A scoping review of hormonal clinical trials in menstrual cycle-related brain disorders: Studies in premenstrual mood disorder, menstrual migraine, and catamenial epilepsy.

Cyclic variations in hormones during the normal menstrual cycle underlie multiple central nervous system (CNS)-linked disorders, including premenstrual mood disorder (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite this foundational mechanistic link, these three fields operate independently of each other. In this scoping review (N = 85 studies), we survey existing human research studies in PMD, MM, and CE to outline the exogenous experimental hormone manipulation trials conducted in these fields. We examine a broad range of literature across these disorders in order to summarize existing diagnostic practices and research methods, highlight gaps in the experimental human literature, and elucidate future research opportunities within each field. While no individual treatment or study design can fit every disease, there is immense overlap in study design and established neuroendocrine-based hormone sensitivity among the menstrual cycle-related disorders PMD, MM, and CE. SCOPING REVIEW STRUCTURED SUMMARY: Background. The menstrual cycle can be a biological trigger of symptoms in certain brain disorders, leading to specific, menstrual cycle-linked phenomena such as premenstrual mood disorders (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite the overlap in chronicity and hormonal provocation, these fields have historically operated independently, without any systematic communication about methods or mechanisms. OBJECTIVE: Online databases were used to identify articles published between 1950 and 2021 that studied hormonal manipulations in reproductive-aged females with either PMD, MM, or CE. We selected N = 85 studies that met the following criteria: 1) included a study population of females with natural menstrual cycles (e.g., not perimenopausal, pregnant, or using hormonal medications that were not the primary study variable); 2) involved an exogenous hormone manipulation; 3) involved a repeated measurement across at least two cycle phases as the primary outcome variable. CHARTING METHODS: After exporting online database query results, authors extracted sample size, clinical diagnosis of sample population, study design, experimental hormone manipulation, cyclical outcome measure, and results from each trial. Charting was completed manually, with two authors reviewing each trial. RESULTS: Exogenous hormone manipulations have been tested as treatment options for PMD (N = 56 trials) more frequently than MM (N = 21) or CE (N = 8). Combined oral contraceptive (COC) trials, specifically those containing drospirenone as the progestin, are a well-studied area with promising results for treating both PMDD and MM. We found no trials of COCs in CE. Many trials test ovulation suppression using gonadotropin-releasing hormone agonists (GnRHa), and a meta-analysis supports their efficacy in PMD; GnRHa have been tested in two MM-related trials, and one CE open-label case series. Finally, we found that non-contraceptive hormone manipulations, including but not limited to short-term transdermal estradiol, progesterone supplementation, and progesterone antagonism, have been used across all three disorders. CONCLUSIONS: Research in PMD, MM, and CE commonly have overlapping study design and research methods, and similar effects of some interventions suggest the possibility of overlapping mechanisms contributing to their cyclical symptom presentation. Our scoping review is the first to summarize existing clinical trials in these three brain disorders, specifically focusing on hormonal treatment trials. We find that PMD has a stronger body of literature for ovulation-suppressing COC and GnRHa trials; the field of MM consists of extensive estrogen-based studies; and current consensus in CE focuses on progesterone supplementation during the luteal phase, with limited estrogen manipulations due to concerns about seizure provocation. We argue that researchers in any of these respective disciplines would benefit from greater communication regarding methods for assessment, diagnosis, subtyping, and experimental manipulation. With this scoping review, we hope to increase collaboration and communication among researchers to ultimately improve diagnosis and treatment for menstrual-cycle-linked brain disorders.

Screening fathers for postpartum depression in a maternal-child health clinic: a program evaluation in a midwest urban academic medical center.

BACKGROUND: Postpartum depression (PPD) impacts fathers as well as mothers, and is estimated to affect between 8 and 13% of fathers. Paternal PPD is a risk factor for worsened quality of life, poor physical and mental health, and developmental and relational harms in the father-mother-child triad. There are no current recommendations for PPD screening among fathers. Paternal PPD screening was piloted in an intergenerational postpartum primary care clinic. METHODS: The pilot was carried out in an intergenerational postpartum primary care clinic located at a Midwest urban academic safety net health system from October 2021 to July 2022. Fathers actively involved in relationships with mothers or infants receiving primary care in the clinic were approached with mothers' permission. A novel survey instrument was used to collect demographic/social data, as well as mental health history and current stress levels; an Edinburgh Postnatal Depression Scale (EPDS) was also administered. Screenings were completed by social workers; data were collected in REDCap and descriptive statistics were calculated in SAS. RESULTS: 29 fathers were contacted and 24 completed screening (83%). Mean age was 31 years (range 19-48). Most (87%) identified as belonging to a racial or ethnic minority group. Fathers self-reported low rates of stress and preexisting mental health conditions, but 30% screened positive for PPD on EPDS (score of ≥ 8, or suicidal ideation). Gaps in health care were found, as one-quarter (26%) of fathers were uninsured and half (54%) did not have a primary care provider. After screening, two requested mental health services, and three established new primary care with a physician. CONCLUSIONS: Participation was high in a PPD screening pilot for fathers in a primary care setting. This small sample of fathers demonstrated significant peripartum mental health challenges unlikely to have been identified otherwise. For some participants, engaging in PPD screening was an effective tool to prompt their subsequent engagement with general health care. This pilot is a step toward incorporating the health of fathers into models for supporting the health of families. Expanding screening for paternal PPD into routine primary care is necessary to reach more affected fathers.

Prevalence of lifetime self-injurious thoughts and behaviors in a global sample of 599 patients reporting prospectively confirmed diagnosis with premenstrual dysphoric disorder.

BACKGROUND: Suicide is the second leading cause of death among Americans ages 10 to 34, with alarming recent increases in suicide rates among those assigned female at birth. A large body of evidence points to menstrual cycle influences on self-injurious thoughts and behaviors (STBs), suggesting that neurobiological hormone sensitivities, such as in premenstrual dysphoric disorder (PMDD), may drive suicide risk in females. However, existing studies of STBs in PMDD use cross-sectional self-report measures of PMDD with poor validity. As a first step to establish accurate prevalence rates of STBs in PMDD, we examined the lifetime prevalence of STBs in a large global survey of patients reporting a diagnosis of PMDD based on daily ratings. METHOD: Individuals with self-reported PMDD symptoms were invited to an online survey through online support groups for PMDD and social media posts from PMDD awareness accounts. Participants reported demographics, whether they had been diagnosed with PMDD by a healthcare provider using daily ratings, STBs using the Columbia Suicide Severity Rating Scale, and history of lifetime comorbid psychiatric diagnoses. RESULTS: Of 2,689 survey completers, 599 (23%) reported a diagnosis with PMDD based on two months of daily ratings and were included in analyses. We observed high rates of lifetime active suicidal ideation (72%), planning (49%), intent (42%), preparing for an attempt (40%), and attempt (34%), as well as non-suicidal self-injury (51%). The majority (70%) of the sample reported at least one lifetime comorbid psychiatric diagnosis. Predictors of lifetime active suicidal ideation included nulliparity, low-to-moderate (vs. high) income, and history of diagnosis with major depression or post-traumatic stress disorder. Predictors of lifetime attempts among those reporting lifetime active ideation included older age, nulliparity, lower income, and history of diagnosis with post-traumatic stress disorder or borderline personality disorder. CONCLUSIONS: These data indicate high rates of STBs among those reporting prospective diagnosis of PMDD and highlight the need for prospective research on mechanisms and prevention of STBs in PMDD. Clinical practice guidelines for PMDD should accommodate comorbidities and recommend frequent screenings for STB risk. STBs should be considered for inclusion in future iterations of the DSM PMDD diagnostic criteria.

Association of pyrethroid pesticide exposure with attention-deficit/hyperactivity disorder in a nationally representative sample of U.S. children.

BACKGROUND: Pyrethroid pesticides cause abnormalities in the dopamine system and produce an ADHD phenotype in animal models, with effects accentuated in males versus females. However, data regarding behavioral effects of pyrethroid exposure in children is limited. We examined the association between pyrethroid pesticide exposure and ADHD in a nationally representative sample of US children, and tested whether this association differs by sex. METHODS: Data are from 8-15 year old participants (N = 687) in the 2001-2002 National Health and Nutrition Examination Survey. Exposure was assessed using concurrent urinary levels of the pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA). ADHD was defined by either meeting Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria on the Diagnostic Interview Schedule for Children (DISC) or caregiver report of a prior diagnosis. ADHD symptom counts were determined via the DISC. Multivariable logistic regression examined the link between pyrethroid exposure and ADHD, and poisson regression investigated the link between exposure and ADHD symptom counts. RESULTS: Children with urinary 3-PBA above the limit of detection (LOD) were twice as likely to have ADHD compared with those below the LOD (adjusted odds ratio [aOR] 2.42; 95 % confidence interval [CI] 1.06, 5.57). Hyperactive-impulsive symptoms increased by 50 % for every 10-fold increase in 3-PBA levels (adjusted count ratio 1.50; 95 % CI 1.03, 2.19); effects on inattention were not significant. We observed possible sex-specific effects: pyrethroid biomarkers were associated with increased odds of an ADHD diagnosis and number of ADHD symptoms for boys but not girls. CONCLUSIONS: We found an association between increasing pyrethroid pesticide exposure and ADHD which may be stronger for hyperactive-impulsive symptoms compared to inattention and in boys compared to girls. Given the growing use of pyrethroid pesticides, these results may be of considerable public health import.

What's Stopping Us? Using GnRH Analogs With Stable Hormone Addback in Treatment-Resistant Premenstrual Dysphoric Disorder: Practical Guidelines and Risk-Benefit Analysis for Long-term Therapy.

Objective: Despite the documented success of gonadotropin-releasing hormone analogs (GnRHa) for the treatment of treatment-resistant premenstrual dysphoric disorder (PMDD), many patients struggle to find providers who have sufficient knowledge of PMDD and its evidence-based treatments and/or who are comfortable treating PMDD after first-line treatment options have failed. Here, we discuss the barriers to initiating GnRHa for treatment-resistant premenstrual dysphoric disorder (PMDD) and offer practical solutions to address these barriers for providers who encounter patients with treatment-resistant PMDD but may not have the necessary expertise or comfort with providing evidence-based treatments (ie, gynecologists, general psychiatrists). We have included supplementary materials including patient and provider handouts, screening tools, and treatment algorithms with the hope that this review may serve as a primer on PMDD and the use of GnRHa with hormonal addback as a treatment, as well as a guideline for clinicians delivering this treatment to patients in need.Options: In addition to offering practical treatment guidelines for first and second lines of treatment for PMDD, this review offers an in-depth discussion of GnRHa for treatment-resistant PMDD.Outcomes: The burden of illness in PMDD is estimated to be similar to that of other mood disorders, and those suffering from PMDD are at a high risk for suicide.Evidence: We present a selective review of relevant clinical trials evidence supporting the use of GnRHa with addback hormones in treatment-resistant PMDD (the most recent evidence cited was published in 2021), highlighting the rationale for addback hormones and presenting the different possible hormonal addback approaches.Values: The PMDD community has and continues to suffer from debilitating symptoms despite the known interventions. This article provides guidance for implementing GnRHa into practice among a broader scope of clinicians including general psychiatrists.Benefits, Harms, and Costs: The primary benefit of implementing this guideline is that a broad range of clinicians beyond reproductive psychiatrists who encounter patients with PMDD will have a template for assessing and treating PMDD and implementing GnRHa treatment when first-line treatments fail. Harms are expected to be minimal; however, some patients may have side effects or adverse reactions to the treatment or may not respond as they had hoped. Costs of GnRHa can be high depending on insurance coverage. We provide information within the guideline to help navigate this barrier.Recommendations: (1) Prospective symptom rating in evaluating for PMDD is necessary for diagnosis and evaluating treatment response. (2) SSRIs and oral contraceptives should be trialed as the first- and second-line treatments for PMDD. (3) When first- and second-line treatments have failed to yield symptom relief, the use of GnRHa with hormone addback should be considered. Risks and benefits of GnRHa should be weighed among clinicians and patients, and potential barriers to access should be discussed.Validation: This article adds to the available systematic reviews on the effectiveness of GnRHa in the treatment of PMDD and Royal College of Obstetrics and Gynecology's guidelines on the treatment of PMDD.

Addressing Maternal Health Disparities: Building a Novel Two-Generation Approach to Comprehensive Postpartum Care.

The United States is facing a maternal health crisis with increasing rates of severe maternal morbidity and mortality. To improve maternal health and promote health equity, the authors developed a novel 2-generation model of postpartum and pediatric care. This article describes the Two-Generation Clinic (Two-Gen) and model of care. The model combines a dyadic strategy for simultaneous maternal and pediatric care with the collaborative care model in which seamless primary and behavioral health care are delivered to address the physical health, behavioral health, and social service needs of families. The transdisciplinary team includes primary care physicians, nurse practitioners, psychiatrists, obstetrician-gynecologists, social workers, care navigators, and lactation specialists. Dyad clinic visits are coscheduled (at the same time) and colocated (in the same examination room) with the same primary care provider. In the Two-Gen, the majority (89%) of the mothers self-identify as racial and ethnic minorities. More than 40% have a mental health diagnosis. Almost all mothers (97.8%) completed mental health screenings, >50.0% have received counseling from a social worker, 17.2% had a visit with a psychiatrist, and 50.0% received lactation counseling. Over 80% of the children were up to date with their well-child visits and immunizations. The Two-Gen is a promising model of care that has the potential to inform the design of postpartum care models and promote health equity in communities with the highest maternal health disparities.

Cone photoreceptor mosaic disruption associated with Cys203Arg mutation in the M-cone opsin.

Missense mutations in the cone opsins have been identified as a relatively common cause of red/green color vision defects, with the most frequent mutation being the substitution of arginine for cysteine at position 203 (C203R). When the corresponding cysteine is mutated in rhodopsin, it disrupts proper folding of the pigment, causing severe, early onset retinitis pigmentosa. While the C203R mutation has been associated with loss of cone function in color vision deficiency, it is not known what happens to cones expressing this mutant opsin. Here, we used high-resolution retinal imaging to examine the cone mosaic in two individuals with genes encoding a middle-wavelength sensitive (M) pigment with the C203R mutation. We found a significant reduction in cone density compared to normal and color-deficient controls, accompanying disruption in the cone mosaic in both individuals, and thinning of the outer nuclear layer. The C203R mosaics were different from that produced by another mutation (LIAVA) previously shown to disrupt the cone mosaic. Comparison of these mosaics provides insight into the timing and degree of cone disruption and has implications for the prospects for restoration of vision loss associated with various cone opsin mutations.

Insight from OPN1LW Gene Haplotypes into the Cause and Prevention of Myopia.

Nearsightedness (myopia) is a global health problem of staggering proportions that has driven the hunt for environmental and genetic risk factors in hopes of gaining insight into the underlying mechanism and providing new avenues of intervention. Myopia is the dominant risk factor for leading causes of blindness, including myopic maculopathy and retinal detachment. The fundamental defect in myopia-an excessively elongated eyeball-causes blurry distance vision that is correctable with lenses or surgery, but the risk of blindness remains. Haplotypes of the long-wavelength and middle-wavelength cone opsin genes (OPN1LW and OPN1MW, respectively) that exhibit profound exon-3 skipping during pre-messenger RNA splicing are associated with high myopia. Cone photoreceptors expressing these haplotypes are nearly devoid of photopigment. Conversely, cones in the same retina that express non-skipping haplotypes are relatively full of photopigment. We hypothesized that abnormal contrast signals arising from adjacent cones differing in photopigment content stimulate axial elongation, and spectacles that reduce contrast may significantly slow myopia progression. We tested for an association between spherical equivalent refraction and OPN1LW haplotype in males of European ancestry as determined by long-distance PCR and Sanger sequencing and identified OPN1LW exon 3 haplotypes that increase the risk of common myopia. We also evaluated the effects of contrast-reducing spectacles lenses on myopia progression in children. The work presented here provides new insight into the cause and prevention of myopia progression.

Selective Serotonin Reuptake Inhibitor Pharmacokinetics During Pregnancy: Clinical and Research Implications.

Pregnancy and associated physiologic changes affect the pharmacokinetics of many medications, including selective serotonin reuptake inhibitors-the first-line pharmacologic interventions for depressive and anxiety disorders. During pregnancy, SSRIs exhibit extensive pharmacokinetic variability that may influence their tolerability and efficacy. Specifically, compared to non-pregnant women, the activity of cytochrome P450 (CYP) enzymes that metabolize SSRIs drastically changes (e.g., decreased CYP2C19 activity and increased CYP2D6 activity). This perspective examines the impact of pharmacokinetic genes-related to CYP activity on SSRI pharmacokinetics during pregnancy. Through a simulation-based approach, plasma concentrations for SSRIs metabolized primarily by CYP2C19 (e.g., escitalopram) and CYP2D6 (e.g., fluoxetine) are examined and the implications for dosing and future research are discussed.

Associations between inpatient psychiatric admissions during pregnancy and adverse obstetrical and birth outcomes.

BACKGROUND: Previous research supports an association between psychiatric diagnoses and adverse obstetrical and neonatal outcomes including low birthweight, preterm birth, and preeclampsia. Women who are admitted for inpatient psychiatric care are regarded as having more acute illnesses than those who are able to be managed as outpatients. Previous research has not yet investigated how the severity of psychiatric illness, as indicated by type of antenatal psychiatric care received, is associated with adverse obstetrical outcomes. OBJECTIVE: This study examines whether the rates of adverse birth and obstetrical outcomes vary with the type of antenatal psychiatric care received when psychiatric care is indicated. STUDY DESIGN: Using a retrospective, observational design, information about women who gave birth between January 1, 2006, and December 31, 2016 was captured from electronic medical records. Women were grouped as follows: (1) those who received antepartum inpatient psychiatric treatment (n=148), (2) those with documented psychiatric history without antepartum inpatient treatment (n=301), and (3) those with no documented psychiatric history or antepartum treatment (n=301). Linear and logistic regression predicted the odds of birth and obstetrical outcomes including gestational age at birth, birthweight, mode of delivery, time to delivery, preterm premature rupture of membranes, meconium-stained amniotic fluid, and 5-minute Apgar score. Measured covariates included maternal age, race, parity, body mass index, maternal medical comorbidities, smoking tobacco, gestational age at first prenatal visit, and psychotropic medication use during pregnancy. RESULTS: Women with a psychiatric history, despite receiving any type of antepartum psychiatric care, had higher rates of adverse outcomes than women without documented psychiatric history. However, women who received antepartum inpatient psychiatric care had longer gestational lengths (38.05±3.0 vs 37.19±4.23 weeks [P<.05]) and gave birth to heavier babies (3047.84±591.99 vs 2906.48±851.85 g [P<.01]) than women with a psychiatric history who did not receive antepartum inpatient care even when adjusting for measured covariates. CONCLUSION: Receiving antepartum inpatient psychiatric care may promote positive birth outcomes for women with acutely severe psychiatric conditions.

Spectral domain optical coherence tomography and adaptive optics: imaging photoreceptor layer morphology to interpret preclinical phenotypes.

Recent years have seen the emergence of advances in imaging technology that enable in vivo evaluation of the living retina. Two of the more promising techniques, spectral domain optical coherence tomography (SD-OCT) and adaptive optics (AO) fundus imaging provide complementary views of the retinal tissue. SD-OCT devices have high axial resolution, allowing assessment of retinal lamination, while the high lateral resolution of AO allows visualization of individual cells. The potential exists to use one modality to interpret results from the other. As a proof of concept, we examined the retina of a 32 year-old male, previously diagnosed with a red-green color vision defect. Previous AO imaging revealed numerous gaps throughout his cone mosaic, indicating that the structure of a subset of cones had been compromised. Whether the affected cells had completely degenerated or were simply morphologically deviant was not clear. Here an AO fundus camera was used to re-examine the retina (~6 years after initial exam) and SD-OCT to examine retinal lamination. The static nature of the cone mosaic disruption combined with the normal lamination on SD-OCT suggests that the affected cones are likely still present.

Race- and sex-related differences in retinal thickness and foveal pit morphology.

PURPOSE: To examine sex- and race-associated differences in macular thickness and foveal pit morphology by using spectral-domain optical coherence tomography (SD-OCT). METHODS: One hundred eighty eyes of 90 healthy patients (43 women, 47 men) underwent retinal imaging with spectral-domain OCT. The lateral scale of each macular volume scan was corrected for individual differences in axial length by ocular biometry. From these corrected volumes, Early Treatment Diabetic Retinopathy Study (ETDRS) grids of retinal thickness were generated and compared between the groups. Foveal morphology was measured with previously described algorithms. RESULTS: Compared with the Caucasians, the Africans and African Americans had reduced central subfield thickness. Central subfield thickness was also reduced in the women compared with the men, although the women also showed significant thinning in parafoveal regions. There was no difference between the sexes in foveal pit morphology; however, the Africans/African Americans had significantly deeper and broader foveal pits than the Caucasians. CONCLUSIONS: Previous studies have reported race- and sex-associated differences in macular thickness, and the inference has been that these differences represent similar anatomic features. However, the data on pit morphology collected in the present study reveal an important and significant variation. Between the sexes, the differences are due to global variability in retinal thickness, whereas the variation in thickness observed between the races appears to be driven by differences in foveal pit morphology. These differences have important implications for the use of SD-OCT in detecting and diagnosing retinal disease.

Integrity of the cone photoreceptor mosaic in oligocone trichromacy.

PURPOSE: Oligocone trichromacy (OT) is an unusual cone dysfunction syndrome characterized by reduced visual acuity, mild photophobia, reduced amplitude of the cone electroretinogram with normal rod responses, normal fundus appearance, and normal or near-normal color vision. It has been proposed that these patients have a reduced number of normal functioning cones (oligocone). This paper has sought to evaluate the integrity of the cone photoreceptor mosaic in four patients previously described as having OT. METHODS: Retinal images were obtained from two brothers (13 and 15 years) and two unrelated subjects, one male (47 years) and one female (24 years). High-resolution images of the cone mosaic were obtained using high-speed adaptive optics (AO) fundus cameras. Visible structures were analyzed for density using custom software. Additional retinal images were obtained using spectral domain optical coherence tomography (SD-OCT), and the four layers of the photoreceptor-retinal pigment epithelium complex (ELM, IS/OS, RPE1, RPE2) were evaluated. Cone photoreceptor length and the thickness of intraretinal layers were measured and compared to previously published normative data. RESULTS: The adult male subject had infantile onset nystagmus while the three other patients did not. In the adult male patient, a normal appearing cone mosaic was observed. However, the three other subjects had a sparse mosaic of cones remaining at the fovea, with no structure visible outside the central fovea. On SD-OCT, the adult male subject had a very shallow foveal pit, with all major retinal layers being visible, and both inner segment (IS) and outer segment (OS) length were within normal limits. In the other three patients, while all four layers were visible in the central fovea and IS length was within normal limits, the OS length was significantly decreased. Peripherally the IS/OS layer decreased in intensity, and the RPE1 layer was no longer discernable, in keeping with the lack of cone structure observed on AO imaging outside the central fovea. CONCLUSIONS: Findings are consistent with the visual deficits being caused by a reduced number of healthy cones in the two brothers and the adult female. In the unrelated adult subject, no structural basis for the disorder was found. These data suggest two distinct groups on the basis of structural imaging. It is proposed that the former group with evidence of a reduction in cone numbers is more in keeping with typical OT, with the latter group representing an OT-like phenotype. These two groups may be difficult to readily discern on the basis of phenotypic features alone, and high-resolution imaging may be an effective way to distinguish between these phenotypes.

Color-deficient cone mosaics associated with Xq28 opsin mutations: a stop codon versus gene deletions.

Our understanding of the etiology of red-green color vision defects is evolving. While missense mutations within the long- (L-) and middle-wavelength sensitive (M-) photopigments and gross rearrangements within the L/M-opsin gene array are commonly associated with red-green defects, recent work using adaptive optics retinal imaging has shown that different genotypes can have distinct consequences for the cone mosaic. Here we examined the cone mosaic in red-green color deficient individuals with multiple X-chromosome opsin genes that encode L opsin, as well as individuals with a single X-chromosome opsin gene that encodes L opsin and a single patient with a novel premature termination codon in his M-opsin gene and a normal L-opsin gene. We observed no difference in cone density between normal trichomats and multiple or single-gene deutans. In addition, we demonstrate different phenotypic effects of a nonsense mutation versus the previously described deleterious polymorphism, (LIAVA), both of which differ from multiple and single-gene deutans. Our results help refine the relationship between opsin genotype and cone photoreceptor mosaic phenotype.