The NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty: Protocol and rationale for methods and measures.

Delineating the relationship between human neurodevelopment and the maturation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty is critical for investigating the increase in vulnerability to neuropsychiatric disorders that is well documented during this period. Preclinical research demonstrates a clear association between gonadal production of sex steroids and neurodevelopment; however, identifying similar associations in humans has been complicated by confounding variables (such as age) and the coactivation of two additional endocrine systems (the adrenal androgenic system and the somatotropic growth axis) and requires further elucidation. In this paper, we present the design of, and preliminary observations from, the ongoing NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty. The aim of this study is to directly examine how the increase in sex steroid hormone production following activation of the HPG-axis (i.e., gonadarche) impacts neurodevelopment, and, additionally, to determine how gonadal development and maturation is associated with longitudinal changes in brain structure and function in boys and girls. To disentangle the effects of sex steroids from those of age and other endocrine events on brain development, our study design includes 1) selection criteria that establish a well-characterized baseline cohort of healthy 8-year-old children prior to the onset of puberty (e.g., prior to puberty-related sex steroid hormone production); 2) temporally dense longitudinal, repeated-measures sampling of typically developing children at 8-10 month intervals over a 10-year period between the ages of eight and 18; 3) contemporaneous collection of endocrine and other measures of gonadal, adrenal, and growth axis function at each timepoint; and 4) collection of multimodal neuroimaging measures at these same timepoints, including brain structure (gray and white matter volume, cortical thickness and area, white matter integrity, myelination) and function (reward processing, emotional processing, inhibition/impulsivity, working memory, resting-state network connectivity, regional cerebral blood flow). This report of our ongoing longitudinal study 1) provides a comprehensive review of the endocrine events of puberty; 2) details our overall study design; 3) presents our selection criteria for study entry (e.g., well-characterized prepubertal baseline) along with the endocrinological considerations and guiding principles that underlie these criteria; 4) describes our longitudinal outcome measures and how they specifically relate to investigating the effects of gonadal development on brain development; and 5) documents patterns of fMRI activation and resting-state networks from an early, representative subsample of our cohort of prepubertal 8-year-old children.

Transdermal estradiol for postpartum depression: results from a pilot randomized, double-blind, placebo-controlled study.

Postpartum depression (PPD) is a common complication following delivery, though evidence-based treatment options are limited. This study explores the feasibility and efficacy of outpatient PPD treatment with transdermal estradiol (TE). In a pilot, double-blind, placebo-controlled trial, women with PPD were randomized to receive transdermal 17ß-estradiol (100 mcg/day) or placebo patch. Over 6 weeks, women completed weekly ratings on the Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS), and Hamilton Depression Scale (HAM-D). Primary outcome measures were treatment response (> 50% decrease from baseline BDI) and remission (BDI < 10) at 6 weeks, and secondary outcome measures included severity on all scales at weeks 3 and 6. Of 12 recruited women, 6 received TE and 6 received placebo. By week 6, 5 women receiving TE responded to treatment and 4 showed symptom remission, compared to 2 responders and 1 remitter in the placebo group. This difference was not significant (p = 0.24). In a mixed-model of BDI ratings, TE was associated with a 9.2 point decrease at 3 weeks (95%CI - 19.5 to + 1.0, p = 0.074) and a 10.5 point decrease at 6 weeks (95%CI - 21.0-0.0, p = 0.049) compared to placebo, though these differences did not survive multiple comparisons correction. Analogous effects were found for HAM-D but not EPDS scores. Interestingly, no significant difference in plasma estradiol levels existed between groups. We were unable to demonstrate a significant therapeutic benefit of TE compared with placebo in PPD. Although limited by under-recruitment and loss to follow-up, our results suggest TE is a feasible option for outpatient PPD management, with preliminary evidence (based on secondary outcomes) for efficacy. Therapeutic effects may be seen as early as 3 weeks and may not directly depend on peripheral measures of estradiol.

Evaluation of incidental pelvic fluid in relation to physiological changes in healthy pubescent children using pelvic magnetic resonance imaging.

BACKGROUND: Peritoneal free fluid can indicate an underlying disease process; however detection of minimal peritoneal free fluid in healthy children is not uncommon. OBJECTIVE: To assess the significance of incidental peritoneal free fluid within healthy children by MRI and its relation to physiological changes during puberty. MATERIALS AND METHODS: This prospective study was performed on 32 healthy volunteers (20 boys) between the ages of 8 years and 13 years, with consecutive follow-ups every 8-10 months for an average of 3 years. Body mass index (BMI) z-score, pubertal status, C-reactive protein and sex hormone concentrations were assessed prior to MRI studies. We reviewed a total of 120 pelvic MRI studies (61 boys) and measured the quantity of peritoneal free fluid. For statistical analysis we used linear mixed-model accounting for within-patient correlations. RESULTS: The mean ± standard deviation volume of peritoneal free fluid was 4.7±5.7 mL in girls and 1.9±3.1 mL in boys, with a maximum volume of 25 mL and 17 mL, respectively. The prevalence of peritoneal free fluid was significantly higher in girls (91%) compared to boys (67%; P=0.0035). In 15% of the girls and 3% of the boys the fluid was greater than 10 mL. The mean volume of peritoneal free fluid in the fourth stage of puberty was higher and significantly different from the mean volume in the first stage of puberty (P=0.01). CONCLUSION: Among healthy pubescent children, the prevalence of peritoneal free fluid is significantly higher in girls. The volume of peritoneal free fluid can reach volumes greater than 10 mL during normal puberty, especially in the fourth stage, and can be assumed normal in the absence of active disease.

Depression during the menopause transition: impact on quality of life, social adjustment, and disability.

The impact of depression on quality of life (QOL) and social support has neither been well characterized in clinical samples of women with perimenopausal depression (PMD) nor have the relative contributions of depression and other menopausal symptoms (e.g., hot flushes) to declining QOL been clarified. In this study, we compared QOL measures, social support, and functional disability in PMD and non-depressed perimenopausal women. We evaluated women aged 40-60 years who presented with menstrual cycle irregularity, elevated plasma FSH levels, and met criteria for perimenopause. A structured clinical interview was administered to determine the presence or absence of major and minor depression. Outcome measures included the Quality of Life Enjoyment Scale Questionnaire, the Sheehan Disability Scale, the Global Assessment of Functioning, the Social Adjustment Scale, and the Duke Social Support Index. Kruskal-Wallis tests and ANOVAs were used to compare outcome measures. Ninety women with PMD and 51 control women participated in this study. Women with PMD reported significantly decreased QOL, social support, and adjustment and increased disability compared with non-depressed perimenopausal women. Neither perimenopausal reproductive status alone nor the presence of hot flushes had a significant negative impact on QOL measures. PMD is accompanied by significant reductions in QOL, social support, and disability similar to depression in women at other stages of life. PMD may also contribute to decreased QOL in community- or clinic-based samples of perimenopausal women. It remains unclear whether the clinical characteristics we identified reflect pre-existing risk factors for depression during the perimenopause or the effects of a current depression. Future clinical and treatment studies in perimenopausal women should distinguish depressed women when outcome measures include QOL.

The development of thought problems: a longitudinal family risk study of offspring of bipolar, unipolar, and well parents.

There is growing evidence that many offspring of parents with bipolar disorder (BD) will develop moderate to severe forms of psychopathology during childhood and adolescence, including thought problems. The purpose of this study was to evaluate the developmental progression of thought problems within the context of a family risk study. Repeated assessments of thought problems, spanning approximately 15 years, were conducted in offspring (N = 192 from 98 families) of parents diagnosed with BD (O-BD), unipolar depression (O-UNI), or no significant psychiatric or medical problems (O-WELL). Survival analysis showed that the O-BD group had the greatest estimated probability of developing thought problems over time, followed by O-UNI, and then O-WELL and O-BD exhibiting higher levels of persistence than O-WELL. Parent-reported thought problems in childhood and adolescence predicted a range of problems in young adulthood. Disturbances in reality testing and other atypical behaviors are likely to disrupt progression through important developmental periods and to associate with poor outcomes. These findings are likely relevant to preventing the occurrence or progression of problems in offspring of bipolar parents. The study of thought problems across development represents an important area of continued research in children at risk for development of affective disorders.

A Combined Region- and Pixel-Based Deep Learning Approach for Quantifying Abdominal Adipose Tissue in Adolescents Using Dixon Magnetic Resonance Imaging.

BACKGROUND: The development of adipose tissue during adolescence may provide valuable insights into obesity-associated diseases. We propose an automated convolutional neural network (CNN) approach using Dixon-based magnetic resonance imaging (MRI) to quantity abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in children and adolescents. METHODS: 474 abdominal Dixon MRI scans of 136 young healthy volunteers (aged 8-18) were included in this study. For each scan, an axial fat-only Dixon image located at the L2-L3 disc space and another image at the L4-L5 disc space were selected for quantification. For each image, an outer and an inner region around the abdomen wall, as well as SAT and VAT pixel masks, were generated by expert readers as reference standards. A standard U-Net CNN architecture was then used to train two models: one for region segmentation and one for fat pixel classification. The performance was evaluated using the dice similarity coefficient (DSC) with fivefold cross-validation, and by Pearson correlation and the Student's t-test against the reference standards. RESULTS: For the DSC results, means and standard deviations of the outer region, inner region, SAT, and VAT comparisons were 0.974 ± 0.026, 0.997 ± 0.003, 0.981 ± 0.025, and 0.932 ± 0.047, respectively. Pearson coefficients were 1.000 for both outer and inner regions, and 1.000 and 0.982 for SAT and VAT comparisons, respectively (all p = NS). CONCLUSION: These results show that our method not only provides excellent agreement with the reference SAT and VAT measurements, but also accurate abdominal wall region segmentation. The proposed combined region- and pixel-based CNN approach provides automated abdominal wall segmentation as well as SAT and VAT quantification with Dixon MRI and enables objective longitudinal assessment of adipose tissues in children during adolescence.

Rapid response to fluoxetine in women with premenstrual dysphoric disorder.

BACKGROUND: Selective serotonin reuptake inhibitors (SRIs) relieve irritability within days in women with premenstrual dysphoric disorder (PMDD); however, the effects on other affective symptoms in PMDD remain to be demonstrated. METHODS: We performed hourly ratings in women with PMDD to test the specificity of the therapeutic effects of SRIs and to determine whether the kinetics of these effects differ from those of the symptom offset accompanying menses. Twelve women with PMDD received fluoxetine (20 mg daily) during the luteal phase of the menstrual cycle. Twelve other women with PMDD received no treatment. Outcome measures included a visual analogue scale completed hourly before and after either the start of SRIs or at menses-onset in the untreated women and the premenstrual tension syndrome (PMTS) scale completed daily. Data were analyzed by ANOVA-R. RESULTS: Hourly VAS scores significantly improved after SRI in irritability as well as sadness, anxiety, and mood swings. Compared with the symptomatic pretreatment baseline, PMTS scores significantly improved on the second day after the start of SRI (p < .01). An identical time course of symptom improvement occurred after both SRI and menses-onset. CONCLUSION AND DISCUSSION: These data document that the rapid response to SRI was not limited to irritability. The similar kinetics in the remission of PMDD after SRIs and after menses-onset suggest both a phenotype reflecting the relative capacity to rapidly change affective state, and a possible therapeutic mechanism by which SRIs recruit this endogenous capacity to change state, normally expressed around menses-onset in women with PMDD.

The short-term effects of estradiol, raloxifene, and a phytoestrogen in women with perimenopausal depression.

OBJECTIVE: We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD). METHODS: Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure. RESULTS: Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (P = 0.34) or Beck Depression Inventory (P = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (P = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (P = 0.0005), and less consistently with placebo (P = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE-15.3 (4.5), raloxifene-16.0 (3.7), Rimostil-14.0 (2.7), and placebo-15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE-5.2(1.1), raloxifene-5.8(1.2), Rimostil-11.2(1.4), and placebo-7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (P values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo. CONCLUSIONS: This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha).

Effects of sex on placebo effects in chronic pain participants: a cross-sectional study.

ABSTRACT: Sex-related differences can influence outcomes of randomized clinical trials and may jeopardize the effectiveness of pain management and other therapeutics. Thus, it is essential to understand the mechanistic and translational aspects of sex differences in placebo outcomes. Recently, studies in healthy participants have shed light on how sex-related placebo effects might influence outcomes, yet no research has been conducted in a patient population. Herein, we used a tripartite approach to evaluate the interaction of prior therapeutic experience (eg, conditioning), expectations, and placebo effects in 280 chronic (orofacial) pain patients (215 women). In this cross-sectional study, we assessed sex differences in placebo effects, conditioning as a proxy of prior therapeutic effects, and expectations evaluated before and after the exposure to positive outcomes, taking into account participant-experimenter sex concordance and hormonal levels (estradiol and progesterone assessed in premenopausal women). We used mediation analysis to determine how conditioning strength and expectations impacted sex differences in placebo outcomes. Independent of gonadal hormone levels, women showed stronger placebo effects than men. We also found significant statistical sex differences in the conditioning strength and reinforced expectations whereby reinforced expectations mediated the sex-related placebo effects. In addition, the participant-experimenter sex concordance influenced conditioning strength, reinforced expectations, and placebo effects in women but not in men. Our findings suggest that women experience larger conditioning effects, expectations, and placebo effects emphasizing the need to consider sex as a biological variable when placebo components of any outcomes are part of drug development trials and in pain management.

The Cortisol and ACTH Response to Dex/CRH Testing in Women With and Without Perimenopausal Depression.

CONTEXT: Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are frequent accompaniments of depression, and studies have documented the role of stress and stressful life events in the ontogeny of perimenopausal depressions (PMD). Because HPA axis function in women is further modulated both by aging and ovarian steroids, it is possible that a dysregulated HPA axis contributes to the increased risk of PMD. OBJECTIVE: We examined HPA axis function in perimenopausal women with and without depression using the combined dexamethasone-corticotropin-releasing hormone (Dex/CRH) test. METHODS: Dex/CRH tests were performed on 20 women with PMD and 20 women who were also perimenopausal but without current or past depression (control women). Main outcome measures were plasma levels of cortisol and adrenocorticotropin (ACTH) and 24-hour urinary free cortisol (UFC). Five women took chronic stable medications, otherwise all women were medically healthy, and both groups were comparable with respect to reproductive stage and age. Standardized symptom rating scales were administered to each woman prior to Dex/CRH testing. RESULTS: No group differences were present in either baseline or stimulated ACTH and cortisol secretion. Baseline plasma measures of estradiol, progesterone, and 24-hour UFC levels similarly did not differ in PMD and control women. CONCLUSION: Despite reports of increased stress responsiveness in PMD, we observed no abnormalities of HPA axis activity associated with PMD compared with women without depression. These findings suggest that PMD is not uniformly associated with HPA dysregulation and could reflect underlying pathophysiologic processes that are distinct from women with nonreproductive-related depressions.

Subgenual cingulate resting regional cerebral blood flow in premenstrual dysphoric disorder: differential regulation by ovarian steroids and preliminary evidence for an association with expression of ESC/E(Z) complex genes.

Substantial evidence suggests that circulating ovarian steroids modulate behavior differently in women with PMDD than in those without this condition. However, hormonal state-related abnormalities of neural functioning in PMDD remain to be better characterized. In addition, while altered neural function in PMDD likely co-exists with alterations in intrinsic cellular function, such a relationship has not been explored. Here, we investigated the effects of ovarian steroids on basal, resting regional cerebral blood flow (rCBF) in PMDD, and, in an exploratory analysis, we tested whether the rCBF findings were linked to the expression of ESC/E(Z) genes, which form an essential ovarian steroid-regulated gene-silencing complex. Resting rCBF was measured with oxygen-15 water PET (189 PET sessions in 43 healthy women and 20 women with PMDD) during three self-as-own-control conditions: GnRH agonist (Lupron)-induced ovarian suppression, estradiol add-back, and progesterone add-back. ESC/E(Z) gene expression data were obtained from RNA-sequencing of lymphoblastoid cell lines performed in a previous study and were examined in relation to hormone-induced changes in rCBF. In the rCBF PET data, there was a significant diagnosis-by-hormone interaction in the subgenual cingulate (PFDR = 0.05), an important neuroanatomical hub for regulating affective state. Whereas control women showed no hormonally-related changes in resting rCBF, those with PMDD showed decreased resting rCBF during both estradiol (P = 0.02) and progesterone (P = 0.0002) add-back conditions. In addition, in PMDD, ESC/E(Z) gene expression correlated with the change in resting rCBF between Lupron-alone and progesterone conditions (Pearson r = -0.807, P = 0.016). This work offers a formulation of PMDD that integrates behavioral, neural circuit, and cellular mechanisms, and may provide new targets for future therapeutic interventions.

Continuity and cascade in offspring of bipolar parents: a longitudinal study of externalizing, internalizing, and thought problems.

There is growing evidence that many offspring of bipolar parents will develop moderate to severe forms of psychopathology during childhood and adolescence. The purpose of this study was to apply growth curve models to evaluate developmental progression with regard to continuity and cascades representative within the context of a family risk study of bipolar disorder (BD). Repeated assessments of externalizing, internalizing, and thought problems, spanning more than a decade, were examined in a total of 94 offspring of parents with BD (O-BD), major depressive disorder (O-UNI), or no significant psychiatric or medical problems (O-WELL). Continuity was defined by the growth curve of the O-WELL group who exhibited low levels of problems from early childhood through late adolescence. Discontinuity, as evidenced by greater complexity of growth curves relative to the O-WELL group, was exhibited in the at- risk offspring groups for internalizing problems. Different patterns of developmental cascades were supported for the at-risk group with O-UNI showing a robust cascade from self-regulatory deficits (externalizing problems) to internalizing problems. There was also support for a cascade from self-regulatory deficits to thought problems across the entire group (with some support that this pattern was accounted for primarily by O-BD). This study not only serves to advance our understanding of the risks associated with a family history of BD, but also provides a novel approach to examining developmental cascades.

OPRM1 rs1799971, COMT rs4680, and FAAH rs324420 genes interact with placebo procedures to induce hypoalgesia.

Genetics studies on the placebo hypoalgesic effect highlight a promising link between single nucleotide polymorphisms (SNPs) in the dopamine, opioid, and endocannabinoid genes and placebo hypoalgesia. However, epistasis and replication studies are missing. In this study, we expanded on previous findings related to the 3 SNPs in the opioid receptor mu subunit (OPRM1 rs1799971), catechol-O-methyltransferase (COMT rs4680), and fatty acid amide hydrolase (FAAH rs324420) genes associated with placebo hypoalgesia and tested the effect of a 3-way interaction on placebo hypoalgesia. Using 2 well-established placebo procedures (verbal suggestion and learning paradigm), we induced significant placebo hypoalgesic effects in 160 healthy participants. We found that individuals with OPRM1 AA combined with FAAH Pro/Pro and those carrying COMT met/met together with FAAH Pro/Pro showed significant placebo effects. Participants with COMT met/val alleles showed significant placebo effects independently of OPRM1 and FAAH allele combinations. Finally, the model that included the placebo procedure and genotypes predicted placebo responsiveness with a higher accuracy (area under the curve, AUC = 0.773) as compared to the SNPs alone indicating that genetic variants can only partially explain the placebo responder status. Our results suggest that the endogenous mu-opioid system with a larger activation in response to pain in the met/val allele carriers as well as the synergism between endogenous mu-opioid system and cannabinoids might play the most relevant role in driving hypoalgesic responses. Future epistasis studies with larger sample sizes will help us to fully understand the complexity of placebo effects and explain the mechanisms that underlie placebo responsiveness.

Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss - results of an exploratory study.

PURPOSE: Roflumilast (Daliresp, Daxas) is a FDA-approved phosphodiesterase 4 (PDE4) inhibitor for the treatment of moderate-to-severe chronic obstructive pulmonary disease. In mice and in limited human studies, this oral medication can cause weight loss and improve insulin sensitivity. We set out to determine the mechanism of its effect on insulin sensitivity. PATIENTS AND METHODS: Eight adults with overweight/obesity and prediabetes received roflumilast for 6 weeks. Before and after roflumilast, subjects underwent tests of insulin sensitivity, mixed meal test, body composition, markers of inflammation, and mitochondria function. Dietary intake and physical activity were also assessed. Our primary outcome was the change in peripheral insulin sensitivity, as assessed by the hyper-insulinemic euglycemic clamp. RESULTS: This study was underpowered for the primary outcome. Pre- and post-roflumilast mean peripheral insulin sensitivity were 48.7 and 70.0 mg/g fat free mass/minute, respectively, (P-value=0.18), respectively. Among the mixed meal variables, roflumilast altered glucagon-like peptide 1 (GLP-1) hormone the most, although the average effect was not statistically significant (P=0.18). Roflumilast induced a trend toward significance in 1) decreased energy intake (from 11,095 KJ to 8,4555 KJ, P=0.07), 2) decreased fat mass (from 34.53 to 32.97 kg, P=0.06), 3) decreased total and LDL cholesterol (P=0.06 for both variables), and 4) increased plasma free fatty acids (from 0.40 to 0.50 mEq/L, P=0.09) The interval changes in adiposity and free fatty acid were significantly associated with the subject's age (P-value range= <0.001 to 0.02 for the correlations). Inflammatory and adhesion markers, though unchanged, significantly correlated with one another and with incretin hormones only after roflumilast. CONCLUSION: We demonstrate, for the first time in humans, increasing percentage of fat mass loss from roflumilast with increasing age in adults with prediabetes and overweight/obesity. We also demonstrate novel associations among roflumilast-induced changes in incretin hormones, inflammatory markers, peripheral insulin sensitivity, and adiposity. We conclude that roflumilast's early effects on insulin sensitivity is indirect and likely mediated through roflumilast's prioritization of lipid over glucose handling. CLINICAL TRIALS REGISTRATION: NCT01862029.

The psychology of antecedents to adult reproductive disorders in adolescent girls.

The normal developmental tasks and roles of adolescence are altered by a diagnosis of a reproductive disorder. The crisis of impaired fertility affects both parent and child, stressing the family system. For the adolescent girl, a reproductive disorder has an impact on her developing sense of self, body-image, and sexuality, which, in turn, can affect her self-esteem and relationships with others. Because of the sexual nature of a reproductive disorder, feelings of embarrassment or protectiveness are often engendered that can make it difficult for families to discuss. Nonetheless, families do best with openness and honesty regarding the condition and should be discouraged from keeping the diagnosis a secret. Adolescence encompasses a broad spectrum of emotional maturity, which needs to be considered by parents and clinicians when communicating information. Understanding that the family is an emotional unit, a family systems approach to deal with health issues is most appropriate. In this context, parents need to first deal with their own feelings about the diagnosis, before they can help their child. Secondly, parents must be provided with tools to build an ongoing conversation with their child that will avoid stigmatizing her condition and handicapping her growth into healthy adulthood. The goal for parent and clinician is to help the adolescent girl formulate positive self-esteem and body image, despite impaired fertility.

Low bone mass in premenopausal women with depression.

BACKGROUND: An increased prevalence of low bone mineral density (BMD) has been reported in patients with major depressive disorder (MDD), mostly women. METHODS: Study recruitment was conducted from July 1, 2001, to February 29, 2003. We report baseline BMD measurements in 89 premenopausal women with MDD and 44 healthy control women enrolled in a prospective study of bone turnover. The BMD was measured by dual-energy x-ray absorptiometry at the spine, hip, and forearm. Mean hourly levels of plasma 24-hour cytokines, 24-hour urinary free cortisol, and catecholamine excretion were measured in a subset of women. We defined MDD according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). RESULTS: The prevalence of low BMD, defined as a T score of less than -1, was greater in women with MDD vs controls at the femoral neck (17% vs 2%; P = .02) and total hip (15% vs 2%; P = .03) and tended to be greater at the lumbar spine (20% vs 9%; P = .14). The mean +/- SD BMD, expressed as grams per square centimeters, was lower in women with MDD at the femoral neck (0.849 +/- 0.121 vs 0.866 +/- 0.094; P = .05) and at the lumbar spine (1.024 +/- 0.117 vs 1.043 +/- 0.092; P = .05) and tended to be lower at the radius (0.696 +/- 0.049 vs 0.710 +/- 0.055; P = .07). Women with MDD had increased mean levels of 24-hour proinflammatory cytokines and decreased levels of anti-inflammatory cytokines. CONCLUSIONS: Low BMD is more prevalent in premenopausal women with MDD. The BMD deficits are of clinical significance and comparable in magnitude to those resulting from established risk factors for osteoporosis, such as smoking and reduced calcium intake. The possible contribution of immune or inflammatory imbalance to low BMD in premenopausal women with MDD remains to be clarified.

Role of placebo effects in pain and neuropsychiatric disorders.

The placebo (and the nocebo) effect is a powerful determinant of health outcomes in clinical disease treatment and management. Efforts to completely eradicate placebo effects have shifted dynamically, as increasingly more researchers are tuned to the potentially beneficial effects of incorporating those uncontrollable placebo effects into clinical therapeutic strategies. In this review, we highlight the major findings from placebo research, elucidating the main neurobiological systems and candidate determinants of the placebo phenomenon, and illustrate a perspective that can effectively frame future research on the topic. Finally, we issue a call for increased research on the efficacy of therapeutic strategies that incorporate placebo "tools," and argue that clinical trials of the placebo response in neuropsychiatric diseases and disorders has important and far-reaching translational and clinical relevance.

Premenstrual Dysphoric Disorder Symptoms Following Ovarian Suppression: Triggered by Change in Ovarian Steroid Levels But Not Continuous Stable Levels.

OBJECTIVE: Premenstrual dysphoric disorder (PMDD) symptoms are eliminated by ovarian suppression and stimulated by administration of ovarian steroids, yet they appear with ovarian steroid levels indistinguishable from those in women without PMDD. Thus, symptoms could be precipitated either by an acute change in ovarian steroid levels or by stable levels above a critical threshold playing a permissive role in expression of an underlying infradian affective "pacemaker." The authors attempted to determine which condition triggers PMDD symptoms. METHOD: The study included 22 women with PMDD, ages 30 to 50 years. Twelve women who experienced symptom remission after 2-3 months of GnRH agonist-induced ovarian suppression (leuprolide) then received 1 month of single-blind (participant only) placebo and then 3 months of continuous combined estradiol/progesterone. Primary outcome measures were the Rating for Premenstrual Tension observer and self-ratings completed every 2 weeks during clinic visits. Multivariate repeated-measure ANOVA for mixed models was employed. RESULTS: Both self- and observer-rated scores on the Rating for Premenstrual Tension were significantly increased (more symptomatic) during the first month of combined estradiol/progesterone compared with the last month of leuprolide alone, the placebo month, and the second and third months of estradiol/progesterone. There were no significant differences in symptom severity between the last month of leuprolide alone, placebo month, or second and third months of estradiol/progesterone. Finally, the Rating for Premenstrual Tension scores in the second and third estradiol/progesterone months did not significantly differ. CONCLUSIONS: The findings demonstrate that the change in estradiol/progesterone levels from low to high, and not the steady-state level, was associated with onset of PMDD symptoms. Therapeutic efforts to modulate the change in steroid levels proximate to ovulation merit further study.

Neuropsychological functioning in adolescent children of mothers with a history of bipolar or major depressive disorders.

BACKGROUND: Growing evidence demonstrates an association of neuropsychological deficits with mood disorders, but it is not yet clear whether these deficits are risk factors or are concomitant with the symptoms. This study examines the neuropsychological functioning of a group of adolescent offspring who are at risk for a mood disorder by virtue of being raised by mothers who have been diagnosed with major depressive disorder (MDD) or bipolar disorder (BPD). METHODS: Adolescent offspring of mothers with BPD (n = 43) or MDD (n = 72) and of psychiatrically well parents (n = 50) completed a battery of neuropsychological tests to assess executive functioning, memory, and attention. RESULTS: Children of mothers with BPD showed deficits in executive functioning and selective deficits in spatial memory and attention, in comparison with children of well mothers. Deficits were not found for children of MDD mothers. CONCLUSIONS: Knowledge of these neurocognitive processes could aid ultimately in determining whether neurocognitive deficits precede BPD, whether unique profiles are associated with various types of mood disorders, and who may benefit from interventions.

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder.

Changes in neurosteroid levels during the luteal phase of the menstrual cycle may precipitate affective symptoms. To test this hypothesis, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion of progesterone to its neurosteroid metabolite allopregnanolone in women with premenstrual dysphoric disorder (PMDD) and in asymptomatic control women. Sixteen women with prospectively confirmed PMDD and 16 control women participated in one of two separate randomized, double-blind, placebo-controlled, cross-over trials, each lasting three menstrual cycles. After one menstrual cycle of single-blind placebo, participants were randomized to receive, for the next two menstrual cycles, either double-blind placebo or dutasteride (low-dose 0.5 mg/day in the first eight PMDD and eight control women or high-dose 2.5 mg/day in the second group of women). All women completed the daily rating form (DRF) and were evaluated in clinic during the follicular and luteal phases of each menstrual cycle. Main outcome measures were the DRF symptoms of irritability, sadness, and anxiety. Analyses were performed with SAS PROC MIXED. In the low-dose group, no significant effect of dutasteride on PMDD symptoms was observed compared with placebo (ie, symptom cyclicity maintained), and plasma allopregnanolone levels increased in women with PMDD from follicular to the luteal phases, suggesting the absence of effect of the low-dose dutasteride on 5α-reductase. In contrast, the high-dose group experienced a statistically significant reduction in several core PMDD symptoms (ie, irritability, sadness, anxiety, food cravings, and bloating) on dutasteride compared with placebo. Dutasteride had no effect on mood in controls. Stabilization of allopregnanolone levels from the follicular to the luteal phase of the menstrual cycle by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolite mitigates symptoms in PMDD. These data provide preliminary support for the pathophysiologic relevance of neurosteroids in this condition.