Integrating Virtual Mindfulness-Based Stress Reduction Into Inflammatory Bowel Disease Care: Mixed Methods Feasibility Trial.

BACKGROUND: Individuals with inflammatory bowel disease (IBD) experience cycles of aggressive physical symptoms including abdominal pain, diarrhea, and fatigue. These acute symptoms regress and return, and chronic symptoms and complications often linger. The nature of the disease can also cause individuals to experience psychological distress including symptoms of anxiety and depression; however, unlike the physical symptoms of IBD, these psychological symptoms often remain untreated. OBJECTIVE: This study aims to evaluate the feasibility, acceptability, and effectiveness of virtual mindfulness-based stress reduction (v-MBSR) for adults with IBD. METHODS: IBD patients with self-reported anxiety or depression were recruited from clinics in Alberta, Canada to participate in an 8-week v-MSBR intervention. Eligible patients participated in v-MBSR delivered by psychiatrists using a videoconferencing platform. Primary feasibility outcomes included trial uptake, adherence, attendance, and attrition rates. Secondary effectiveness outcomes included measures of anxiety, depression, quality of life (QoL), and mindfulness. Effectiveness data were collected at 3 time points: baseline, at intervention completion, and 6 months after completion. To further assess feasibility and acceptability, participants were invited to participate in a semistructured interview after completing v-MBSR. RESULTS: A total of 16 of the 64 (25%) referred patients agreed to participate in v-MBSR with the most common reason for decline being a lack of time while 7 of the 16 (43.8%) participants completed the program and experienced encouraging effects including decreased anxiety and depression symptoms and increased health-related QoL with both improvements persisting at 6-month follow-up. Participants described improved coping strategies and disease management techniques as benefits of v-MBSR. CONCLUSIONS: Patients with IBD were interested in a psychiatrist-led virtual anxiety management intervention, but results demonstrate v-MBSR may be too time intensive for some patients with IBD patients. v-MBSR was acceptable to those who completed the intervention, and improvements to anxiety, depression, and QoL were promising and sustainable. Future studies should attempt to characterize the patients with IBD who may benefit most from interventions like v-MBSR.

The impact of matching for reproductive status on the comparison of magnetic spectroscopic measurements of glutamate and gamma-aminobutyric acid + in the medial prefrontal cortex of women with major depression.

OBJECTIVES: The role played by medial prefrontal cortex (MPFC) glutamate (Glu) and gamma-aminobutyric acid (GABA) in the pathophysiology and the treatment of major depression (MD) is increasingly recognized. Although measurements of MPFC GABA and Glu have been shown to be sensitive to physiological fluctuations of female hormones, none of the magnetic resonance spectroscopy (MRS) investigations of MPFC Glu and GABA in MD have controlled for possible bias effect of the reproductive stage of the women included. METHODS: MPFC Glu and GABA+ (which include homocarnosine and macromolecules) referenced to creatine and phosphocreatine, were measured via magnetic resonance spectroscopy (MRS) using a 3-Tesla magnet in 24 women with MD and 24 healthy women paired for reproductive status. All participants were unmedicated. RESULTS: There were no statistical differences in either MPFC Glu [95 % CI: (-0.025, 0.034)] or MPFC GABA+ [95 % CI: (-0.005, 0.017)] between women with MD and healthy controls. CONCLUSIONS: Our investigation does not support abnormalities in measurement of MPFC Glu and GABA in MD women when stringent control for reproductive status is performed. As a result of the inherent limitations of MRS methodology, our results do not preclude glutamatergic and GABAergic dysregulations in the MPFC of women with MD.

Decreased GABA+ ratios referenced to creatine and phosphocreatine in the left dorsolateral prefrontal cortex of females of reproductive age with major depression.

BACKGROUND: It has been suggested that the dorsolateral prefrontal cortex (DLPFC), especially the left DLPFC, has an important role in the pathophysiology and the treatment of major depressive disorder (MDD); furthermore, the contributory and antidepressant role of γ-aminobutyric acid (GABA) is increasingly recognized. Given that most female patients with MDD are of reproductive age, we sought to assess in vivo baseline GABA levels in the left DLPFC among unmedicated females of reproductive age with depression. METHODS: We compared healthy females and females with MDD. Both groups were of reproductive age. We confirmed absence of current or past psychiatric diagnosis among healthy controls or a current diagnosis of MDD via a structured interview. We measured GABA+ (including homocarnosine and macromolecules), referenced to creatine and phosphocreatine, via magnetic resonance spectroscopy using a 3 Tesla magnet. RESULTS: We included 20 healthy controls and 13 participants with MDD. All participants were unmedicated at the time of the study. All females were scanned during the early follicular phase of the menstrual cycle. Levels of GABA+ in the left DLPFC were significantly lower among participants with MDD (median 0.08) than healthy controls (median 0.10; U = 66.0, p = 0.02, r = 0.41). LIMITATIONS: When we adjusted for fit error as a covariate, we lost statistical significance for left DLPFC GABA+. However, when we adjusted for signal-to-noise ratio, statistical significance was maintained. CONCLUSION: Our results suggest that GABA+ levels in the left DLPFC may vary by depression status and should be examined as a possible treatment target.

Decreased GABA+ Levels in the Medial Prefrontal Cortex of Perimenopausal Women: A 3T 1H-MRS Study.

OBJECTIVE: Perimenopause is associated with an increased risk of developing a major depressive (MD) episode. A significant number of women develop their first MD episode during perimenopause, suggesting a unique pathophysiology of perimenopausal (PM) depression. Previous research has shown that depression is associated with decreased gamma-aminobutyric acid (GABA) levels in the medial prefrontal cortex (MPFC) of MD patients. The objective of this study was to compare MPFC GABA+ levels in healthy reproductive-aged (RD) and PM women. METHODS: A total of 18 healthy PM and 20 RD women were included in the study. MPFC GABA+ levels, which include homocarnosine and macromolecules, were measured via magnetic resonance spectroscopy using a 3 Tesla magnet. MPFC GABA+ levels were referenced to creatine + phosphocreatine (Cr+PCr). Absence of current or past psychiatric diagnosis was confirmed via a structured interview. RD participants were scanned during the early follicular phase of the menstrual cycle. PM women were scanned outside of ovulatory cycles. RESULTS: Mean MPFC GABA+ concentrations (relative to Cr+PCr) were decreased in the PM group compared with the RD group (PM mean = 0.08 ± 0.02, RD mean = 0.09 ± 0.02, t = -2.03, df = 36, P = .05) even after correcting for in percentage in gray matter (GM). Because PM women were inherently older than RD women (aged 48.8 ± 3.55 and 31.5 ± 9.66 years, respectively), the age difference between the 2 groups was statistically significant (P < .001). When age was treated as an independent covariate and included in the model, the difference in GABA+ between PM and RD women was no longer significant (P = .092). CONCLUSION: Perimenopause is associated with decreased MPFC GABA+/Cr+PCr levels, which may contribute to the increased risk of experiencing a MD episode during PM.

A comparative magnetic resonance spectroscopy study of GABA+ and glutamate referenced to creatine and phosphocreatine in the left dorsolateral prefrontal cortex of perimenopausal women and women of reproductive age.

Objective: The perimenopause is associated with an increased risk of developing a major depressive (MD) episode. The biological changes occurring during perimenopause responsible for this increased risk of depression remain to be elucidated. Postmortem and magnetic resonance spectroscopy (MRS) studies have revealed decreased gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the dorsolateral prefrontal cortex (DLPFC) of MD patients. The objective of this study was to compare LDLPFC GABA+ and Glu ratios (referenced to creatine and phosphocreatine) in healthy reproductive-aged (RD) and perimenopausal (PM) women. Materials and methods: Eighteen healthy PM and 20 RD women were included in the study. Our dependent variables, LDLPFC Glu and GABA+ ratios which include homocarnosine and macromolecules, were measured via MRS, using a 3 Tesla magnet. Absence of current or past psychiatric diagnosis was confirmed via a structured interview. RD participants were scanned during the early follicular phase of the menstrual cycle (MC). PM women were scanned outside of ovulatory cycles. Results: Mean LDLPFC GABA+ and Glu ratios were not statistically different between the PM group and RD group (PM mean = 0.10 ± 0.06, RD mean = 0.11 ± 0.04, t = -0.383, df = 36, d = -0.13, p = 0.70) (PM mean = 0.56 ± 0.06, RD mean = 0.57 ± 0.05, t = -0.794, df = 36, d = -0.26, p = 0.43), respectively. The perimenopause demarcates the end of the reproductive life. Unsurprisingly PM women were older than RD women (PM women: 48.8 ± 3.55 years, range 41-53 years old; RD women: 31.5 ± 9.66 years, range 18-47 years old) (p < 0.001). This inherent entanglement of group and age is a limitation of our study. Conclusion: Contrary to our previous findings of decreased GABA+ and Glu in the medial prefrontal cortex in perimenopausal women, the perimenopause is not associated with decreased GABA+ or Glu ratios in the LDLPFC. This suggests that brain areas playing a role in MD display different sensitivity to the female hormones fluctuations associated with perimenopause.

Prospective Investigation of Glutamate Levels and Percentage Gray Matter in the Medial Prefrontal Cortex in Females at Risk for Postpartum Depression.

BACKGROUND: The substantial female hormone fluctuations associated with pregnancy and postpartum have been linked to a greater risk of developing depressive symptoms, particularly in high-risk women (HRW), i.e. those with histories of mood sensitivity to female hormone fluctuations. We have shown that glutamate (Glu) levels in the medial prefrontal cortex (MPFC) decrease during perimenopause, a period of increased risk of developing a major depressive episode. Our team has also demonstrated that percentage gray matter (%GM), another neural correlate of maternal brain health, decreases in the MPFC during pregnancy. OBJECTIVE: To investigate MPFC Glu levels and %GM from late pregnancy up to 7 weeks postpartum in HRW and healthy pregnant women (HPW). METHODS: Single-voxel spectra were acquired from the MPFC of 41 HPW and 22 HRW using 3- Tesla in vivo proton magnetic resonance spectroscopy at five different time points. RESULTS: We observed a statistically significant interaction between time and group for the metabolite Glu, with Glu levels being lower for HRW during pregnancy and early postpartum (p<0.05). MPFC %GM was initially lower during pregnancy and then significantly increased over time in both groups (p<0.01). CONCLUSION: This investigation suggests that the vulnerability towards PPD is associated with unique fluctuations of MPFC Glu levels during pregnancy and early postpartum period. Our results also suggest that the decline in MPFC %GM associated with pregnancy seems to progressively recover over time. Further investigations are needed to determine the specific role that female hormones play on the physiological changes in %GM during pregnancy and postpartum.

Decreased Medial Prefrontal Cortex Glutamate Levels in Perimenopausal Women.

Objective: There is an increased risk of experiencing depression during perimenopause (PM), a period of rapidly changing female hormone concentrations. Women at particular risk of developing major depression (MD) during PM are those with history of mood sensitivity to female hormone fluctuations i.e., women with a history of premenstrual dysphoric disorder (PMDD) and/or post-partum depression (PPD). Depressive symptomology has been associated with fluctuations of glutamate (Glu) levels in the medial prefrontal cortex (MPFC) in MD patients as well as PMDD and PPD patients. The objective of the study was to compare MPFC Glu levels in healthy perimenopausal and reproductive-aged (RD) women. Methods: Medial prefrontal cortex Glu levels in healthy perimenopausal (n = 15) and healthy RD women (n = 16) were compared via Magnetic Resonance Spectroscopy (MRS) scan using a 3 Tesla (T) magnet. Absence of depressive symptomology and psychiatric comorbidity was confirmed via semi-structured interview. Participants were scanned during the early follicular phase (FP) of the menstrual cycle (MC). Results: Mean MPFC Glu concentrations were decreased in the PM group compared to RD group (PM mean = 0.57 ± 0.03, RD mean = 0.63 ± 0.06, t = -3.84, df = 23.97, p = 0.001). Conclusion: Perimenopause is associated with decreases in MPFC Glu levels. This decrease may be contributing to the increased risk of experiencing depression during PM. Further research should assess MPFC Glu levels in perimenopausal women suffering from MD.

Decreased serum L-arginine and L-citrulline levels in major depression.

RATIONALE: It has been suggested that endothelial dysfunction caused by a decreased endothelial production of nitric oxide (NO) may contribute to the consistently observed increased risk of developing cardiovascular disease (CVD) in physically healthy patients suffering from major depression (MD). NO is a gas synthesized from Larginine (a conditionally essential amino acid) and oxygen by endothelial nitric oxide synthase (eNOS). The end products of NO production include both NO and L-citrulline. NO is rapidly reduced to the anions nitrite and nitrate, classically referred to as NO metabolites. Their measurement has been used as a surrogate measurement for endothelial NO production. We and others have shown decreased levels of NO metabolites in the serum of MD patients. The mechanism of this decreased production of NO by the endothelium has not yet been elucidated. OBJECTIVES: The purpose of this study is to assess serum levels of L-arginine and L-citrulline in patients with MD. METHODS: Levels of L-arginine and L-citrulline were measured in 35 unmedicated physically healthy MD patients and 36 healthy controls (HCs). RESULTS: L-arginine and L-citrulline concentrations were significantly lower in MD patients than in healthy controls (L-arginine, 73.54 + 21.53 µmol/L and 84.89 + 25.16, p = 0.04 µmol/L and L-citrulline 31.58 + 6.05 µmol/L and 35.19 + 6.85 µmol/L, p = 0.03, respectively). CONCLUSIONS: The decrease in L-arginine levels in MD patients is a possible explanation for the decrease in NO metabolites in MD patients and therefore may contribute, through endothelial dysfunction, to the increased CV risk associated with MD.

Pentagastrin-induced hemoconcentration in healthy volunteers and patients with panic disorder: effect of pretreatment with ethinyl estradiol.

Panic disorder has been associated with both an increased risk of coronary events as well as an increased risk of stroke. Hemoconcentration, with both a decrease in plasma volume and an increase in plasma viscosity, is a possible contributor to the risk of acute ischemic events. Our objectives were to demonstrate the process of hemoconcentration in response to induced panic symptoms and to assess the effect of pretreatment with ethinyl estradiol on panic-induced hemoconcentration. Fifteen male patients with panic disorder and 10 male healthy volunteers were included in a double-blind cross-over placebo-controlled design consisting of two injections of pentagastrin following randomized pretreatment with placebo and ethinyl estradiol. Plasma levels of hematocrit and hemoglobin were assessed at baseline and post-injections, and used to calculate an indirect estimation of the change in plasma volume. Pentagastrin-induced panic symptoms were associated with a mean decrease in plasma volume of 4.8% in the placebo pretreatment condition. Pretreatment with ethinyl estradiol attenuated this effect. The acute hemoconcentration observed in relation to pentagastrin-induced panic symptoms may be relevant to the increased risk of stroke and acute coronary events found in patients with panic disorder.

Frequency and correlates of gambling problems in outpatients with major depressive disorder and bipolar disorder.

OBJECTIVE: To investigate the frequency of gambling in people who have been diagnosed with major depressive disorder (MDD) or bipolar disorder (BD). Secondary objectives were to examine: sex differences in the rates of gambling behaviour, the temporal relation between onset of mood disorders and problem gambling, psychiatric comorbidities associated with problem gambling, and the influences of problem gambling on quality of life. METHOD: People (aged 18 years and older) who met criteria for lifetime Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-defined MDD or BD I or II, and were confirmed by the Mini International Neuropsychiatric Interview, were enrolled. Participants were recruited from 5 sites in Canada and 1 in the United States. Prevalence of past-year problem gambling was assessed with the Canadian Problem Gambling Index. Associated comorbidities with problem gambling are presented. RESULTS: A total of 579 participants were enrolled (female: n = 379, male: n = 200). Prevalence of problem gambling did not differ significantly between the MDD (12.5%) and the BD (12.3%) groups. There was a significant difference in the prevalence of problem gambling between males (19.5%) and females (7.8%) in the BD group (chi-square = 8.695, df = 1, P = 0.003). Among people meeting criteria for problem gambling, the mood disorder was the primary onset condition in 71% of cases. People with a mood disorder with comorbid current panic disorder (OR = 1.96; 95% CI 1.02 to 3.75), obsessive-compulsive disorder (OR = 1.86; 95% CI 1.01 to 3.45), specific phobia (OR = 2.36; 95% CI 1.17 to 4.76), alcohol dependence (OR = 5.73; 95% CI 3.08 to 10.65), or lifetime substance dependence (OR = 2.05; 95% CI 1.17 to 3.58), had significantly increased odds of problem gambling. Problem gambling across MDD and BD populations was also associated with lower quality of life ratings. CONCLUSION: These results reaffirm a higher prevalence of gambling both in BD and in MDD populations, compared with previously published community samples. Our study also identifies risk factors for gambling behaviours within these populations.

Cost-effectiveness of escitalopram for generalized anxiety disorder in Canada.

BACKGROUND: Generalized Anxiety Disorder (GAD) is a common chronic disease with a lifetime prevalence estimated to range from 4.2% to 12.7%. GAD places a substantial burden upon patients and healthcare resources. OBJECTIVE: To determine the cost-effectiveness of escitalopram for GAD in a Canadian primary care setting from two perspectives [Ministry of Health (MoH) and society (SOC)]. METHODS: A 24-week decision-analytic model was constructed using Data/TreeAge software. Patients were treated with escitalopram or generic paroxetine. Clinical rates were determined from the literature; expert opinion guided model pathway development. Effectiveness was measured as 'symptom-free days' (SFDs). Analyses from MoH perspective focused on direct costs of treatment (drugs, physician visits), while SOC also accounted for indirect costs associated with workdays lost due to GAD. Unit costs of healthcare services and wage rates were obtained from standard Canadian sources (2005 Canadian $ values). Cost-effectiveness was expressed as the incremental cost-effectiveness ratio (ICER). Extensive one-way and probabilistic sensitivity analyses were conducted. RESULTS: Escitalopram was associated with higher expected number of SFDs than paroxetine (86.4 vs. 77.0 SFD, respectively). From the MoH perspective, expected costs were Can$724 and Can$663 for escitalopram and paroxetine arms, respectively, resulting in the ICER for escitalopram vs. paroxetine of Can$6.56/SFD (Can$2362/symptom free year). From the SOC perspective, escitalopram dominated paroxetine as more effective on SFDs and less costly. Sensitivity analyses demonstrated robustness of the model. Limitations include the absence of comorbidities, which are common in practice, lack of long-term data, and assuming that dropouts in trials reflect those in practice. CONCLUSION: Escitalopram was found to be cost-effective compared with paroxetine in treatment of GAD from the Canadian MoH perspective, and dominating paroxetine from the SOC perspective. Therefore, a possible advantage may exist at the population level in the treatment of GAD with escitalopram in Canada.

Proton magnetic resonance spectroscopy measurement of brain glutamate levels in premenstrual dysphoric disorder.

BACKGROUND: Women who suffer from premenstrual dysphoric disorder (PMDD) classically display depressive and anxiety symptoms in the premenstrum. Preclinical and clinical studies have suggested a role of glutamate in anxiety and depression. This investigation aims at demonstrating fluctuations of glutamate across the menstrual cycle in the medial prefrontal cortex of women who suffer from PMDD and healthy control subjects (HCs). METHODS: Twelve PMDD women and 13 HCs were randomized to two single-voxel 3 Tesla proton magnetic resonance spectroscopy examinations of the medial prefrontal cortex during the follicular phase and the luteal phase. RESULTS: A phase effect was observed; the levels of glutamate/creatine plus phosphocreatine (Cr) were significantly lower during the luteal phase compared with the follicular phase. However, no statistically significant diagnosis or phase x diagnosis effects were found. CONCLUSIONS: The optimized stimulated echo acquisition mode (STEAM) pulse timings selected in this study (echo time [TE], mixing time [TM] = 240, 27 msec) allow us to interpret our results as the first report of alterations of brain glutamate levels across the menstrual cycle. Hormonal fluctuations associated with the menstrual cycle likely contribute to these glutamate level variations. Although PMDD women undergo a similar decrease in glutamate during the luteal phase as the HCs, PMDD women may display an increased behavioral sensitivity to those phase-related alterations. These menstrual cycle-related variations of glutamate levels may also contribute to the influence of the phases of the menstrual cycle in other neuropsychiatric disorders.

Delayed increase in LDL cholesterol following pentagastrin-induced panic attacks.

OBJECTIVE: Panic disorder (PD) has been associated with an increased risk for cardiovascular (CV) morbidity and mortality. There are inconsistent reports of increased low-density lipoprotein cholesterol (LDL-C) in patients with PD. Studies have reported a correlation between cholesterol levels and the intensity and frequency of panic attacks (PAs), suggesting that an elevation in cholesterol could be due to physiological and neurochemical changes that occur during and after a PA. The objective of our study was to show that the occurrence of a PA is associated with an increase in LDL-C. MATERIALS AND METHODS: We used a double-blind, placebo-controlled crossover design with randomized injections of placebo and pentagastrin in 18 patients with PD (11 men, 7 women) and 33 healthy-control subjects (24 men, 9 women). RESULTS: Pentagastrin-induced PAs were associated with a statistically significant 10.4% delayed (24 h) increase in LDL-C levels in male subjects. Such an effect was not observed in female subjects. CONCLUSION: LDL-C levels are directly affected by the occurrence of a PA in males. These findings, in association with previous reports of increased cholesterol levels in PD patients, suggest that a chronic increase in LDL-C as a result of frequent PAs may be one of the mechanisms that contributes, at least in male patients, to previously reported increased CV risk in patients with PD. The gender difference and the temporal association between PAs and increased LDL-C may explain the inconsistency in the findings of previous investigations of cholesterol levels in PD patients.

The relevance of neuroactive steroids in schizophrenia, depression, and anxiety disorders.

1. Neuroactive steroids are steroid hormones that exert rapid, nongenomic effects at ligand-gated ion channels. There is increasing awareness of the possible role of these steroids in the pathology and manifestation of symptoms of psychiatric disorders. The aim of this paper is to review the current knowledge of neuroactive steroid functioning in the central nervous system, and to assess the role of neuroactive steroids in the pathophysiology and treatment of symptoms of schizophrenia, depression, and anxiety disorders. Particular emphasis will be placed on GABAA receptor modulation, given the extensive knowledge of the interactions between this receptor complex, neuroactive steroids, and psychiatric illness. 2. A brief description of neuroactive steroid metabolism is followed by a discussion of the interactions of neuroactive steroids with acute and chronic stress and the HPA axis. Preclinical and clinical studies related to psychiatric disorders that have been conducted on neuroactive steroids are also described. 3. Plasma concentrations of some neuroactive steroids are altered in individuals suffering from schizophrenia, depression, or anxiety disorders compared to values in healthy controls. Some drugs used to treat these disorders have been reported to alter plasma and brain concentrations in clinical and preclinical studies, respectively. 4. Further research is warranted into the role of neuroactive steroids in the pathophysiology of psychiatric illnesses and the possible role of these steroids in the successful treatment of these disorders.

Alteration of decreased plasma NO metabolites and platelet NO synthase activity by paroxetine in depressed patients.

Although major depression (MD) and cardiovascular disease (CVD) have been conclusively linked in the literature, the mechanism associating MD and CVD is yet undetermined. The purpose of this paper is to further investigate a potential mechanism involving nitric oxide (NO) and to examine the effect of the selective serotonin reuptake inhibitor paroxetine on NO production by both platelets and the endothelium. In total, 17 subjects with MD and 12 healthy controls (HCs) with no known history of cardiovascular illness completed the study. Paroxetine was administered to both the MD patients and HCs over an 8-week period, and then medication was discontinued. Blood samples were taken at various times throughout paroxetine treatment and after discontinuation. Plasma NO metabolite (NOx) levels were measured by a chemiluminescence method. Platelet endothelial NO synthase (eNOS) activity was examined through the conversion of L-[14C]arginine to L-[(14)C]citrulline. Data were analyzed using t-tests and a linear mixed effects model. Baseline levels of both plasma NOx and platelet NOS activity were significantly lower in subjects with MD compared to HCs. Throughout paroxetine treatment, plasma NOx levels increased in both HCs and MD patients. However, platelet eNOS activity decreased in HCs, while no statistically significant change was evidenced in MD patients. These data suggest that, in MD patients, decreased peripheral production of NO, a potential contributor to increased cardiovascular risk, is modified by administration of the antidepressant paroxetine.

Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorder.

BACKGROUND: Major depression (MD) has been associated with increased cardiovascular mortality in patients with coronary heart disease (CHD) and has been described as an independent risk factor for the development of CHD in healthy subjects; however, the mechanism of the association between MD and CHD remains to be determined. Nitric oxide (NO) plays a major role in cardiovascular regulation, and decreased NO production has been associated with several cardiovascular risk factors. We hypothesized that in patients with MD, NO production by both platelets and the endothelium would be reduced when compared with healthy control subjects (HCs). METHODS: Blood samples were obtained from 15 subjects with MD and 16 HCs with no known history of cardiovascular illness. Plasma NO metabolite (NOx) levels were analyzed by chemiluminescence. Platelet endothelial NO synthase (eNOS) activity was examined through the conversion of l-[(14)C]arginine to l-[(14)C]citrulline. RESULTS: The levels of both plasma NOx and platelet eNOS activity were significantly lower in subjects with MD compared with HCs. CONCLUSIONS: These data suggest that decreased NO production by the vascular wall and platelets might contribute to the increased CHD risk observed in patients with MD.

Response to flumazenil in the late luteal phase and follicular phase of the menstrual cycle in healthy control females.

RATIONALE: Animal studies of short-term progesterone administration and withdrawal model the natural increase and abrupt decrease in progesterone levels which occur in the late luteal phase (LP) of the human menstrual cycle (MC). Previously, studies in animals have shown that abrupt cessation of chronic or short-term progesterone administration results in pharmacological changes at the GABAA receptor, resulting in altered sensitivity to GABAA receptor neuromodulators such as benzodiazepines and flumazenil, a GABAA receptor antagonist. OBJECTIVES: This study's goal was to compare the response to flumazenil in the follicular phase (FP) and late LP in female healthy controls (HCs). We postulated that HC females would exhibit a greater psychological and somatic response to flumazenil in the late LP, a period of progesterone withdrawal, compared to the FP. METHODS: Twelve healthy females, without history of psychiatric disorder, were randomized to receive two injections of a 2 mg bolus injection of flumazenil (one in the late LP and one in the FP) and two injections of placebo (one in the late LP and one in the FP). Following injection, subjects were asked to rate the occurrence and intensity of panic symptoms on the panic symptom scale (PSS). RESULTS: A main treatment effect was detected for the PSS score response after flumazenil injection (P=0.008). However, there was no significant treatment-by-phase interaction observed (P=0.449). CONCLUSIONS: These findings indicate that MC phase did not affect the response to flumazenil in HC females. This result is contrary to our hypothesis of altered sensitivity to flumazenil in the late LP.