Glucocorticoid Receptor (GR) antagonism as disease-modifying treatment for MDD with childhood trauma: protocol of the RESET-medication randomized controlled trial.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous psychiatric disorder. Childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18) is one of the largest and most consistent risk factors for development and poor course of MDD. Overactivity of the HPA-axis and the stress hormone cortisol is thought to play a role in the vulnerability for MDD following exposure to CT. Rodent experiments showed that antagonism of the glucocorticoid receptor (GR) at adult age reversed the effects of early life stress. Similarly, we aim to target MDD in individuals with CT exposure using the GR antagonist mifepristone. METHODS: The RESET-medication study is a placebo-controlled double-blind randomized controlled trial (RCT) which aims to include 158 adults with MDD and CT. Participants will be randomized (1:1) to a 7-day treatment arm of mifepristone (1200 mg/day) or a control arm (placebo). Participants are allowed to receive usual care for MDD including antidepressants. Measurements include three face-to-face meetings at baseline (T0), day 8 (T1), week 6 (T2), and two online follow-up meetings at 12 weeks (T3) and 6 months (T4). A subgroup of participants (N = 80) are included in a fMRI sub-study (T0, T2). The main study outcome will be depressive symptom severity as measured with the Inventory of Depressive Symptomatology-Self Rated (IDS-SR) at T2. Secondary outcomes include, among others, depressive symptom severity at other time points, disability, anxiety, sleep and subjective stress. To address underlying mechanisms mifepristone plasma levels, cortisol, inflammation, epigenetic regulation and fMRI measurements are obtained. DISCUSSION: The RESET-medication study will provide clinical evidence whether GR antagonism is a disease-modifying treatment for MDD in individuals exposed to CT. If effective, this hypothesis-driven approach may extend to other psychiatric disorders where CT plays an important role. TRIAL REGISTRATION: The trial protocol has been registered 01-02-2022 on ClinicalTrials.gov with ID "NCT05217758".

Effects of 12 weeks of water aerobics on body composition in those affected by breast cancer.

Exercise may prevent changes in body composition and provide an effective means of improving the side effects of treatment without causing lymphedema. PURPOSE: Test the effectiveness of a 12-week water aerobics program on body composition and lymphedema risk in breast cancer survivors. METHODS: Body composition analysis was completed at weeks 0, 6, and 12 weeks. RESULTS: Ten females completed all testing. Baseline subject characteristics were as follows: age (59.40 ± 8.22 years), weight (169.91 ± 41.70 lbs), body fat percent (%BF) (40.15 ± 9.84%), body fat mass (BFM) (71.27 ± 31.50 lbs), lean body mass (LBM) (98.66 ± 13.24 lbs), skeletal muscle mass (SMM) (53.17 ± 8.09 lbs), intracellular water (ICW) (44.24 ± 6.18 lbs), and extracellular water (ECW) (28.91 ± 3.62 lbs). One-way ANOVA showed no statistically significant differences over time as determined for weight (F(2.27) = 0.002, P = 0.96), %BF (F(2.27) = 0.004, P = 0.97), BFM (F(2.27) = 0.001, P = 0.97), LBM (F(2.27) = 0.013, P = 0.95), SMM (F(2.27) = 0.027, P = 0.91), ICW (F(2.27) = 0.021, P = 0.93), and ECW (F(2.27) = 0.01, P = 0.94) across the 12 weeks. CONCLUSIONS: A water aerobics program for 12 weeks was not enough to observe changes in body composition nor did it increase the risk for lymphedema and may be a safe exercise method for breast cancer survivors.

The Andro Project: physiological and hormonal influences of androstenedione supplementation in men 35 to 65 years old participating in a high-intensity resistance training program.

BACKGROUND: Since the passage of The Dietary Supplement Health and Education Act in 1994, there has been a flood of new "dietary" supplements promoting anti-aging benefits such as the enhancement of growth hormone or testosterone levels. Androstenediol and androstenedione are such products. This study's purpose was to elucidate the physiological and hormonal effects of 200 mg/d of oral androstenediol and androstenedione supplementation in men aged 35 to 65 years while participating in a 12-week high-intensity resistance training program. METHODS: Fifty men not consuming any androgenic-enhancing substances and with normal total testosterone levels, prostate-specific antigen, hemoglobin, and hematocrit, and with no sign of cardiovascular or metabolic diseases participated. Subjects were randomly assigned to a placebo, androstenediol (diol), or androstenedione (dione) group using a double-blind study design. Main outcomes included serum sex hormone profile, body composition assessment, muscular strength, and blood lipid profiles. RESULTS: During the 12 weeks of androstenedione or androstenediol use, a significant increase in the aromatization by-products estrone and estradiol was observed in both groups (P =.03). In the dione group, total testosterone levels significantly increased 16% after 1 month of use, but by the end of 12 weeks, they returned to pretreatment levels. This return to baseline levels resulted from increases in aromatization and down-regulation in endogenous testosterone synthesis based on the fact that luteinizing hormone was attenuated 18% to 33% during the treatment period. Neither androstenediol nor androstenedione enhanced the adaptations to resistance training compared with placebo for body composition or muscular strength. However, both androstenediol and androstenedione supplementation adversely affected high-density lipoprotein cholesterol (HDL-C) levels, coronary heart disease risk (representing a 6.5% increase), and each group's respective (low-density lipoprotein cholesterol [LDL-C]/HDL-C)/(apolipoprotein A/apolipoprotein B) lipid ratio (diol: +5.2%; dione: +10.5%; P =.05). In contrast, the placebo group's HDL-C levels increased 5.1%, with a 12.3% decline in the (LDL-C/HDL-C)/(apolipoprotein A/apolipoprotein B) lipid ratio. These negative and positive lipid effects occurred despite no significant alterations in body composition or dietary intakes in the supplemental groups or placebo group, respectively. CONCLUSIONS: Testosterone precursors do not enhance adaptations to resistance training when consumed in dosages recommended by manufacturers. Testosterone precursor supplementation does result in significant increases in estrogen-related compounds, dehydroepiandrosterone sulfate concentrations, down-regulation in testosterone synthesis, and unfavorable alterations in blood lipid and coronary heart disease risk profiles of men aged 35 to 65 years.

In vivo 4-androstene-3,17-dione and 4-androstene-3 beta,17 beta-diol supplementation in young men.

To determine if known androgenic hormone precursors for testosterone in the androgen pathway would be readily transformed to testosterone, eight male subjects [mean age 23.8 (SEM 3) years, bodymass 83.1 (SEM 8.7) kg, height 175.6 (SEM 8.5) cm] underwent a randomized, double-blind, cross-over, placebo-controlled oral treatment with 200 mg of 4-androstene-3,17-dione (delta 4), 4-androstene-3 beta,17 beta-diol (delta 4 Diol), and placebo (PL). The periods of study were separated by 7 days of washout. Blood was drawn at baseline and subsequently every 30 min for 90 min after treatment. Analysis revealed mean area-under-the-curve (AUC) serum delta 4 concentrations to be higher during delta 4 treatment [2177 (SEM 100) nmol.l-1] than delta 4Diol [900 (SEM 96) nmol.l-1] or PL [484 (SEM 82) nmol.l-1; P < 0.0001]. The delta 4 treatment also revealed a significant effect on total testosterone with a mean AUC [1632.5 (SEM 121) nmol.l-1] that was greater than PL [1418.5 (SEM 131) nmol.l-1; P < 0.05] but not significantly different from those observed after delta 4Diol treatment [1602.9 (SEM 119) nmol.l-1; P = 0.77]. Free testosterone concentrations followed a similar pattern where mean AUC for the delta 4 treatment [6114.0 (SEM 600) pmol.l-1] was greater than after PL [4974.6 (SEM 565) pmol.l-1; P < 0.06] but not significantly different from those observed after delta 4Diol [5632.0 (SEM 389) pmol.l-1; P = 0.48]. The appearance and apparent conversion to total and free testosterone over 90 min was stronger for the delta 4 treatment (r = 0.91, P < 0.045) than for delta 4Diol treatment (r = 0.69, NS) and negatively correlated for PL (r = -0.90, P < 0.02). These results would suggest that delta 4, and perhaps delta 4Diol, taken by month are capable of producing in vivo increases in testosterone concentrations in apparently healthy young men as has already been observed in women after treatment with delta 4.

Relationship of fitness and gross motor skills for five- to six-yr.-old children.

51 kindergarten children participated to assess how various fitness components, 1/2-mile run, the Prudential PACER test, body composition, shoulder stretch, trunk lift, sit-and-reach, curl-up, and flex arm-hang related to motor performance on the Bruininks-Oseretsky test battery including running, speed, agility, balance, bilateral coordination, and strength. All values recorded in the fitness components were compared with standardized motor skill scores. Analysis indicated that 1/2-mile run performance was significantly correlated with body weight and relative body fat, showing that as body weight or relative body fat increased run performance times were slower. Comparisons between the fitness parameters and motor skills indicated that the 1/2-mile run performance also was negatively correlated with measures of balance, bilateral coordination, and strength while the Prudential PACER test was positively correlated with strength. During continuous walk-jog movements (half-mile run) in a relatively homogeneous sample, increases in body size improved balance, bilateral coordination, and strength but negatively affected running during the 1/2-mile fitness test. In more interval-related activities such as the Prudential PACER test, an increase in strength was related to improved performance.

Effects of hydration changes on bioelectrical impedance in endurance trained individuals.

PURPOSE: The purpose of this study was to determine how differences in hydration states and ion content of hydrating fluids affected bioelectrical impedance (BI) and hydrostatic weighing (HW) measurements. METHODS: Fifteen athletic subjects aged 19-56 yr were recruited. Relative body fat (%), fat-weight (FW), and fat-free weight (FFW) were assessed using BI and HW under normal conditions (N), hypohydration (HPO), rehydration (RHY), and superhydration (SHY) states. During the RHY and SHY trial periods, subjects were hydrated with either distilled water or an electrolyte solution (ELS). HPO and SHY levels were set at 3% of each person's normally hydrated body weight. RESULTS: Comparison between the distilled water and the ELS trials indicated that hydration solution had no effect on BI or HW. Thus, the results presented are the trial means of both hydration solutions combined. Both BI and HW were shown to be highly test-retest reliable (r-values: 0.96 and 0.99, respectively). The effects of exercise induced HPO followed by RHY on body composition values indicated that HW was very stable across measurement periods while BI was not. From N to the HPO state, BI %BF declined from 14.4 +/- 5.3% to 12.3 +/- 5.3%, respectively. After RHY, BIA %BF increased to 15.5 +/- 5.8%. Similar findings occurred when subjects were superhydrated (N-BI = 13.2 +/- 5.3%; SHY-BI = 15.4 +/- 5.6%). With a comparison of the intercepts and slopes of HW and BIA for the N and SHY states, it was clear hydration status significantly affected the intercepts (HW: 0.37 vs. BI: 1.85) and not the slopes (HW: 1.00 vs BI: 0.99). As a result, a majority of all fluid changes were interpreted as FW by BI. During HPO, 82% of the weight loss was considered FW while during RHY or SHY, 128% and 85% of the water weight regain/gain was considered FW. CONCLUSION: These results indicate that BI is not a valid technique in athletes, especially when wanting to determine body composition effects of training/detraining. This study indicates that even small fluid changes such as those that occur with endurance training may be interpreted incorrectly as changes in an athlete's body fat content.

Assessing body composition before and after resistance or endurance training.

This study's purpose was to determine the validity of near-infrared interactance (NIR) and bioelectric impedance (BIA) in tracking changes in body composition over 12 wk of either a high intensity endurance (ET) or resistance (RT) training program in nondieting weight-stable untrained males. Prior to and following the control or training period, each subject completed a series of body composition analyses including hydrostatic weighing (HW) with a measurement of residual volume: anthropometric measurements including height, weight, skinfold, and girth: BIA measurement: and NIR measurements. Based on the HW results, there were no significant body composition changes in the control group. For the ET group, a significant decline in relative body fat resulted from a reduction in fat weight (FW) with no change in fat-free weight (FFW). In the RT group, both a significant decline in FW and an increase in FFW contributed to this group's decline in relative body fat. Tracking changes in relative body fat, FW, and FFW, skinfolds agree reasonably well with HW in all groups while BIA and NIR did not always track body composition changes well. For example, SF and BIA were significantly correlated with the changes in FFW (HW = +4.1%, SF = +4.5%. BIA = +3.1%. NIR = -0.7%) observed in the RT group compared to HW (SF: r-value = 0.45, SEE = 2.5; BIA: r = 0.33, SEE = 3.4) while the NIR measurements were nonsignificant (r = 0.09, SEE = 5.0). Interestingly, NIR underestimated the gain in FFW in the resistance trained group while BIA underestimated the changes in relative body fat. FW, and FFW in the endurance trained group. Based on these results, BIA and NIR appear not to be appropriate measurement tools for tracking body composition changes in endurance and resistance training individuals respectively.

Effects of propranolol and pindolol on cardiac output during extended periods of low-intensity physical activity.

The effects of a nonselective beta-adrenergic blocking agent with (pindolol) and without (propranolol) intrinsic sympathomimetic activity properties, compared with placebo-controlled conditions, on metabolic and cardiorespiratory function during long-duration (2 hours) physical activity were examined. After initial cardiorespiratory testing, subjects performed 2-hour walks at 25 and 45% of maximal oxygen consumption (VO2max) under each of the following 3 treatments: pindolol, propranolol and placebo. Medication distribution was randomized and double-blinded. A supine resting blood pressure and electrocardiogram were obtained before each exercise trial. Oxygen consumption, heart rate, stroke volume, cardiac output and blood pressure were determined after 5 minutes of quiet sitting and every 30 minutes during each 2-hour exercise trial. Cardiac output was not significantly different at rest or during exercise, comparing pindolol and propranolol with placebo conditions. Cardiac output tended to decrease over time earlier during propranolol treatment for the 25% VO2max trials in trained normotensive subjects than for the other treatments. Cardiac output decreased at approximately the same time across treatments during the 45% VO2max trials in trained normotensive and untrained hypertensive groups. Finally, owing to the observation that a reduction in cardiac output was delayed or prevented in trained normotensive subjects when compared with that in untrained hypertensives while exercising at 25% VO2max, developing a subject's cardiovascular fitness level may be important in the maintenance of cardiac output during extended periods of low-to-moderate physical activities while under the influence of beta-adrenergic blockade.

The effects of aerobic fitness on resting metabolic rate.

A cross-sectional study was designed to determine the relationship between aerobic fitness and resting metabolic rate (RMR) in 69 males exhibiting a wide range of aerobic fitness levels (VO2max = 32.8-78.1 mL.kg-1.min-1). The results of this study indicated that RMR was not significantly different between trained and untrained individuals when expressed in kJ.kg fat-free weight-1.hr-1 or using an ANCOVA with fat-free weight as the covariate and RMR as the dependent variable (F ratio = 0.353, P less than 0.70). In addition, this study also failed to support a previously suggested hypothesis that an elevated RMR may only be observed in those individuals exhibiting both high VO2max values and currently training a minimum of 12-16 h/wk. Thus, the results of this study strongly suggest that RMR is independent of both a person's current aerobic level and training status.

The effects of either high-intensity resistance or endurance training on resting metabolic rate.

The effects of either 12-wk of high-intensity endurance or resistance training on resting metabolic rate (RMR) were investigated in 47 males aged 18-35 y. Subjects were randomly assigned to either a control (C), resistance-trained (RT) or endurance-trained (ET) group. After training both exercise groups showed significant declines in relative body fat either by reducing their total fat weight and maintaining fat-free weight (ET) or by reducing their total fat weight and increasing fat-free weight (RT). RMR did not significantly change after either training regimen although a small decline in energy intake was observed along with an increase in energy expenditure [ET, 2.721 MJ (650 kcal) per training day]. These results suggest that both endurance and resistance training may help to prevent an attenuation in RMR normally observed during extended periods of negative energy balance (energy intake less than expenditure) by either preserving or increasing a person's fat-free weight.

Is there energy conservation in amenorrheic compared with eumenorrheic distance runners?

The female distance runner is considered at high risk for secondary amenorrhea and reduced spinal bone mineral, and recent studies have suggested that these disturbances might be nutritionally or metabolically linked. The present study investigated 1) whether there is a physiological basis by which the amenorrheic runner might maintain weight at a lower than expected caloric intake, i.e., conservation of energy, and 2) the potential interactions of reduced energy intake, secondary amenorrhea, and reductions in bone density. Subjects included 13 elite female distance runners, 8 amenorrheic and 5 eumenorrheic, and 5 untrained female controls. Body composition by hydrostatic weighing, bone density and mineral content by dual-photon absorptiometry, and blood samples for hormonal analyses (once per week for 4 wk) were obtained, as were duplicate measures for resting metabolic rate, thermic effect of a meal, and the energy cost of specific (treadmill) and nonspecific (cycle ergometer) physical activity. Energy intake and energy expenditure were estimated by 3-day logs. Energy intakes did not differ (1,781, 1,690, and 1,763 kcal), nor did energy expenditures (2,480, 2,314, and 2,268 kcal), for the amenorrheic and eumenorrheic runner and control groups, respectively. The difference between reported energy intake and estimated energy expenditure of 500-700 kcal was likely due to underreporting or restricting intake, inasmuch as there was no evidence of energy conservation. A possible link was suggested between disordered eating, secondary amenorrhea, and bone mineral loss.

Stroke volume during submaximal exercise in endurance-trained normotensive subjects and in untrained hypertensive subjects with beta blockade (propranolol and pindolol).

The effect of beta-adrenergic blockade on stroke volume (SV) at increasing submaximal exercise intensities was studied in 12 endurance-trained normotensive and 12 untrained hypertensive (diastolic blood pressure greater than 95 mm Hg) men, aged 18 to 34 years. Subjects were assigned to each of 3 treatments in a double-blind, randomized order: placebo, propranolol (80 mg twice daily) and pindolol (10 mg twice daily) for 10 days, with a period of 48 to 60 hours from the initial dose to the first treadmill test and a 4-day washout period between drugs. Cardiac output was measured using the carbon dioxide rebreathing method and SV was calculated from cardiac output and heart rate as follows: SV = cardiac output/heart rate. Cardiac outputs were estimated at rest and while walking on a treadmill at 25, 45, 60 and 75% of the subject's previously determined maximal oxygen uptake (VO2max). No significant differences were found in cardiac output between either of the drugs and placebo at rest, or at any of the 4 rates of work. Propranolol significantly increased SV above placebo values (p less than 0.05) for both trained and untrained groups at the intensities of 45, 60 and 75%. Significant differences in SV were found between pindolol and placebo only at the intensities of 60 and 75% in the trained group. Contrary to expectations, SV showed no indication of a plateau with propranolol in the trained subjects throughout the 4 different exercise intensities, whereas a plateau was established under placebo conditions by 45% of VO2max in both trained and untrained subjects. These results suggest that both trained and untrained hypertensive persons can exercise with beta-adrenergic blockade at submaximal levels without compromised cardiac function.

The metabolic consequences of low and moderate intensity exercise with or without feeding in lean and borderline obese males.

The purpose of this study was to investigate the role of exercise intensity on the post-exercise thermogenic effect (PETE), with or without feeding, in five lean (less than 15 percent body fat) and five borderline obese (between 20 and 25 percent body fat) individuals when the total caloric expenditure during exercise was equated to 720 kcal by adjusting exercise duration. Each subject participated in six testing sessions, including the measurement of resting metabolic rate (RMR), dietary induced thermogenesis (DIT) following a 720 kcal liquid meal, and four exercise trials including: (1) exercising on a treadmill at both 30 percent and 60 percent of VO2 max followed by a 720 kcal liquid meal (30F and 60F); and (2) exercising on a treadmill at both 30 percent and 60 percent of VO2 max followed by a non-caloric liquid meal substitute (water) matched by volume to the caloric liquid meal (30NF and 60NF). Indirect calorimetry was used to determine metabolic rate prior to each treatment (0-30 min RMR) and at 0-30, 50-60, 80-90, 110-120, 140-150, and 170-180 min following the feeding, exercise only, or exercise and feeding treatments. A significant difference in the post-exercise oxygen consumption was found between the two calorically equated exercise bouts (720 kcal) at 30 percent and 60 percent of each subject's VO2 max without feeding when all measurement periods following exercise were averaged together (60NF = 13.5 percent increase and 30NF = 5.5 percent). This difference was observed in both the lean and borderline obese subjects, with no significant difference between the two groups. In addition, when walking at either 30 percent or 60 percent of VO2 max preceded feeding, a significant attenuation in the rise of post-feeding RER values was observed in both groups with the higher exercise intensity showing the greatest RER attenuation when compared to the DIT trial. These results suggest that exercise intensity may play a significant role independent of the total energy expenditure in potentiating a person's post-exercise oxygen consumption rate and post-exercise substrate utilization for periods of up to 180 mins.

Changes in plasma free fatty acids and glycerols during prolonged exercise in trained and hypertensive persons taking propranolol and pindolol.

The extent to which lipolysis is attenuated during prolonged submaximal exercise during beta blockade was determined in 12 normotensive endurance-trained and 12 hypertensive sedentary men using nonselective drugs with and without intrinsic sympathomimetic activity (ISA). Initially, subjects performed a graded treadmill test to determine maximal oxygen uptake (VO2max). This was followed by 2-hour walks at 25 and 45% of the subject's VO2max under each of 3 treatments: pindolol (ISA), propranolol (non-ISA) and placebo. The distribution of medication was randomized and double blinded. Blood samples taken at rest and every 30 minutes during the 2-hour walks were analyzed to determine the concentrations of free fatty acids (FFA) and glycerol. On the basis of the respective changes in FFA, glycerols and the respiratory exchange ratio, beta-adrenergic blockade did not attenuate lipolysis in the untrained hypertensive subjects when compared with the placebo administration. However, beta blockade did demonstrate a tendency to attenuate lipolysis in the trained, normotensive subjects when compared with results after placebo administration. This was particularly evident at 30 minutes of exercise, when both glycerol and FFA concentrations were not increased above resting values under both conditions of beta blockade. No differences between pindolol and propranolol were observed. Therefore, a beta-blocking agent with ISA properties appears to have no clear benefit with respect to lipid metabolism during low and moderate intensity exercise. Furthermore, these data demonstrate that beta blockade does not inhibit exercise-induced lipolysis at low and moderate intensities of exercise as formerly believed, and is unlikely to be the cause of fatigue normally observed during work in patient populations taking beta-blocking medication.

Comparison of the effects of pindolol and propranolol on exercise performance in young men with systemic hypertension.

To determine the effect of intrinsic sympathomimetic activity (ISA) on exercise performance during beta blockade, 12 hypertensive men were studied. The subjects underwent graded treadmill testing while taking pindolol (a beta blocker with ISA), propranolol (a beta blocker without ISA) and placebo, in a double-blind, crossover fashion. Blood pressure, heart rate, oxygen consumption (VO2), cardiac output and stroke volume were determined at 25, 45, 60 and 75% of each subject's VO2 max. Heart rate was significantly lower with pindolol compared with placebo at all stages of exercise, but significantly higher compared with propranolol at all stages of exercise except at 75% of VO2 max and at VO2 max (no significant differences between the 2 beta blockers were recorded at these stages). Mean arterial pressure was statistically equivalent with pindolol and propranolol at all stages of exercise and significantly lower while beta-blocked compared with placebo conditions at 45, 60 and 75% of VO2 max. Cardiac output and VO2 were statistically equivalent across all 3 treatments at all submaximal levels of exercise. It was concluded that, although heart rate was significantly higher with pindolol compared with propranolol at the 3 lower rates of work, cardiac output and VO2 were not different between the drugs, thus making little impact on exercise performance.