Therapeutic tragedies of the past, ethical concerns, and legal risks, among other factors have led to a conservative approach to clinical research during pregnancy, resulting in a de facto exclusion ...of pregnant women from most clinical therapeutics trials. As a result, there is a deficit of knowledge regarding the safety and proper dosing of medications during pregnancy, leaving prescribers with limited information available to support clinical decision-making. Additionally, there is little development of treatments for pregnancy-specific conditions.
This review describes the current need for therapeutic development in pregnant women, summarizes the history of regulations impacting this research area, and describes current efforts to increase the information used to help make decisions regarding the use of drugs during pregnancy and lactation. This is a brief review of the literature, federal regulations, and policies on research in pregnant women.
While therapeutic development in pregnant women has been limited in the past, recent efforts by academic researchers, bioethicists, industry, advocacy groups, and federal agencies have sought to enhance strategies to increase the participation of pregnant women in clinical research that may benefit them and/or their fetus.
Collaborative efforts from all stakeholders, including industry, academia, advocacy groups, regulators, and other governmental agencies, if successful will increase the information needed to help make decisions regarding the use of drugs during pregnancy and lactation.
Abstract Background The heterogeneity of mood disorders has been a challenge to our understanding of their underlying biologic and genetic pathways. This report examines the specificity of the ...familial aggregation of atypical and melancholic subtypes of depression and their clinical correlates in a large community based family study of affective spectrum disorders. Methods The sample includes 457 probands and their directly interviewed adult first degree relatives from the National Institute of Mental Health (NIMH) Family Study of Affective Spectrum Disorder. Depression subtypes were based on best estimate diagnoses using information from semi-structured diagnostic interviews by experienced clinical interviews and multiple family history reports. Results Atypical depression in probands was significantly associated with the atypical subtype of depression in relatives (OR 1.75 95%CI 1.02-3.02, p=0.04), independent of proband and relative comorbid disorders. Melancholic depression in probands was not associated with melancholic depression in relatives (OR 1.25 95%CI 0.62-2.55, p=.53). The familial heritability of the atypical subtype was 0.46 (95%CI 0.21-0.71), whereas that of the melancholic subtype was 0.33 (95%CI 0.21-0.45). Melancholic depression was associated with greater severity in terms of treatment, global functioning, suicide attempts, comorbid disorders, and an earlier age at onset of depression. Limitations The subsample of interviewed relatives necessary to assess specific subtypes of depression reduced the power to detect the specificity of mood disorder subtypes. Conclusion The results indicate that the atypical subtype should be incorporated in future treatment, genetic and other etiologic studies of major depression. Findings further suggest that melancholic subtype may be an indicator of clinical severity of depression.
A burgeoning literature documents the convergence of reproductive endocrine and central serotonergic systems in the regulation of a variety of behaviors. This review will focus on one element of this ...interaction, the modulation of serotonergic function by estrogen. After describing the manifold neuroregulatory effects of gonadal steroids, we summarize the effects of estrogen on central serotonin systems in animals and humans as inferred from studies demonstrating the impact of gender, estrus (or menstrual) cycle, or hormone manipulation. Finally, we summarize the putative roles of estrogen and serotonin in two reproductive-endocrine-related mood disorders: premenstrual syndrome and perimenopausal depression.
Despite observations of age-dependent sexual dimorphisms in hypothalamic-pituitary-adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been ...examined. We assessed this role by performing CRH stimulation tests in 10 men (ages 18-45 years) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (p<0.05, 0.005, and 0.01, respectively) during testosterone replacement compared with the induced hypogonadal condition (leuprolide plus placebo); cortisol area under the curve was lower at a trend level (p<0.1). Paradoxically, CRH-stimulated corticotropin (ACTH) was increased significantly during testosterone replacement (p<0.05). The cortisol : ACTH ratio, a measure of adrenal sensitivity, was lower during testosterone replacement (p<0.1). A mixed effects regression model showed that testosterone but not estradiol or CBG significantly contributed to the variance of cortisol. These data demonstrate that testosterone regulates CRH-stimulated HPA axis activity in men, with the divergent effects on ACTH and cortisol suggesting a peripheral (adrenal) locus for the suppressive effects on cortisol. Our results further demonstrate that the enhanced stimulated HPA axis activity previously described in young men compared with young women cannot be ascribed to an activational upregulation of the axis by testosterone.
Previous studies in animals indicate that reproductive steroids are potent modulators of the hypothalamic-pituitary-adrenal (HPA) axis, a physiologic system that is typically dysregulated in ...affective disorders, such as major depression. Determination of the role of reproductive steroids in HPA axis regulation in humans is of importance when attempting to understand the pathophysiology of premenstrual syndrome (PMS), a disorder characterized by affective symptoms during the luteal phase of the menstrual cycle. We performed two studies using treadmill exercise stress testing to determine the effect of menstrual cycle phase and diagnosis on the HPA axis in women with PMS and controls and the role of gonadal steroids in HPA axis modulation in control women. The results of these studies indicate that women with PMS fail to show the normal increased HPA axis response to exercise during the luteal phase and that progesterone, not estradiol, produces increased HPA axis response to treadmill stress testing in control women. These data demonstrate that women with PMS, when symptomatic, appear to have an abnormal response to progesterone and, furthermore, do not display the HPA axis abnormalities characteristic of major depression.
Accumulating evidence indicates that gonadal steroids modulate
functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which has
been closely linked to the pathophysiology of anxiety and ...depression.
However, the effect of the natural menstrual cycle on HPA axis
responsivity to stress has not been clearly described. In nine healthy
women, metabolic and hormonal responses to treadmill exercise stress
during the early follicular phase of the menstrual cycle, when gonadal
steroid levels are low, were compared with responses in the midluteal
phase of the cycle, when both progesterone and estrogen levels are
relatively high. Exercise intensity was gradually increased over 20 min
to reach 90% of each subject’s maximal oxygen consumption during the
final 5 min of exercise. Basal plasma lactate, glucose, ACTH,
vasopressin, oxytocin, and cortisol levels were similar in the two
cycle phases. However, in response to exercise stress, women in the
midluteal phase had enhanced ACTH (P < 0.0001),
vasopressin (P < 0.01), and glucose
(P < 0.001) secretion. These findings suggest that
relatively low levels of gonadal steroids during the early follicular
phase of the menstrual cycle provide protection from the impact of
stress on the HPA axis.
OBJECTIVE: The authors investigated the role of acute serotonergic modulation in the efficacy of selective serotonin reuptake inhibitors (SSRIs) in women with premenstrual dysphoric disorder. METHOD: ...Patients with premenstrual dysphoric disorder (whose symptoms had remitted during treatment with fluoxetine) and a group of unmedicated healthy comparison women received the serotonin receptor antagonist metergoline as part of a double-blind, placebo-controlled crossover study. RESULTS: The patients with premenstrual dysphoric disorder experienced a return of symptoms 24 hours after treatment with metergoline but not diphenhydramine (active placebo). The comparison women experienced no changes in mood. CONCLUSIONS: These data support the role of altered serotonergic transmission in the efficacy of SSRI treatment for premenstrual dysphoric disorder.
Purpose
The previously reported 6-month angiographic and 12-month clinical outcomes of the CONSEQUENT trial demonstrated the safety and efficacy of a novel paclitaxel–resveratrol-coated balloon for ...the treatment of lesions in the femoropopliteal segment. The purpose of this report is to present the 2-year results including a cost-benefit analysis for Germany.
Materials and Methods
Patients with symptomatic peripheral artery occlusive disease in femoropopliteal lesions were randomized either to drug-coated balloon (DCB,
n
= 78) or plain old balloon angioplasty (POBA,
n
= 75). As secondary endpoints, the 2-year clinical results consisting of target lesion revascularization (TLR), patency and increase in walking distance were recorded. Based on the Kaplan–Meier analyses for TLR and other adverse events, a cost-benefit analysis was conducted for the German DRG system.
Results
There were no additional TLRs in both groups between 14 and 24 months so that the corresponding rates remained significantly different between the treatment groups (DCB: 19.1 vs. POBA 40.6%,
p
= 0.007). At 2 years, the patency rate was significantly higher in the DCB group (72.3 vs. 48.4%,
p
= 0.006). The walking distance increase was also significantly higher after DCB angioplasty (172 ± 103 vs. 52 ± 136 m,
p
= 0.001). We estimated 2-year cost savings of € 1111.97 per patient treated with DCB instead of POBA.
Conclusions
The use of paclitaxel–resveratrol matrix-coated peripheral balloons compared to POBA was associated with a significantly reduced TLR rate, superior patency and substantial cost savings at 2 years.
ClinicalTrials.gov Identifier
NCT01970579.
Most breastfeeding individuals take at least one prescription drug, yet limited data from lactation studies are available to inform the safety of these drugs during breastfeeding. As a result, ...healthcare providers (HCPs) rely on available information about safety of drugs used during pregnancy or on personal experiences to inform prescribing/counseling decisions for breastfeeding individuals. To improve risk communication regarding drugs used during lactation, the U.S. Food and Drug Administration published the Pregnancy and Lactation Labeling Rule (PLLR) in 2015, which added a narrative summary of available risk information to the lactation section of Prescribing Information (PI). Prior studies on labeling in PLLR format revealed that although HCPs found these details valuable, they regarded the narrative as too long to support decision-making during patient encounters.
This qualitative study's objective was to assess the utility of adding a concise summary to the Lactation subsection of PI to complement the narrative and succinctly communicate to busy HCPs a drug's risks when used during lactation. The concise summary consisted of a bolded headline, bulleted descriptions of available study findings and potential adverse reactions, and recommendations for risk mitigation.
Twenty-five online focus groups were conducted with five segments of HCPs to obtain their feedback on the concise summary and discuss their prescribing/counseling decisions for four fictitious prescription drugs including one vaccine.
HCPs utilized the concise summary to make initial prescribing/counseling decisions. Many also used the labeling narrative for a comprehensive benefit-risk assessment.
The findings indicate a need to continue to improve communication about safety of drugs used during lactation, and that the concise summary may help facilitate this communication. The study also highlights the need to educate HCPs about PI limitations when clinical data are lacking and the need to encourage clinical studies to be conducted to support actionable recommendations about use of prescription drugs during lactation.
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