and self-report psychologic questionnaires to assess coping style and mood disturbance. RESULTS: Overall, 75% of FDRs said that they would definitely want to be tested for BRCA1 and 20% said they probably would. In bivariate analyses, interest was associated positively with education, perceived likelihood of being a gene carrier, perceived risk of ovarian cancer, ovarian cancer worries, and mood disturbance. In logistic regression analysis, perceived likelihood of being a gene carrier was associated strongly with interest (odds ratio, 3.7; P = .006). Results of stepwise linear regression modeling indicated that an anticipated negative impact of genetic testing was associated with being younger (beta = -.66, P = .009), having more mood disturbance (beta = .015, P = .01), and having an information-seeking coping style (beta = .19, P = .002). CONCLUSION: These results suggest that the demand for genetic testing for BRCA1 among FDRs of cancer patients may be great. Moreover, those who elect to participate may represent a more psychologically vulnerable subgroup of high-risk women.

BRCA1/2 testing: complex themes in result interpretation.

Since the cloning of BRCA1 and BRCA2, genetic testing for breast and ovarian cancer susceptibility has become more widespread. However, interpretation of test results is not always straightforward. To illustrate this point, five vignettes adapted from actual cases are presented. As these cases demonstrate, in many high-risk families, a deleterious mutation in BRCA1 or BRCA2 is not identified in an affected proband. There are several potential explanations for such a finding, namely that an undetected mutation in BRCA1 or BRCA2 may exist, or there could be a mutation in a rare or undiscovered gene. In addition, the possibility that women with breast cancer represent sporadic cases within hereditary cancer families must also be considered. Finally, the occurrence of BRCA1/2 variants of uncertain significance, often missense mutations, further complicates the risk assessment. In some of these instances, extending testing to relatives can be helpful to clarify results. When hereditary breast cancer cannot be ruled out, individuals may still be at increased risk for cancer and therefore need to obtain appropriate surveillance. The process of genetic counseling is critical both before and after testing to ensure that patients understand the potential medical and psychosocial implications of testing and are aware of available options and resources. A multidisciplinary approach to service delivery, which includes clinicians in genetics and oncology, can facilitate patients' decision making and provide continued access to information and support.

Telephone counseling improves adherence to colposcopy among lower-income minority women.

PURPOSE: A randomized trial was conducted to evaluate the impact of a telephone counseling intervention to improve patient adherence to colposcopic examination for suspected cervical intraepithelial neoplasia (CIN). METHODS: Subjects were lower-income, minority women who missed a scheduled initial appointment for colposcopy at an urban medical clinic. Patients were randomly assigned to either a control condition (n = 42) or a telephone counseling condition (n = 48). The 15-minute, structured telephone counseling intervention protocol addressed educational, psychosocial, and practical barriers to colposcopy adherence. RESULTS: The most common patient-reported barriers to colposcopy adherence included a lack of understanding of the purpose of colposcopy (50%), worry about or fear of cancer (25%), and forgetting (23%). Telephone counseling was found to be highly effective in addressing these barriers and improving adherence to diagnostic follow-up and treatment. Of patients in the control condition, 43% complied with a rescheduled colposcopy appointment, compared with 67% in the telephone counseling condition. Logistic regression analysis indicated that the effect of telephone counseling was independent of sociodemographic confounder variables (odds ratio = 2.6; P less than .003). Additionally, 74% of patients who received the initial telephone counseling adhered to recommended treatment, compared with 53% of patients in the control condition. CONCLUSION: Brief, structured telephone contact may be a cost-effective mechanism for improving adherence to diagnostic follow-up and treatment for a variety of cancer screening tests.

Genetic counseling and testing for breast-ovarian cancer susceptibility: what do women want?

PURPOSE: To assess preferences for the content and process of genetic counseling and testing for breast-ovarian cancer susceptibility among women at high risk for breast cancer. METHODS: Ninety-eight healthy women who had a family history of breast cancer in at least two first-degree relatives participated in a structured telephone survey that evaluated preferences for type of provider and the content and process of pretest education and posttest genetic counseling. RESULTS: Forty-two percent of women preferred that pretest education be delivered by a genetic counselor, while 22% preferred an oncologist. This preference was positively associated with a desire to discuss psychosocial issues during the session (P = .001). For posttest counseling, 38% of women preferred an oncologist, while 20% preferred a genetic counselor. However, women who desired supportive counseling during this session were significantly more likely to prefer a genetic counselor to an oncologist (P = .02). Fewer women wished to see a primary care physician or gynecologist for pretest education (11%) or posttest counseling (22%). With regard to the counseling process, 82% of women wished to self-refer for genetic counseling, but 63% desired advice and recommendations about whether to be tested. CONCLUSION: When feasible, the optimal approach may be for oncologists to work with genetic counselors to provide pretest education and medical recommendations. Elicitation of patients' preferences may be useful to determine the level of counseling services needed.

What you don't know can hurt you: adverse psychologic effects in members of BRCA1-linked and BRCA2-linked families who decline genetic testing.

PURPOSE: To identify members of hereditary breast and ovarian cancer families who are at risk for adverse psychologic effects of genetic testing. PATIENTS AND METHODS: A prospective cohort study with baseline (preeducation) assessments of predictor variables (ie, sociodemographic factors, cancer history, and cancer-related stress symptoms) was performed. The primary outcome variable (presence of depressive symptoms) was assessed at baseline and at 1- and 6-month follow-up evaluations. Participants were 327 adult male and female members of BRCA1- and BRCA2-linked hereditary breast and ovarian cancer families, who were identified as carriers, noncarriers, or decliners of genetic testing. RESULTS: The presence of cancer-related stress symptoms at baseline was strongly predictive of the onset of depressive symptoms in family members who were invited but declined testing. Among persons who reported high baseline levels of stress, depression rates in decliners increased from 26% at baseline to 47% at 1-month follow-up; depression rates in noncarriers decreased and in carriers showed no change (odds ratio [OR] for decliners v noncarriers=8.0; 95% confidence interval [CI], 1.9 to 33.5; P=.0004). These significant differences in depression rates were still evident at the 6-month follow-up evaluation (P=.04). CONCLUSION: In BRCA1/2-linked families, persons with high levels of cancer-related stress who decline genetic testing may be at risk for depression. These family members may benefit from education and counseling, even if they ultimately elect not to be tested, and should be monitored for potential adverse effects.

Monoamine reuptake inhibition and nicotine receptor antagonism reduce amplitude and gating of auditory evoked potentials.

BACKGROUND: Sensory encoding deficits have been extensively studied as endophenotypic markers of schizophrenia using auditory evoked potentials. In order to increase understanding of the neurochemical basis of such deficits, we utilized an animal model to test whether monoamine reuptake inhibition and nicotine receptor antagonism reduce the amplitude and gating of the P20 and N40 auditory components. METHODS: C57BL/6J mice received 12 days of chronic vehicle, bupropion, haloperidol or bupropion plus haloperidol. Auditory evoked potentials were then recorded in alert mice to measure the amplitude and gating of evoked components during a paired click paradigm similar to tasks used to measure the P50 and N100 auditory potentials in schizophrenia. Evoked potentials were recorded prior to and following acute nicotine. RESULTS: Bupropion reduced the amplitude and gating of the N40 evoked potential in mice, similar to the P50 and N100 endophenotypes associated with sensory encoding deficits in schizophrenia. This deficit was fully reversed only by the combination of haloperidol and nicotine, suggesting that dopamine reuptake inhibition and nicotine antagonism both contribute to the observed phenotype. Furthermore, nicotine increased P20 amplitude across all groups supporting a role for nicotine agonists in pre-attentive sensory encoding deficits. CONCLUSIONS: We propose that the combination of monoamine inhibition and nicotine receptor antagonism may serve as a useful model for preclinical screening of pharmaceutical compounds aimed at treating sensory encoding deficits in schizophrenia.