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Genetic risk-factors for anxiety in healthy individuals: polymorphisms in genes important for the HPA axis.
Lindholm, H, Morrison, I, Krettek, A, Malm, D, Novembre, G, Handlin, L
BMC medical genetics. 2020;21(1):184
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Anxiety is a complex disorder that involves alterations in hormones secreted from glands in the brain. Genetic variations in these hormones can mean that some individuals are more susceptible to anxiety disorders. The aim of this observational study was to investigate possible relationships between genetic changes in brain hormones and anxiety in 72 individuals. The results showed that women were more likely than men to report feelings of anxiety and there were several relationships between genetic variations in brain hormones and self-reported measures of anxiety. It was concluded that genetic variations in brain hormones are associated with anxiety disorders in healthy individuals. This study could be used by healthcare professionals to understand how genetics could play a role in anxiety and that certain genes could be used to identify individuals at risk of anxiety disorders.
Abstract
BACKGROUND Two important aspects for the development of anxiety disorders are genetic predisposition and alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In order to identify genetic risk-factors for anxiety, the aim of this exploratory study was to investigate possible relationships between genetic polymorphisms in genes important for the regulation and activity of the HPA axis and self-assessed anxiety in healthy individuals. METHODS DNA from 72 healthy participants, 37 women and 35 men, were included in the analyses. Their DNA was extracted and analysed for the following Single Nucleotide Polymorphisms (SNP)s: rs41423247 in the NR3C1 gene, rs1360780 in the FKBP5 gene, rs53576 in the OXTR gene, 5-HTTLPR in SLC6A4 gene and rs6295 in the HTR1A gene. Self-assessed anxiety was measured by the State and Trait Anxiety Inventory (STAI) questionnaire. RESULTS Self-assessed measure of both STAI-S and STAI-T were significantly higher in female than in male participants (p = 0.030 and p = 0.036, respectively). For SNP rs41423247 in the NR3C1 gene, there was a significant difference in females in the score for STAI-S, where carriers of the G allele had higher scores compared to the females that were homozygous for the C allele (p < 0.01). For the SNP rs53576 in the OXTR gene, there was a significant difference in males, where carriers of the A allele had higher scores in STAI-T compared to the males that were homozygous for the G allele (p < 0.01). CONCLUSION This study shows that SNP rs41423247 in the NR3C1 gene and SNP rs53576 in the OXTR gene are associated with self-assessed anxiety in healthy individuals in a gender-specific manner. This suggests that these SNP candidates are possible genetic risk-factors for anxiety.
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Anxiety reduction through art therapy in women. Exploring stress regulation and executive functioning as underlying neurocognitive mechanisms.
Abbing, A, de Sonneville, L, Baars, E, Bourne, D, Swaab, H
PloS one. 2019;14(12):e0225200
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Anxiety treatments currently involve medication and changing an individual’s beliefs through cognitive behavioural therapy (CBT). Art therapy (AT) is often used as a CBT treatment strategy, although little is known about its effectiveness. This randomised control trial of 47 adult women with anxiety aimed to understand the role of AT in anxiety treatment over three months. The results showed improvements in self-reported measures of anxiety, the ability to control emotions, memory and the ability to manage tasks with AT, however subjects were just as susceptible to stress following treatment. It was concluded that anxiety reduction was related to improvements in emotions, memory and task management and this was as a result of AT. This study could be used by healthcare professionals to recommend AT to individuals with symptoms of anxiety as part of their treatment management plan.
Abstract
OBJECTIVES To explore possible working mechanisms of anxiety reduction in women with anxiety disorders, treated with art therapy (AT). METHODS A RCT comparing AT versus waiting list (WL) condition on aspects of self-regulation. Stress regulation (heart rate and heart rate variability) and executive functioning (daily behavioural and cognitive performance aspects of executive functioning (EF)) were evaluated in a pre-post design. Participants were women, aged 18-65 years with moderate to severe anxiety symptoms. RESULTS Effectiveness of AT compared to WL was demonstrated in a higher resting HRV post treatment, improvements in aspects of self-reported daily EF (emotion control, working memory, plan/organize and task monitor), but not in cognitive performance of EF, stress responsiveness and down regulation of stress. The decrease in anxiety level was associated with improvements in self-reported daily EF. CONCLUSIONS AT improves resting HRV and aspects of EF, the latter was associated with art therapy-related anxiety reduction.
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A Large Randomized Trial: Effects of Mindfulness-Based Stress Reduction (MBSR) for Breast Cancer (BC) Survivors on Salivary Cortisol and IL-6.
Lengacher, CA, Reich, RR, Paterson, CL, Shelton, M, Shivers, S, Ramesar, S, Pleasant, ML, Budhrani-Shani, P, Groer, M, Post-White, J, et al
Biological research for nursing. 2019;21(1):39-49
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Breast cancer survivors (BCS) often experience physiological and psychological stressors related to their diagnosis and treatment, and a disruption of cortisol function can affect cancer risk and progression. Increased levels of the stress hormone cortisol and interleukin-6 (IL-6), a pro-inflammatory immune mediator, have been associated with acute and chronic stress levels. Mindfulness-Based Stress Reduction (MBSR) is a clinical stress-reducing program, which has been found to decrease psychological and physical symptoms associated with stress. The purpose of this randomised study, involving 299 BCS, was to evaluate the efficacy of MBSR in reducing cortisol and IL-6 levels, compared to a usual-care control treatment. Statistically significant reductions in cortisol levels were seen after the delivery of the MBSR program at both time points (week 1 and 6), and at week 6 only for IL-6. There was no significant difference in change in cortisol or IL6 levels over time between the MBSR and the usual-care groups. An association was observed between levels of IL-6 and psychological and physical symptoms and quality of life, but not for cortisol. The authors conclude that MBSR can alleviate the stress response in the short term for breast cancer survivors.
Abstract
Breast cancer survivors (BCS) often experience psychological and physiological symptoms after cancer treatment. Mindfulness-based stress reduction (MBSR), a complementary and alternative therapy, has reduced subjective measures of stress, anxiety, and fatigue among BCS. Little is known, however, about how MBSR affects objective markers of stress, specifically the stress hormone cortisol and the pro-inflammatory cytokine interleukin-6 (IL-6). In the present study, BCS ( N = 322) were randomly assigned to a 6-week MBSR program for BC or usual-care control. Measurements of cortisol, IL-6, symptoms, and quality of life were obtained at orientation and 6 weeks. Cortisol and IL-6 were also measured prior to and after the MBSR(BC) class Weeks 1 and 6. The mean age of participants was 56.6 years and 69.4% were White non-Hispanic. Most had Stage I (33.8%) or II (35.7%) BC, and 35.7% had received chemotherapy and radiation. Cortisol levels were reduced immediately following MBSR(BC) class compared to before the class Weeks 1 and 6 (Wilcoxon-signed rank test; p < .01, d = .52-.56). IL-6 was significantly reduced from pre- to postclass at Week 6 (Wilcoxon-signed rank test; p < .01, d = .21). No differences were observed between the MBSR(BC) and control groups from baseline to Week 6 using linear mixed models. Significant relationships with small effect sizes were observed between IL-6 and both symptoms and quality of life in both groups. Results support the use of MBSR(BC) to reduce salivary cortisol and IL-6 levels in the short term in BCS.
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A mindfulness-based intervention to increase resilience to stress in university students (the Mindful Student Study): a pragmatic randomised controlled trial.
Galante, J, Dufour, G, Vainre, M, Wagner, AP, Stochl, J, Benton, A, Lathia, N, Howarth, E, Jones, PB
The Lancet. Public health. 2018;3(2):e72-e81
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There has been a recent increase in students accessing university counselling services, though the reasons for this are currently unclear. Mindfulness-based stress reduction has gained increased attention as evidence has shown mindfulness training can improve anxiety and depression. The aim of this trial was to therefore assess whether a mindfulness course, Mindfulness Skills for Students (MSS), would improve university students’ resilience to stress. Participants were randomly assigned to either enrol in the 8-week MSS course alongside mental health support or receive mental health support alone. A total of 449 participants completed the study and self-reported psychological distress was the primary outcome. Students enrolled in MSS showed reduced distress scores during the examination period compared with those receiving support as usual. Based on these results, the authors conclude that offering mindfulness training could be an effective, feasible component of a wider university mental health strategies. Further controlled studies are required to better understand preventative mental health interventions for students.
Abstract
BACKGROUND The rising number of young people going to university has led to concerns about an increasing demand for student mental health services. We aimed to assess whether provision of mindfulness courses to university students would improve their resilience to stress. METHODS We did this pragmatic randomised controlled trial at the University of Cambridge, UK. Students aged 18 years or older with no severe mental illness or crisis (self-assessed) were randomly assigned (1:1), via remote survey software using computer-generated random numbers, to receive either an 8 week mindfulness course adapted for university students (Mindfulness Skills for Students [MSS]) plus mental health support as usual, or mental health support as usual alone. Participants and the study management team were aware of group allocation, but allocation was concealed from the researchers, outcome assessors, and study statistician. The primary outcome was self-reported psychological distress during the examination period, as measured with the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM), with higher scores indicating more distress. The primary analysis was by intention to treat. This trial is registered with the Australia and New Zealand Clinical Trials Registry, number ACTRN12615001160527. FINDINGS Between Sept 28, 2015, and Jan 15, 2016, we randomly assigned 616 students to the MSS group (n=309) or the support as usual group (n=307). 453 (74%) participants completed the CORE-OM during the examination period and 182 (59%) MSS participants completed at least half of the course. MSS reduced distress scores during the examination period compared with support as usual, with mean CORE-OM scores of 0·87 (SD 0·50) in 237 MSS participants versus 1·11 (0·57) in 216 support as usual participants (adjusted mean difference -0·14, 95% CI -0·22 to -0·06; p=0·001), showing a moderate effect size (β -0·44, 95% CI -0·60 to -0·29; p<0·0001). 123 (57%) of 214 participants in the support as usual group had distress scores above an accepted clinical threshold compared with 88 (37%) of 235 participants in the MSS group. On average, six students (95% CI four to ten) needed to be offered the MSS course to prevent one from experiencing clinical levels of distress. No participants had adverse reactions related to self-harm, suicidality, or harm to others. INTERPRETATION Our findings show that provision of mindfulness training could be an effective component of a wider student mental health strategy. Further comparative effectiveness research with inclusion of controls for non-specific effects is needed to define a range of additional, effective interventions to increase resilience to stress in university students. FUNDING University of Cambridge and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care East of England.
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How Does the Brain Implement Adaptive Decision Making to Eat?
Compan, V, Walsh, BT, Kaye, W, Geliebter, A
The Journal of neuroscience : the official journal of the Society for Neuroscience. 2015;35(41):13868-78
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While food intake is critical for survival, adaptive decision-making can be altered through various mechanisms and eventually lead to disordered eating patterns. Feeding behaviour is dependent on homeostatic rules, motivational drives, biological predispositions and external stressors. This complex web elucidates how humans can decide to satisfy or abstain from hunger cues, and the underlying mechanisms of this behaviour have been increasingly explored. This review summarises the overall neural circuitry in restrictive food choice and binge eating. Serotonergic systems play a key role in eating disorders because they are involved in responses to stress, emotions and feeding behaviour. The decision to overeat or abstain from eating is a reward, and this goal-directed and persistent behaviour mirror some aspects of drug dependence. This review found that voluntary processes in the nervous system could be modified to predominate over homeostatic control of hunger. Eating disorders may emerge when serotonin neurons reach their limit of adaptive capacities, potentially to the extent of compromised survival. This study provides a basis for developing more effective interventions for this population.
Abstract
Adaptive decision making to eat is crucial for survival, but in anorexia nervosa, the brain persistently supports reduced food intake despite a growing need for energy. How the brain persists in reducing food intake, sometimes even to the point of death and despite the evolution of multiple mechanisms to ensure survival by governing adaptive eating behaviors, remains mysterious. Neural substrates belong to the reward-habit system, which could differ among the eating disorders. The present review provides an overview of neural circuitry of restrictive food choice, binge eating, and the contribution of specific serotonin receptors. One possibility is that restrictive food intake critically engages goal-directed (decision making) systems and "habit," supporting the view that persistent caloric restriction mimics some aspects of addiction to drugs of abuse. SIGNIFICANCE STATEMENT An improved understanding of the neural basis of eating disorders is a timely challenge because these disorders can be deadly. Up to 70 million of people in the world suffer from eating disorders. Anorexia nervosa affects 1-4% of women in United States and is the first cause of death among adolescents in Europe. Studies relying on animal models suggest that decision making to eat (or not) can prevail over actual energy requirements due to emotional disturbances resulting in abnormal habitual behavior, mimicking dependence. These recent studies provide a foundation for developing more specific and effective interventions for these disorders.
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No effect of caloric restriction on salivary cortisol levels in overweight men and women.
Tam, CS, Frost, EA, Xie, W, Rood, J, Ravussin, E, Redman, LM
Metabolism: clinical and experimental. 2014;63(2):194-8
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Alterations in normal cortisol patterns have been observed in people who are obese. The effect of weight loss on cortisol levels, a measure of hypothalamic pituitary adrenal (HPA) activity, in overweight individuals is not known. The aim of this study was to test the hypothesis that 6 months of moderate caloric restriction would alter morning and diurnal salivary cortisol levels. Thirty-five overweight adults (average BMI 27.8 kg/m2) took part in this randomised control trial. Participants were assigned to either calorie restriction (CR: 25% reduction in energy intake), calorie restriction+exercise (CR+EX: 12.5% reduction in energy intake+12.5% increase in exercise energy expenditure) or control (healthy weight-maintenance diet) for 6 months. Salivary cortisol was measured at 8:00, 8:30, 11:00, 11:30, 12:30, 13:00, 16:00 and 16:30. Morning cortisol was defined as the mean cortisol concentration at 08:00 and 08:30. Diurnal cortisol was calculated as the mean of the 8 cortisol measures across the day. Across all groups, higher morning and diurnal cortisol levels were associated with impaired insulin sensitivity. There was no significant effect of group, time or sex on morning or diurnal cortisol levels. The authors concluded that a 10% weight loss with a 25% CR diet alone or with exercise did not impact morning or diurnal salivary cortisol levels in overweight individuals. Their findings suggest that prolonged restriction of energy intake is not perceived by the body as a stressor, and therefore CR may present a viable intervention.
Abstract
OBJECTIVE The effect of weight loss by diet or diet and exercise on salivary cortisol levels, a measure of hypothalamic pituitary adrenal activity, in overweight individuals is not known. The objective was to test the hypothesis that 24 weeks of moderate caloric restriction (CR) (25%) by diet or diet and aerobic exercise would alter morning and diurnal salivary cortisol levels. DESIGN AND SETTING Randomized control trial in an institutional research center. PARTICIPANTS Thirty-five overweight (BMI: 27.8±0.7 kg/m(2)) but otherwise healthy participants (16 M/19 F). INTERVENTION Participants were randomized to either calorie restriction (CR: 25% reduction in energy intake, n=12), calorie restriction+exercise (CR+EX: 12.5% reduction in energy intake+12.5% increase in exercise energy expenditure, n=12) or control (healthy weight-maintenance diet, n=11) for 6 months. MAIN OUTCOME MEASURE Salivary cortisol measured at 8:00, 8:30, 11:00, 11:30, 12:30, 13:00, 16:00 and 16:30. Morning cortisol was defined as the mean cortisol concentration at 08:00 and 08:30. Diurnal cortisol was calculated as the mean of the 8 cortisol measures across the day. RESULTS In the whole cohort, higher morning and diurnal cortisol levels were associated with impaired insulin sensitivity (morning: P=0.004, r(2)=0.24; diurnal: P=0.02, r(2)=0.15). Using mixed model analysis, there was no significant effect of group, time or sex on morning or diurnal cortisol levels. CONCLUSION A 10% weight loss with a 25% CR diet alone or with exercise did not impact morning or diurnal salivary cortisol levels.
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Enhanced cortisol production rates, free cortisol, and 11beta-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss.
Purnell, JQ, Kahn, SE, Samuels, MH, Brandon, D, Loriaux, DL, Brunzell, JD
American journal of physiology. Endocrinology and metabolism. 2009;296(2):E351-7
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Excess abdominal fat in men is a risk factor for both type 2 diabetes and cardiovascular disease. The aim of this study was to test the hypothesis that increased cortisol levels contribute to increased abdominal fat and insulin resistance in men. Twenty-four healthy men aged 18-70 took part in the study. Eight of the participants, who were obese, were put on a calorie-controlled weight loss diet. Cortisol production rate (CPR) and free cortisol (FC) were correlated with increased intra-abdominal fat (IAF) and decreased insulin sensitivity (Si). Cortisol levels were not correlated with subcutaneous fat (SQF). CPR and FC did not change with weight loss, suggesting that cortisol levels could influence the distribution of body fat upon weight regain. The authors concluded that their findings support a role for activation of the HPA axis and abnormal cortisol secretion in determining body fat distribution and predisposing these men to type 2 diabetes.
Abstract
Controversy exists as to whether endogenous cortisol production is associated with visceral obesity and insulin resistance in humans. We therefore quantified cortisol production and clearance rates, abdominal fat depots, insulin sensitivity, and adipocyte gene expression in a cohort of 24 men. To test whether the relationships found are a consequence rather than a cause of obesity, eight men from this larger group were studied before and after weight loss. Daily cortisol production rates (CPR), free cortisol levels (FC), and metabolic clearance rates (MCR) were measured by stable isotope methodology and 24-h sampling; intra-abdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (S(I)) by frequently sampled intravenous glucose tolerance test; and adipocyte 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1) gene expression by quantitative RT-PCR from subcutaneous biopsies. Increased CPR and FC correlated with increased IAF, but not SQF, and with decreased S(I). Increased 11beta-HSD-1 gene expression correlated with both IAF and SQF and with decreased S(I). With weight loss, CPR, FC, and MCR did not change compared with baseline; however, with greater loss in body fat than lean mass during weight loss, both CPR and FC increased proportionally to final fat mass and IAF and 11beta-HSD-1 decreased compared with baseline. These data support a model in which increased hypothalamic-pituitary-adrenal activity in men promotes selective visceral fat accumulation and insulin resistance and may promote weight regain after diet-induced weight loss, whereas 11beta-HSD-1 gene expression in SQF is a consequence rather than cause of adiposity.
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Lysine fortification reduces anxiety and lessens stress in family members in economically weak communities in Northwest Syria.
Smriga, M, Ghosh, S, Mouneimne, Y, Pellett, PL, Scrimshaw, NS
Proceedings of the National Academy of Sciences of the United States of America. 2004;101(22):8285-8
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The risk of protein deficiency, particularly lysine, is high among communities that depend on wheat for their protein supply. In experimental animals, prolonged lysine inadequacy increases stress-induced anxiety, however the evidence of nutritional benefits for fortifying wheat with lysine is limited. The aim of this study was to investigate whether consuming lysine-fortified wheat for three months would reduce stress and anxiety in Northwest Syrian rural communities. This study indicated that lysine fortification significantly reduced anxiety in males. These results suggest that some stress responses among economically weak populations consuming wheat-based diets can be improved with lysine fortification.
Abstract
Lysine is a limiting amino acid in diets based on wheat as the staple. In experimental animals, prolonged dietary lysine inadequacy increases stress-induced anxiety. If observed in humans, such a result would have a strong implication for the relationship between nutrition and communal quality of life and mental health. As part of a 3-month randomized double-blind study, we tested whether lysine fortification of wheat reduces anxiety and stress response in family members in poor Syrian communities consuming wheat as a staple food. In the lysine-fortified group, the plasma cortisol response to the blood drawing as a cause of stress was reduced in females, as was sympathetic arousal in males as measured by skin conductance. Lysine fortification also significantly reduced chronic anxiety as measured by the trait anxiety inventory in males. These results suggest that some stress responses in economically weak populations consuming cereal-based diets can be improved with lysine fortification.
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Hypersensitivity of the corticotropic axis to the serotoninergic agent clomipramine in obese women.
Laferrère, B, Lahlou, N, Saltiel, H, Roger, M, Basdevant, A, Oppert, JM, Guy-Grand, B
Obesity research. 1994;2(4):328-36
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It is thought that the neurotransmitter serotonin may play a role in the development of obesity, due to its effects on satiety, nutrient selection, and the reward system. The aim of this study was to measure the effects of a selective serotonin reuptake inhibitor (SSRI) on the hormones prolactin, corticotropin and cortisol. In this double-blind, placebo-controlled trial, a single intravenous dose of the SSRI clomipramine (CMI) was given to 12 obese and 6 non-obese women, and their hormone levels measured before and after. Six of the obese women went on to lose between 8-12% of their body weight and their response to CMI was measured again. No difference was found in the baseline levels of hormones between the non-obese, obese before and after weight loss. Levels of prolactin, corticotropin and cortisol rose significantly across all groups after administration of CMI, with the corticotropin and cortisol responses being greater in the obese group. The peak cortisol value was around 30% greater in the obese compared to the non-obese group. Weight loss did not seem to affect the hormonal response to CMI. The results of this study support the assumption that the hypothalamic pituitary adrenal axis (HPA) in obese women is unusually sensitive to serotonin and that losing weight does not normalise this.
Abstract
Serotoninergic control of food intake has been shown to be abnormal in obese persons with a decrease in serotoninergic tone. The neuroendocrine effects of intravenous I.V. administration of clomipramine (CMI), a serotonin uptake inhibitor, were studied in normal-weight (n=7) and obese subjects before (n=12) and after (n=6) dietary restriction. Under double-blind, placebo-controlled conditions, a single 12.5 mg dose of CMI was administered. There was no difference in baseline values of prolactin (PRL), corticotropin (ACTH) and cortisol in non-obese controls, obese before and obese after weight loss. CMI led to significant increases of PRL, ACTH, and cortisol concentrations in the controls as well as the obese group. The ACTH and cortisol responses to CMI in obese subjects were somewhat greater than the responses in normal-weight subjects. The area under the curve AUC for ACTH after clomipramine was 6202 +/- 976 pg/ml x 150 minutes for tile obese before weight loss and 3274 +/- 512 pg/ml x 150 minutes for the controls and the difference was significant at the level of p=0.052. The cortisol peak value after clomipramine was 163.71 +/- 14.31 ng/ml in the non-obese and 214.66 +/- 12.59 ng/ml in the obese (p=0.025). However, there was no difference in the obese subjects before and after weight loss. These data support the assumption that obese women have an abnormal sensitivity to the serotoninergic control of the hypothalamic pituitary adrenal axis (HPA), and that a mild weight loss does not significantly modify their serotoninergic tone.