Kathryn A. Czarkowski

Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy.

BACKGROUND Given that nicotine modulates amino acid neurotransmission, we sought to examine the impact of nicotine on cortical gamma-aminobutyric acid (GABA) levels in male and female smokers. METHODS Healthy nicotine-dependent men (n = 10) and women (n = 6) underwent proton magnetic resonance spectroscopy (1H-MRS) to measure occipital cortex GABA concentrations. A subset of the smoking men (n = 5) underwent 1H-MRS scans before and after 48 hours of smoking abstinence, whereas each of the women were scheduled to undergo pre- and postabstinence scans during the follicular and luteal phases of one menstrual cycle. Healthy nonsmoking men (n = 7) and women (n = 13) underwent 1H-MRS for comparison. RESULTS Short-term abstinence had no significant effect on cortical GABA concentrations in either men or women. There was, however, a significant effect of sex, diagnosis (smoker/nonsmoker), and menstrual cycle phase on cortical GABA levels, such that female smokers experienced a significant reduction in cortical GABA levels during the follicular phase and no cyclicity in GABA levels across the menstrual cycle, whereas cortical GABA levels were similar in smoking and nonsmoking men. CONCLUSIONS Taken together with previous 1H-MRS data showing abnormalities in occipital cortex GABA concentrations in several affective disorders, our preliminary finding that nicotine modulation of GABA levels varies by sex provides a further rationale for investigating the impact of nicotine on central GABAergic function as a potential risk factor for women to experience depressive symptoms during smoking cessation.

Preliminary evidence of reduced occipital GABA concentrations in puerperal women: a 1H-MRS study

RationaleChildbirth is associated with rapid neuroendocrine fluctuations, which are thought to contribute to the phatogenesis of postpartum major depression (PPD).ObjectivesThe aim of this proton magnetic resonance spectroscopy (1H-MRS) study was two-fold; 1) to examine whether puerperium is associated with alterations in occipital cortex gamma-aminobutyric acid (GABA) concentrations and 2) to determine whether such alterations may be more prominent in women with PPD.Materials and methodsNine women with PPD, 14 postpartum healthy controls, and ten healthy follicular phase females underwent 1H-MRS at 2.1 Tesla to measure occipital cortex GABA concentrations. Postpartum women were scanned within 6 months of delivery and prior to resumption of menstruation. Healthy non-puerperal controls, drawn from a historical sample, were scanned during the early to mid-follicular phase when ovarian hormone levels would be similar to those found in the puerperium. GABA data were analyzed using analysis of covariance, and regression models were used to explore the relationship between cortical GABA concentrations and blood levels of estradiol, progesterone, and neurosteroids.ResultsCortical GABA and plasma allopregnanolone (ALLO) concentrations were reduced in both groups of postpartum women, regardless of PPD diagnosis, compared to healthy follicular phase women. There was no correlation between cortical GABA concentrations and estradiol, progesterone, ALLO, or pregnenolone (PREG).ConclusionsThis study is the first to describe reductions in occipital cortex GABA levels in the postpartum period, a time of increased vulnerability to mood disturbances in women. The concomitant reduction in peripheral ALLO levels provides further evidence of alterations in the balance between cortical excitation and inhibition during the puerperium. Women with PPD may represent a subgroup of women who fail to adequately adapt to this alteration in the neuroendocrine milieu.

Luteal-Phase Accentuation of Acoustic Startle Response in Women with Premenstrual Dysphoric Disorder

Alterations in central nervous system response to menstrual cycle-related fluctuations in neuroactive steroids are thought to underlie the emergence of negative affect in the luteal phase of the menstrual cycle in women with premenstrual dysphoric disorder (PMDD). Such changes in the neuroendocrine milieu may lead to heightened arousal and response to stress in women with PMDD. Using the acoustic startle paradigm, we sought to determine whether women with PMDD have an accentuated physiologic response to a mildly aversive stimulus during the luteal compared to follicular phase. Further, we also examined the impact of visual affective stimuli on acoustic startle response (ASR) magnitude. During the follicular and luteal phases of the menstrual cycle, acoustic stimuli (103 dB) were delivered to 15 women with PMDD and 14 healthy menstruating women of similar age. After obtaining baseline ASR, the procedure was repeated when subjects viewed pleasant, neutral and unpleasant pictures. There was a significant group by menstrual cycle phase interaction for baseline ASR magnitude, which can be attributed to the heightened startle magnitude in women with PMDD compared to healthy women during the luteal relative to the follicular phase. The direction and degree to which picture viewing modulated the startle magnitude did not vary by group or menstrual cycle phase. These data suggest that menstrual cycle phase has a powerful modulatory effect on physiologic reactivity in women with PMDD but not in healthy women. Physiologic response to affective stimuli appears to be intact in women with PMDD across the menstrual cycle.

Estradiol and Tryptophan Depletion Interact to Modulate Cognition in Menopausal Women

Despite an abundance of data in animals, there is little research in humans regarding how estrogen and serotonin (5-HT) may interact to influence cognition. Through the use of estrogen treatment (ET) and tryptophan depletion (TRP-D) in a within-subject design involving healthy menopausal women, we have manipulated both estrogen and 5-HT in order to evaluate their individual and joint effects. Although neither manipulation influenced visuospatial learning, a significant interaction suggested that estrogen exerted a protective effect on verbal memory, such that TRP-D impaired performance to a greater extent before the administration of ET. In consonance with this finding, ET was associated with a small, but positive mood effect on the day following active TRP-D. In addition, ET significantly improved letter-cued verbal fluency with and without TRP-D. Finally, time since last menstrual period was significantly associated with verbal memory scores, such that longer length of hypogonadism resulted in decreased verbal memory performance. These data support the interaction of estrogen and 5-HT in nonreproductive behavior in humans as well as highlight the role of ovarian steroids in cognition.

Platelet serotonin in newborns and infants: ontogeny, heritability, and effect of in utero exposure to selective serotonin reuptake inhibitors.

Ontogeny of platelet serotonin (5-hydroxytryptamine, 5-HT) during the first year of life was examined in newborns and infants. The effects of in utero exposure to selective serotonin reuptake inhibitors (SSRI, including fluoxetine, sertraline, and citalopram) were examined by comparing cord blood 5-HT levels in exposed and unexposed newborns. Heritability was assessed by correlation of the platelet 5-HT values observed for mother-infant pairs. No age effect was observed in 1–49 wk-old infants (r = 0.13, p = 0.49) and mean platelet 5-HT levels in infants (241 ± 102 ng/mL, n = 33; 615 ± 320 ng/109 platelets, n = 32) were similar to those reported for older children and adults. However, significantly lower blood 5-HT levels were observed in newborns (81.3 ± 32.5 ng/mL, n = 16, p < 0.0001; 297 ± 101 ng/109 platelets, n = 11, p = 0.0007) compared with the 1–49 wk-old infants. The mean cord blood 5-HT concentra tions in newborns exposed in utero to SSRI (n = 8) were substantially lower than that seen in unexposed (n = 16) new borns (20.6 ± 14.4 versus. 81.3 ± 32.5 ng/mL, p = 0.0001; 90.7 ± 55.4 versus. 297 ± 101 ng/109 platelets, p = 0.0005). Platelet serotonin levels (ng/109 platelets) in mother-child pairs (n = 32) were significantly correlated (r = 0.415, p = 0.018). The results indicate that, although platelet 5-HT is low at birth, values quickly increase and stabilize at near-adult levels by 1 mo of age. Gestational exposure to SSRI appears to substantially reduce platelet 5-HT uptake in the fetus, strongly suggesting that such exposure has important physiologic effects. The observed mother-infant correlation agrees with a previous report of high heritability in a large adult population.

Exploring the impact of gender and reproductive status on outcomes in a randomized clinical trial of naltrexone augmentation of nicotine patch

In a series of exploratory analyses, we examined the roles of gender, reproductive status and negative affect on smoking abstinence in subjects participating in a large (n=385) 6-week randomized clinical trial (RCT) of nicotine patch therapy, with varying doses of oral naltrexone (0mg, 25mg, 50mg, 100mg) treatment. Negative affect was assessed daily during the first post-quit week via telephone interactive voice response (IVR). Weight and adverse events were recorded weekly. In the intent to treat sample, the effects of dose on continuous abstinence were non-significant in the overall model for men and women. In the 295 study completers, there was a significant effect of dose on continuous abstinence in women only (F=8.53, p=0.04). In the 100mg group, 71% of women were continuously abstinent compared to 41% in the placebo group (p<0.05). Women in the active naltrexone groups gained less weight (F=2.91, df=3, p=0.04). Women in the 100mg vs. placebo group were less adherent with medication (F=3.19, p<0.05). These effects were not significant in men. Naltrexone treatment condition (100mg vs. placebo, p=0.02, odds ratio (OR)=0.28), gender (OR=0.55 p=0.09), and IVR ratings of negative affect (OR 1.02, p=0.04) predicted abstinence at Week 1 in study completers. Menstrual cycle status on quit day had a modest affect on abstinence. These data suggest that naltrexone dose, gender, and negative affect play a role in smoking abstinence, particularly in the early stages of treatment. When used in conjunction with nicotine replacement therapy, naltrexone dose may be important in women.

The Relationship Between Bipolar Disorder, Seasonality, and Premenstrual Symptoms

Cyclical mood disorders characterized by shifting affective states include bipolar disorder, seasonal affective disorder, and premenstrual syndrome/premenstrual dysphoric disorder. In this article, we explore the relationship between these disorders and bring the reader up to date on the advances made in the past year in understanding the relationship between bipolar disorder, seasonality, and premenstrual symptoms.

The resistance to depressive relapse in menopausal women undergoing tryptophan depletion: preliminary findings

Changes in neuroendocrine function may predispose menopausal women to psychological disturbances characterized by depressed mood, anxiety, irritability, fatigue, insomnia, forgetfulness and decline in Libido. The acute tryptophan depletion paradigm was employed to examine the serotonergic contribution to mood and cognitive function in menopausal women who were within 4 weeks of recovery from an episode of major depression. MenopausaL women whose depression was responsive to treatment with oestradiol, the selective serotonin reuptake inhibitor fluoxetine, or a combination of both treatments underwent assessment of mood and verbal memory on active tryptophan depLetion and sham depLetion test days. Although performance on the deLayed paragraph recall subtest of the Wechsler Memory Scale was impaired by tryptophan depletion, no subjects experienced a relapse of depression or a significant worsening of mood. Results from this pilot study indicate that menopausal women who have recently recovered from a major depressive episode do not experience a worsening of mood with acute tryptophan depletion, despite the existence in this sample of some known risk factors for depressive relapse as a result of these procedures. While preliminary, the results suggest that serotonin may be Less critical to the pathogenesis of depression during the menopause.

Defensive Projection, Superimposed On Simplistic Object Relations, Erodes Patient-Provider Relationships in High-Risk Pregnancy: an Empirical Investigation

In an attempt to illustrate the relevance of psychoanalytic theory and research to behavior medicine, an empirical investigation was conducted of females treated at a high-risk pregnancy specialty clinic (N = 58). Drawing from psychoanalytic object relations theory, it was hypothesized and confirmed that use of projection as a defense mechanism during pregnancy, superimposed on simplistic object relations, predicted an erosion of patient-provider relationships during the pregnancy/postdelivery period. Findings are interpreted through the perspective of mentalization, pertaining to individuals’ ability to understand the mental states of self and others, specifically under significant stress. Implications for psychoanalytically oriented assessment and treatment, and for the rift between psychoanalysis and research, are discussed.

Predictors of Satisfaction with Obstetric Care in High-risk Pregnancy: The Importance of Patient–Provider Relationship

The study set out to examine the predictive effects of patients’ emotional distress and their relationships with their health care providers on satisfaction with obstetric services in high-risk pregnancies. Participants were 104 pregnant women with a history of recurrent losses, fetal demise, previous or current fetal genetic abnormality, advanced maternal age, or obstetric or medical complications of the present pregnancy. Self-report measures of emotional distress and the quality of their relationships with their medical provider were administered. Hierarchical multiple regression analyses were conducted to assess the predictive effect of these variables on satisfaction with services. Provision of information, constructive communication, and good relationships predicted elevated satisfaction with health services. Provision of information also buffered against the adverse effect of emotional distress on satisfaction with health services. These findings elucidate the central role of provider–patient interaction, particularly as it is related to provision of information, in high-risk pregnancy.