Ellen Sullivan Mitchell

Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone Maintained Patients: A Randomized Double-Blind Placebo-Controlled Efficacy Trial

CONTEXT Cocaine dependence, which affects 2.5 million Americans annually, has no US Food and Drug Administration-approved pharmacotherapy. OBJECTIVES To evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence. DESIGN A 24-week, phase 2b, randomized, double-blind, placebo-controlled trial with efficacy assessed during weeks 8 to 20 and follow-up to week 24. SETTING Cocaine- and opioid-dependent persons recruited from October 2003 to April 2005 from greater New Haven, Connecticut. PARTICIPANTS One hundred fifteen methadone-maintained subjects (67% male, 87% white, aged 18-46 years) were randomized to vaccine or placebo, and 94 subjects (82%) completed the trial. Most smoked crack cocaine along with using marijuana (18%), alcohol (10%), and nonprescription opioids (44%). INTERVENTION Over 12 weeks, 109 of 115 subjects received 5 vaccinations of placebo or succinylnorcocaine linked to recombinant cholera toxin B-subunit protein. Main Outcome Measure Semiquantitative urinary cocaine metabolite levels measured thrice weekly with a positive cutoff of 300 ng/mL. RESULTS The 21 vaccinated subjects (38%) who attained serum IgG anticocaine antibody levels of 43 microg/mL or higher (ie, high IgG level) had significantly more cocaine-free urine samples than those with levels less than 43 microg/mL (ie, low IgG level) and the placebo-receiving subjects during weeks 9 to 16 (45% vs 35% cocaine-free urine samples, respectively). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the subjects with a high IgG level than in subjects with a low IgG level (53% of subjects vs 23% of subjects, respectively) (P = .048). The most common adverse effects were injection site induration and tenderness. There were no treatment-related serious adverse events, withdrawals, or deaths. CONCLUSIONS Attaining high (>or=43 microg/mL) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters. Trial Registration clinicaltrials.gov Identifier: NCT00142857.

Vaccine Pharmacotherapy for the Treatment of Cocaine Dependence

BACKGROUND Cocaine abuse has no established pharmacotherapy, but active immunotherapy with a cocaine vaccine shows promise as a therapeutic intervention. METHODS An open label, fourteen week, dose-escalation study evaluated the safety, immunogenicity, and clinical efficacy of a novel human cocaine vaccine (TA-CD) in eighteen cocaine dependent subjects. Ten subjects (400 microg total dose group) received four-100 microg injections over the course of eight weeks. Subsequently, eight subjects (2000 microg total dose group) received five-400 microg vaccinations over twelve weeks. Intent to treat analysis of thrice weekly urine toxicologies and cocaine antibody titers were compared. RESULTS Sixteen of 18 subjects completed the study. There were no serious adverse reactions and the vaccine was well tolerated. The 2000 microg total dose group had a significantly higher mean antibody titer response (2000 units) as compared to the 400 microg total dose group (1000 units) (p = .05). The 2000 microg group was more likely to maintain cocaine free urines than those in the 400 microg group (Z = -3.12, p = .002). Despite relapse in both groups, most reported an attenuation of cocaines usual euphoric effects at the six month follow-up time points (63% in the 400 microg and 100% in the 2000 microg groups). CONCLUSIONS The conjugated cocaine vaccine was well tolerated and cocaine specific antibodies persisted at least six months. The likelihood of using cocaine decreased in subjects who received the more intense vaccination schedule.

Adipokines, inflammation, and visceral adiposity across the menopausal transition: a prospective study.

CONTEXT Postmenopausal women have greater visceral adiposity compared with premenopausal women. Adipokines are associated with increased adiposity, insulin resistance, and atherosclerosis. OBJECTIVE The objective of the study was to assess changes in adipokines and inflammatory markers through the menopausal transition and correlate them with changes in visceral adiposity. DESIGN AND SETTING This was a prospective cohort study of women through the menopausal transition conducted at the University of Washington. PARTICIPANTS Sixty-nine healthy women were followed up longitudinally from premenopausal (aged 45-55 yr) to postmenopausal status (aged 49-60 yr). OUTCOME On premenopausal and postmenopausal visits, fasting blood was drawn for adiponectin, leptin, serum amyloid A (SAA), C-reactive protein (CRP), monocyte-chemotactic protein-1, tissue plasminogen activator antigen (tPA), IL-6, and TNF-alpha. Body composition measures were assessed by body mass index, whole-body dual x-ray absorptiometry scan, and computed tomography scan of the abdomen at the lumbar 4-5 level. RESULTS Women had a statistically significant increase in SAA, tPA, monocyte-chemotactic protein-1, and adiponectin between the two measurement occasions (P = 0.04, P = 0.02, P = 0.001, and P < 0.001, respectively). The increase in intraabdominal fat was correlated positively with the change in SAA (r = 0.31, P = 0.02), CRP (r = 0.56, P < 0.001), tPA (r = 0.40, P = 0.002), and leptin (r = 0.41, P = 0.002) and negatively correlated with the change in adiponectin (r = -0.37, P = 0.005). After adjustment for change in sc abdominal fat, the correlation between change in CRP, tPA, leptin, and adiponectin remained significantly associated with change in intraabdominal fat. CONCLUSIONS Women going through the menopausal transition have deleterious changes in inflammatory markers and adipokines that correlate with increased visceral adiposity.

Pathways to depressed mood for midlife women: Observations from the Seattle Midlife Women's Health Study

To differentiate women who experience patterns of depressed mood with respect to their perceptions of menopausal changes and those that were part of everyday life, women (N=347) from the Seattle Midlife Womens Health Study were studied. Women participated in in-depth interviews, kept symptom diaries, and responded to mailed health updates. Data for years 1 and 2 on the Center for Epidemiologic Studies Depression Scale revealed four patterns of depressed mood: consistent depressed mood, emerging depressed mood, resolving depressed mood, and absence of depressed mood. Discriminant function analyses differentiated women with consistent, emerging, and resolving depressed mood from those with absence of depressed mood. Patterns of depressed mood were related to stressful life context, past/present health status, and social learning about midlife. Menopausal status did not differentiate women with patterns of depressed mood from those without depressed mood. Vasomotor symptoms, history of premenstrual syndrome, and postpartum blues helped differentiate women with consistently depressed mood from those recovering from depressed mood.

Three stages of the menopausal transition from the Seattle Midlife Women's Health Study: toward a more precise definition.

Objectives: As more interest centers on the years surrounding menopause, the inconsistent use of nonspecific terminology to define these years becomes a problem. Our objective was to describe the development of specific criteria that define stages within the menopausal transition and to apply these criteria to classify midlife women into a stage of transition. Design: A total of 184 midlife women from the Seattle Midlife Womens Health Study taking no hormones and for whom data were available about initial menstrual cycle changes were studied. Questionnaires about menstrual cycle changes and menstrual calendars were mailed yearly. Intra‐individual analyses for type and chronology of menstrual cycle changes during midlife for change in flow amount or duration, cycle length change, cycle irregularity, or skipped periods were conducted. Results: Changes in flow or cycle length most frequently preceded irregularity without skipped periods, which preceded skipped periods. Initial changes began in the early 30s and most frequently between ages 40 and 44. Only 14% had irregularity as the initial change. Three stages of the menopausal transition were identified: early (flow and/or cycle length changes), middle (irregularity without skipping), and late (skipped periods). Age did not differentiate the three stages. Conclusions: These findings provide evidence for a progression of menstrual cycle events through the menopausal transition, which form the basis for three stages of the transition: early, middle, and late transition. Studies about the entire transition need to include women younger than 45. Both menstrual calendars and questionnaire data are needed to identify these three stages, and precise definitions of irregularity and skipped period are necessary. (Menopause 2000;7:334‐349.

Symptom experiences of midlife women: observations from the Seattle midlife women's health study

UNLABELLED Symptoms experienced by perimenopausal women are varied with little agreement about their nature, cause or stability. OBJECTIVE To describe the type and stability of symptoms experienced by midlife women. METHODS A community-based sample of 301 women ages 35-55 (Mean 41.1; S.D. = 4.2), had at least one menstrual period in the past year, and took no ovarian hormones. Women completed a daily symptom diary for at least one cycle for 3 consecutive years. Symptoms were rated from zero to four. The 5 premenses days were targeted for consistency and as those most symptomatic. Twenty-eight symptoms commonly reported as perimenopausal were factor analyzed using principal components analysis with varimax rotation. Test-retest reliability and stability estimates were calculated according to the method of Heise (Heise, D. Am Sociol Rev 1969; 34: 93-101) that accounts for expected change over time. RESULTS Twenty-five of the 28 symptoms loaded on five factors labeled dysphoric mood, vasomotor, somatic, neuromuscular, and insomnia together accounting for 51.7% of the variance. Test-retest reliability estimates were highest for dysphoric mood (r = 0.78) and somatic (r = 0.70) symptoms. The reliability for the other three clusters ranged from r = 0.65 to r = 0.53). The stability of the clusters across 3 years was high for dysphoric mood, neuromuscular, and insomnia. The vasomotor and somatic clusters had the most change between years 1 and 3. DISCUSSION These results indicate that dysphoric mood is not a part of vasomotor symptoms or insomnia or other somatic symptoms suggesting an origin for vasomotor symptoms apart from the other symptoms. The stability of dysphoric mood across 3 years suggests a chronic situation possibly due to high stress, overwork, or an ongoing emotional illness. The stability of the neuromuscular and insomnia symptoms suggests underlying chronic physical conditions. The reduction in stability of vasomotor symptoms may reflect the changing nature of hormones as women approach menopause. Finally, the low stability of somatic symptoms suggests that they represent acute episodic illnesses. Together the identification of five distinct symptom clusters with varying stability over 3 years suggests that they are due to different underlying mechanisms and are not all attributed to the changing hormone patterns associated with the menopausal transition. Many other events in a midlife womans life can account for these symptoms including life stress and acute and chronic illnesses.

Sexual desire during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

AIMS To describe levels of sexual desire across the menopausal transition (MT) and early postmenopause (PM), including effects of age, MT-related factors, health, stress, symptoms (hot flash, sleep, mood), and social opportunity factors. METHODS A subset of Seattle Midlife Womens Health Study (SMWHS) participants who provided data during the early reproductive, early and late menopausal transition stages, or postmenopause (n = 286), including menstrual calendars for staging the MT, annual health reports between 1990 and 2005, and morning urine samples assayed for estrone glucuronide (E(1)G), testosterone (T), and follicle-stimulating hormone (FSH) was included. Multilevel modeling using the R program was used to test factors related to sexual desire. RESULTS Women experienced a significant decrease in sexual desire during the late MT stage (p < 0.01) and early PM (p < 0.0001). Those with higher urinary E(1)G and T reported significantly higher levels of sexual desire, whereas those with higher FSH levels reported significantly lower sexual desire (p < 0.0001, 0.06, and 0.0002, respectively). Women using hormone therapy also reported higher sexual desire (p = 0.02). Those reporting higher perceived stress reported lower sexual desire (p < 0.0001), but history of sexual abuse did not have a significant effect. Those most troubled by symptoms of hot flashes, fatigue, depressed mood, anxiety, difficulty getting to sleep, early morning awakening, and awakening during the night also reported significantly lower sexual desire (p range from <0.03 to 0.0001), but there was no effect of vaginal dryness. Women with better perceived health reported higher sexual desire (p < 0.0001), and those reporting more exercise and more alcohol intake also reported greater sexual desire (p < 0.0001). Having a partner was associated with lower sexual desire. CONCLUSIONS Clinicians working with women traversing the MT should be aware that promoting healthy sexual functioning among midlife women requires consideration of their changing biology as well as ongoing life challenges.

Medical student distress. A longitudinal study.

This longitudinal study investigated the relative importance of correlates of psychological distress in first year medical students (N = 312) in September and May. Anxiety levels were one SD above the mean when compared with nonpatient levels in both September and May, and the percentage of students reporting depression doubled over the study period. Problem-focused coping decreased, emotion-focused coping increased, and satisfaction with social supports decreased over the year. In contrast, type A behavior and anger expression were more stable. Students distressed in September were at higher risk for distress in May. Students distressed in May were also characterized by higher scores for suppressed anger and type A behavior in May, even after controlling for distress in September.

The new woman: Health‐promoting and health‐damaging behaviors

Compared with their mothers, contemporary women are better educated, live alone more of their adult lives, and participate in the labor force more consistently throughout their lives. Most studies of the New Woman have focused on the effects of the configuration of her roles on her health and health-related behavior. Few have considered both the influence of womens roles and the broader context of their lives on their health. Moreover, investigators have devoted little attention to the health behavior patterns of the New Woman, despite the demonstrable impact of health-related behaviors on mortality and morbidity. The present study was designed to test models relating womens roles, gender role norms, social demands and resources, and health-promoting and -damaging behaviors. Women who resided in middle-income and racially mixed neighborhoods (N = 659) were interviewed in their homes. The women were a mean age of 32.7 years and had an educational level of 14.2 years. Approximately 57% were married or partnered, and 76% reported some level of employment outside the home. Women who had fewer life stressors and were better educated performed more health-promoting behaviors. Women who experienced more stressors, were less well educated, had more contemporary attitudes toward women, were not partnered, or experienced depressed mood engaged in more health-damaging behaviors. These results underscore the importance of considering womens social context in health promotion efforts and as a deterrent to health-damaging behaviors.

Effects of progesterone treatment on cocaine responses in male and female cocaine users

We recently reported that progesterone treatment attenuated some of the subjective effects of smoked cocaine in female cocaine users. In this study, we further examined the interaction between progesterone and cocaine in both male and female cocaine users using subjective, physiological and behavioral outcomes. A total of 10 subjects, 6 male and 4 female cocaine users, had two experimental sessions. Before each session, participants received either two oral doses of 200 mg of progesterone or placebo. Two hours after the second dose of medication treatment, the participants received a 0.3 mg/kg dose of cocaine intravenously and started the self-administration period, in which five optional doses of cocaine were available. Progesterone treatment attenuated the cocaine-induced diastolic blood pressure increases without affecting the systolic blood pressure and heart rate increases. Progesterone treatment also attenuated the subjective ratings of high and feel the effect of last dose in response to cocaine but did not affect cocaine self-administration behavior. These results suggest that progesterone attenuates some of the physiological and subjective effects of cocaine in both male and female participants. The effects of progesterone treatment on cocaine dependence need to be further studied in controlled trials.