HPA Axis Dysregulation Research Articles

The Lausanne-Geneva cohort study of offspring of parents with mood disorders: methodology, findings, current sample characteristics, and perspectives.

Studies focusing on the offspring of affected parents utilize the well-established familial aggregation of mood disorders as a powerful tool for the identification of risk factors, early clinical manifestations, and prodromes of mood disorders in these offspring. The major goals of the Lausanne-Geneva mood cohort study are to: (1) assess the familial aggregation of bipolar and unipolar mood disorders; (2) prospectively identify risk factors for mood disorders as well as their early signs and prodromes; (3) identify their endophenotypes including cognitive features, alterations in brain structure, HPA-axis dysregulation, and abnormalities of the circadian rhythm of activity. Probands with bipolar disorders, major depressive disorder, and controls with at least one child aged from 4 to 17.9 years at study intake, their offspring, as well as their spouses are invited to take part in follow-up assessments at predetermined ages of the offspring. Direct semi-structured diagnostic interviews have been used for all participants. Probands, spouses, and adult offspring also undergo neurocognitive testing, anthropomorphic measures and biochemical exams, structural Magnetic Resonance Imaging, as well as objective assessments of physical activity using accelerometers in combination with ecological momentary assessments. Currently, our study has up to seven follow-up assessments extending over a period of 20 years. There are 214 probands and 389 offspring with one direct interview before age 18 as well as a second assessment over follow-up. Data on 236 co-parents are also available from whom 55% have been directly interviewed. First publications support the specificity of the familial aggregation of BPD and the strong influence of an early onset of the parental BPD, which amplifies the risk of developing this disorder in offspring. Information from clinical, biological, cognitive, and behavioral measures, based on contemporary knowledge, should further enhance our understanding of mood disorder psychopathology, its consequences, and underlying mechanisms.

Loneliness in older adults is associated with diminished cortisol output

ObjectiveLoneliness in older adults has been associated with increased mortality and health problems. One of the assumed underlying mechanisms is dysregulation of the hypothalamic-pituitary-adrenocortical axis (HPA–axis). The purpose of this study was to investigate whether loneliness in older adults is associated with HPA-axis dysregulation and whether this association differs between depressed and non-depressed persons. MethodsCross-sectional data of 426 lonely and non-lonely older adults in the Netherlands Study of Depression in Older Persons (NESDO) were used. Linear regression analyses and multinominal logistic regression analyses were performed to examine the association between loneliness and morning cortisol, cortisol awakening response, diurnal slope and dexamethasone suppression ratio. In all analyses, confounders were introduced. In order to examine whether the association between loneliness and cortisol measures is different in depressed versus non-depressed persons, an interaction term for loneliness x depression diagnosis was tested. ResultsCortisol output in the first hour after awakening and dexamethasone suppression ratio was lower in lonely participants. There were no significant interactions between loneliness and depression diagnosis in the association with the cortisol measures. ConclusionThis study is the first to investigate the association between the HPA–axis and loneliness in a large group of older adults aged 60–93years. We found lower cortisol output in the first hour after awakening and lower dexamethasone suppression ratio in lonely older depressed and non–depressed adults. Whether diminished cortisol output is the underlying mechanism that leads to health problems in lonely older adults is an interesting object for further study.

Telmisartan attenuates diabetes induced depression in rats

Role of brain renin angiotensin system (RAS) is well understood and various clinical studies have proposed neuroprotective effects of ARB's. It is also assumed that diabetic depression is associated with activation of brain RAS, HPA axis dysregulation and brain inflammatory events. Therefore, the present study was designed to investigate the antidepressant effect of low dose telmisartan (TMS) in diabetes induced depression (DID) in rats. Diabetes was induced by injecting streptozotocin. After 21days of treatment the rats were subjected to forced swim test (FST). The rats, with increased immobility time, were considered depressed and were treated with vehicle or TMS (0.05mg/kg, po) or metformin (200mg/kg, po) or fluoxetine (20mg/kg, po). A separate group was also maintained to study the combination of metformin and TMS. At the end of 21days of treatments, FST, open field test (OFT) and elevated plus maze (EPM) paradigm were performed. Blood was drawn to estimate serum cortisol, nitric oxide (NO), interleukin-6 (IL-6) and interleukin-1β (IL-1β). Persistent hyperglycemia resulted in depression and anxiety in rats as observed by increased immobility, reduced latency for immobility, reduced open arm entries and time spent. The depressed rats showed a significant rise in serum cortisol, NO, IL-6 and IL-1β (p<0.001). TMS antagonized depression and anxiety. It also significantly attenuated serum cortisol, NO, IL-6 and IL-1β (p<0.001). Low dose TMS and its combination with metformin normalizes depressive mood, reduces pro-inflammatory mediators and ameliorates the HPA axis function; thereby providing beneficial effects in DID.

Heterogeneity in HPA axis dysregulation and serotonergic vulnerability to depression

Variability in the serotonin transporter (5-HTTLPR) gene can influence the risk of depression associated with adversity, as well as cortisol stress reactivity, although not consistently. No study has examined the impact of both a stressful environment and corticotropic-axis dysfunction on depression, as a function of 5-HTTLPR. This population-based study included 334 subjects aged 65 and older. Depression was measured at both diagnostic (major depression according to DSM-IV) and symptomatic (subthreshold depression) levels of caseness, in addition to 5-HTTLPR and rs25531 genotyping and diurnal cortisol measures. For participants with the SS genotype, higher morning cortisol levels were associated with a 4-fold increased risk of depression. Among LL participants, both evening cortisol levels and recent stressful events increased depression risk, although only the latter remained significant after multivariable adjustment. Conversely, SL individuals appeared somewhat resilient to depression in terms of cortisol and recent stress. These findings indicate that 5-HTTLPR genetic variability appears to influence the association between stress-related factors and late-life depression, although the gene-environment interactions failed to reach statistical significance levels. Participants homozygous for the short allele appeared to have a cortisol-related neuroendocrine vulnerability to depression, while long allele homozygotes were more reactive to stressful events in terms of depression risk.

Further evidence of HPA-axis dysregulation and its correlation with depression in Autism Spectrum Disorders: Data from girls

To further describe Hypothalamus-Pituitary-Adrenal (HPA) axis activity in children with Autism Spectrum Disorder (ASD), the Diurnal Fluctuation (DF) and Cortisol Awakening Response (CAR) were investigated in a sample of 39 high functioning girls with ASD. Although group mean data conformed to the DF and CAR models, over half of the participants showed inverse CAR and over 14% had inverted DF cortisol concentrations. Examination of three potential sets of predictor factors (physiological, ASD-related, and mood) revealed that only self-reported Major Depressive Disorder was significantly associated with CAR status, and that the girls' concern about dying or suicide was the most powerful contributor to the variance in CAR status. These findings add to the literature regarding the HPA axis dysfunction in children with ASD.

Cortisol awakening response among women exposed to intimate partner violence

The studies of the effects of intimate partner violence (IPV) on the cortisol awakening response (CAR) are scarce and contradictory. While some of the studies suggested that female victims of IPV showed high CAR, other studies found low CAR. Mixed results may be related to differences in sample characteristics as well as other potential covariates associated with the cortisol, as femalés history of abuse, chronicity, severity and type of IPV, psychological distress, posttraumatic stress disorder, and social support. The study examined individual differences in CAR among 149 female victims of severe IPV reported to authorities, including 76 (51%) living in shelter and 73 (49%) living with the abusive partners. Results revealed several individual differences in CAR that may contribute to understanding the mixed results found in literature, including women with cortisol that decreased between the baseline and 30min later, women with no increase of cortisol, and women whose cortisol increased above baseline. Additionally, women without CAR experienced more chronic and severe violence, more psychological distress and PTSD symptoms. However, hierarchical multiple regression indicated that chronic severe violence was the only independent variable that significantly explained 13% of the variance in CAR, even after including all covariates in the model, and adjusting for sociodemographic variables. In conclusion, this study suggests that the HPA axis dysregulation is influenced by chronic severe violence among women victims of IPV.

The emerging role of the FKBP5 gene polymorphisms in vulnerability-stress model of schizophrenia: further evidence from a Serbian population.

Increased reactivity to stress is observed in patients with schizophrenia spectrum disorders and their healthy siblings in comparison with the general population. Additionally, higher levels of neuroticism, as a proposed psychological measure of stress sensitivity, increase the risk of schizophrenia. HPA axis dysregulation is one of the possible mechanisms related to the vulnerability-stress model of schizophrenia, and recent studies revealed a possible role of the functional genetic variants of FK506-binding protein 51 (FKBP5) gene which modulate activity of HPA axis. The purpose of the present study was to investigate impact of FKBP5 on schizophrenia in Serbian patients and to explore relationship between genetic variants and neuroticism by using the case-sibling-control design. In 158 subjects, we measured psychotic experiences, childhood trauma and neuroticism. Nine single-nucleotide polymorphisms (rs9295158, rs3800373, rs9740080, rs737054, rs6926133, rs9380529, rs9394314, rs2766533 and rs12200498) were genotyped. The genetic influence was modeled using logistic regression, and the relationship between genetic variants and neuroticism was assessed by linear mixed model. Our results revealed genetic main effect of FKBP5 risk alleles (A allele of rs9296158 and T allele of rs3800373) and AGTC "risk" haplotype combination (rs9296158, rs3800373, rs9470080 and rs737054, respectively) on schizophrenia, particularly when childhood trauma was set as a confounding factor. We confirmed strong relationship between neuroticism and psychotic experiences in patients and siblings and further showed relationship between higher levels of neuroticism and FKBP5 risk variants suggesting potential link between biological and psychosocial risk factors. Our data support previous findings that trauma exposure shapes FKBP5 impact on schizophrenia.

Qigong/Tai Chi Easy for fatigue in breast cancer survivors: Rationale and design of a randomized clinical trial

IntroductionBreast cancer survivors (BCSs) often report fatigue that persists for years following treatment. Despite a growing body of evidence for meditative movement practices to improve symptoms among BCSs, few studies have explored using Qigong/Tai Chi to reduce fatigue. Additionally, few have examined the biological mechanisms through which fatigue may be reduced using Qigong/Tai Chi. Methods/study designWe will recruit 250 fatigued, post-menopausal women diagnosed with breast cancer (stage 0-III), between 6months and 5years past primary treatment and randomize to a standardized Qigong/Tai Chi Easy (QG/TCE) intervention, a “sham” Qigong group (movements without a focus on the breath and meditative state) (SQG), or an educational support (ES) group. The primary outcome (fatigue), secondary outcomes (anxiety, depression, sleep quality, cognitive function, physical activity), and a biomarker of HPA axis dysregulation (diurnal cortisol) will be assessed at baseline, post-intervention and 6months postintervention, and biomarkers of inflammation (IL1ra, IL6, TNFα and INFᵧ) at pre/post-intervention. We hypothesize that QG/TCE will reduce fatigue (and improve other symptoms associated with fatigue) in BCSs experiencing persistent cancer-related fatigue more than SQG and ES. Biomarkers will be examined for relationships to changes in fatigue. ConclusionsFindings from this study may reveal the effects of the unique mind-body aspects of QG/TCE on fatigue in BCSs with a complex design that separates the effects of low-intensity physical activity (SQG) and social support/attention (ES) from the primary intervention. Further, results will likely contribute greater understanding of the biological mechanisms of these practices related to improved symptoms among BCSs.

Neuroanatomical correlates of HPA axis biomarkers among children at elevated risk for schizophrenia

Background: The hypothalamic-pituitary-adrenal (HPA) axis disturbances observed in psychosis might feasibly contribute to some of the structural brain abnormalities associated with the disorder (i.e., via the potentially toxic effects of elevated glucocorticoid levels on the brain). However, the association between brain structure and cortisol has rarely been investigated. The current study examined relationships between salivary cortisol and regional brain volumes among at-risk children aged 11-14 years, who present multiple antecedents of schizophrenia (ASz=30) or a family history of illness (FHx=22), and typically-developing children (TD=32). Methods: Volumes of specific brain regions known to express glucocorticoid receptors were extracted from structural brain images using FreeSurfer. Diurnal cortisol levels and the cortisol awakening response (CAR) were determined from multiple salivary cortisol samples obtained throughout the day. Results: In the FHx group only, higher diurnal cortisol was correlated with smaller right amygdala and white matter hypointensity volumes (r=-0.51 and -0.62, respectively, p<0.05). In post-hoc analyses, a higher CAR was associated with smaller bilateral cerebellum, bilateral hippocampus, right ventral diencephalon, and total subcortical grey matter volumes among FHx children with a first-degree relative with schizophrenia. In FHx children with an affected second-degree relative, increased diurnal cortisol levels were associated with smaller left hippocampal and white matter hypointensity volumes. Conclusions: Our findings are consistent with the few previous studies examining cortisol and brain structure among adults with established psychosis. These associations may not necessarily reflect a direct effect of cortisol on the developing brain; indeed, abnormal neurodevelopment affecting these brain regions may contribute to HPA-axis dysregulation. Funding: This work was supported by a Sir Henry Wellcome Postdoctoral Fellowship (107395/Z/15/Z) and a Waterloo Foundation Child Development Fund grant (164/1719)

Hair cortisol concentration and glycated hemoglobin in African American adults

BackgroundAfrican Americans have higher diabetes prevalence compared to Whites. They also have elevated cortisol levels − indicating possible HPA axis dysregulation − which may raise blood glucose as part of the biological response to physiological and psychosocial stress. Little is known about chronic cortisol levels in African Americans, and even less about the role of chronically elevated cortisol in type 2 diabetes development in this racial group. PurposeWe used analysis of cortisol in hair to examine associations of long-term (∼3months) cortisol levels with glycated hemoglobin (HbA1c) in a group of African American adults. In exploratory analyses, we also studied the relationship of hair dehydroepiandrosterone (DHEA) with HbA1c. MethodParticipants were 61 community-dwelling African American adults (85% female; mean age 54.30 years). The first 3cm of scalp-near hair were analyzed for cortisol and DHEA concentration using enzyme-linked immunoassay analysis. Glycated hemoglobin was assessed, and regression analyses predicting HbA1c from hair cortisol and DHEA were performed in the full sample and in a subsample of participants (n=20) meeting the National Institute of Diabetes and Digestive Kidney Disease (NIDDK) criteria for type 2 diabetes (HbA1c≥6.5%). ResultsIn the full sample, HbA1c increased with hair cortisol level (β=0.22, p=0.04, f2=0.10), independent of age, sex, chronic health conditions, diabetes medication use, exercise, and depressive symptoms. In the subsample of participants with an HbA1c≥6.5%, hair cortisol was also positively related to HbA1c (β=0.45, p=0.04, f2=0.32), independent of diabetes medication use. Glycated hemoglobin was unrelated to hair DHEA in both the full sample and HbA1c≥6.5% subsample. ConclusionLong-term HPA axis dysregulation in the form of elevated hair cortisol is associated with elevated HbA1c in African American adults.

A randomized, double-blind, placebo-controlled, crossover trial of mifepristone in Gulf War veterans with chronic multisymptom illness

No pharmacological treatments have been demonstrated to effectively treat chronic multisymptom illness (CMI) in Gulf War veterans (GWV). This study assessed the effect of the glucocorticoid receptor antagonist mifepristone in GWV with CMI. A randomized, double-blind, cross-over trial of mifepristone, with two six-week treatment phases separated by a one-month washout period, was conducted at a Veterans Affairs (VA) hospital between 2008 and 2011. Participants were randomized to receive either 200mg of mifepristone per day or matched placebo first. The primary clinical outcome measure was change in self-reported physical health. Neurocognitive functioning and self-reported measures of depression, PTSD, and fatigue were secondary outcomes. Sixty-five participants enrolled, of whom 36 were randomized and 32 (mean age, 49.1 (7.2) years) completed the study. Physical and mental health status and neurocognitive functioning were poor at baseline. Mifepristone treatment was not associated with improvement in self-reported physical health (p=0.838) or in other self-reported measures of mental health. Mifepristone treatment was significantly associated with improvements in verbal learning (p=0.008, d=0.508), in the absence of improvement in other cognitive measures (working memory (p=0.914), visual learning (p=0.643) and a global composite measure (p=0.937). Baseline morning cortisol levels and lysozyme IC50-DEX, a measure of peripheral glucocorticoid sensitivity, displayed a significant relationship with endpoint verbal learning scores (p=0.012 and p=0.007, respectively). The magnitude of cortisol change during treatment mediated the improvement in verbal learning.This study was negative for the primary and secondary clinical outcomes. However, the data suggest a moderate dose of mifepristone may have circumscribed cognitive-enhancing effects in CMI. Further study is warranted to determine whether and through which mechanisms mifepristone treatment can yield clinically meaningful improvement in cognitive function in CMI or other neuropsychiatric conditions associated with HPA axis dysregulation.

Age of Trauma Onset and HPA Axis Dysregulation Among Trauma-Exposed Youth.

The hypothalamic-pituitary-adrenal axis (HPA axis) is a pathway through which childhood trauma may increase risk for negative health outcomes. The HPA axis is sensitive to stress throughout development; however, few studies have examined whether timing of exposure to childhood trauma is related to differences in later HPA axis functioning. Therefore, we examined the association between age of first trauma and HPA axis functioning among adolescents, and whether these associations varied by sex. Parents of 97 youth (aged 9-16 years) completed the Early Trauma Inventory (ETI), and youth completed the Socially-Evaluated Cold-Pressor Task (SECPT). We measured salivary cortisol response to the SECPT, the cortisol awakening response, and diurnal regulation at home across 2 consecutive weekdays. Exposure to trauma during infancy related to delayed cortisol recovery from peak responses to acute stress, d = 0.23 to 0.42. Timing of trauma exposure related to diverging patterns of diurnal cortisol regulation for males, d = 0.55, and females, d = 0.57. Therefore, the HPA axis may be susceptible to developing acute stress dysregulation when exposed to trauma during infancy, whereas the consequences within circadian cortisol regulation may occur in the context of later trauma exposure and vary by sex. Further investigations are warranted to characterize HPA axis sensitivity to exposure to childhood trauma across child development.

Effects of early adversity on young children's diurnal cortisol rhythms and externalizing behavior.

Early adversity is associated with biological and behavioral dysregulation in early childhood. We examined whether early adversity (i.e., poverty and involvement with child protective services [CPS]) had an indirect effect on externalizing behavior through HPA axis dysregulation, specifically blunted diurnal cortisol patterns. Participants included 94 children between the ages of 3.94 and 6.52 years old, who had a history of CPS involvement (n = 53) or no history of CPS involvement (n = 41). Cortisol samples were collected at wake-up and bedtime across 3 days, and parent-reported externalizing behavior was assessed using the Child Behavior Checklist. Results showed that history of CPS involvement and poverty were associated with blunted cortisol patterns, which in turn led to elevated externalizing behavior. The indirect effect of CPS involvement on externalizing behavior through blunted cortisol was significant, whereas the indirect effect of poverty on externalizing behavior was nonsignificant. Findings add to our understanding of neurobiological mechanisms linking early adversity to psychopathology.

HPA axis dysregulation in patients with hypersexual disorder

HPA axis dysregulation in patients with hypersexual disorder

The effects of anticipated challenge on indices of diurnal cortisol secretion in recreational users of ecstasy

Stress Test (TSST) was administered to induce an endocrine stress response. Both tests were administered at study inclusion, after 8 weeks, and 1-year follow up. Relations between stress hormone responses and reward learningwere separately probed inMDDand control subjects. Further, we evaluated whether HPA axis dysregulation predicted reward responsiveness at follow up in MDD. Results: At baseline, a negative correlation between ACTH release and reward learning emerged among depressed women (R2 =0.23, F=7.91, p=0.009). Conversely, among depressed women, blunted baseline ACTH sensitivity predicted reduced reward learning ability one year later (R2 =0.18, F=5.0, p=0.04). Conclusions: Among depressed women, potentiated ACTH release in response to TSST was associated with reduced reward learning. In addition, HPA dysregulation prospectively predicted blunted reward learning one year later making the current finding the first prospective evidence that HPA dysregulation predicts blunted reward learning ability in MDD over time.

Decreased dehydroepiandrosterone sulphate levels in adolescents with post-traumatic stress disorder after single sexual trauma

Background: Recent evidence shows that the hypothalamic–pituitary–adrenal (HPA) axis can be dysregulated in chronic sexual abuse victims with post-traumatic stress disorder (PTSD). We hypothesized that PTSD in adolescents exposed to a single sexual trauma may function as a chronic stressor leading to HPA-axis dysregulation. Aims: The objective of this study was to assess dehydroepiandrosterone sulphate (DHEA-S) and cortisol levels in female adolescents |with single sexual trauma-related PTSD compared to healthy controls. Method: We assessed 20 female adolescent (age 12–18) single sexual trauma victims with PTSD from the Ondokuz Mayis University Department of Child and Adolescent Psychiatry between December 2013 and December 2014. PTSD symptoms were assessed using the Child Depression Inventory (CDI) and Child Posttraumatic Stress Reaction Index (CPSRI). Blood cortisol and DHEA-S were measured in 20 female adolescent sexual abuse victims with PTSD and 20 healthy adolescents after 12-h fasting using the chemiluminescence method. Results: Compared to age-matched controls, female adolescent sexual abuse victims with PTSD had significantly lower DHEA-S levels (U = 70.00, Z = − 3.517, p = 0.01, r = 0.55). There was also a significant negative correlation between DHEA-S and CDI scores (Spearman r = − 0.522, p < 0.01). Conclusions: Decreased DHEA-S levels and correlation with depressive symptoms are evidence for a dysregulated HPA-axis in female adolescent single sexual trauma victims with PTSD. Further research is now recommended with large patient groups in order to maximize generalizations.

Effect of a novel 5-HT3 receptor antagonist 4i, in corticosterone-induced depression-like behavior and oxidative stress in mice

Stress in our daily life severely affects the normal physiology of the biological system. Dysregulation of hypothalamic–pituitary–adrenal (HPA) axis has been implicated in the development of depression-like behavior, which remains under diagnosed and poorly treated. Exogenous corticosterone (CORT) administration has been demonstrated to develop a depression model, which has shown to mimic HPA-axis induced depression-like state in rodents. In the present study, the effect of a novel 5HT3 receptor, 4i was examined on CORT induced depression in mice. CORT (30mg/kg, subcutaneously) was given for 4-weeks to mice in control group, while mice in drug treated group were given 4i (0.5–1mg/kg, intraperitoneally)/fluoxetine (as a positive control, 10mg/kg), for the last 2-weeks of CORT dosing. Repeated CORT dosing caused depression-like behavior in mice as indicated by increased despair effects in forced swim test (FST) and anhedonia in sucrose preference test. In addition, CORT administration induced oxidative load in the brain with significant increase in pro-oxidant (lipid peroxidation and nitrite levels) markers and a substantial decline in anti-oxidant defense (catalase and reduced glutathione levels) system, indicating a direct effect of stress hormones in the induction of the brain oxidative damage. On the other hand, 4i and fluoxetine treatment reversed the CORT induced depressive-like deficits. Furthermore, 4i and fluoxetine prevented CORT induced oxidative brain insults, which may plausibly demonstrate one of the key mechanisms for antidepressant-like effects of the compounds. Thus, the study suggests that 5HT3 antagonist; 4i may be implicated as pharmacological intervention targeting depressive-like anomaly associated with HPA-axis dysregulation.

Ovarian hormone fluctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: a novel heuristic model.

In this conceptual review, the authors propose a novel mechanistic candidate in the etiology of depression with onset in the menopause transition ("perimenopausal depression") involving alterations in stress-responsive pathways, induced by ovarian hormone fluctuation. The relevant literature in perimenopausal depression, including prevalence, predictors, and treatment with estrogen therapy, was reviewed. Subsequently, the growing evidence from animal models and clinical research in other reproductive mood disorders was synthesized to describe a heuristic model of perimenopausal depression development. The rate of major depressive disorder and clinically meaningful elevations in depressive symptoms increases two- to threefold during the menopause transition. While the mechanisms by which ovarian hormone fluctuation might impact mood are poorly understood, growing evidence from basic and clinical research suggests that fluctuations in ovarian hormones and derived neurosteroids result in alterations in regulation of the HPA axis by γ-aminobutyric acid (GABA). The authors' heuristic model suggests that for some women, failure of the GABAA receptor to regulate overall GABA-ergic tone in the face of shifting levels of these neurosteroids may induce HPA axis dysfunction, thereby increasing sensitivity to stress and generating greater vulnerability to depression. The proposed model provides a basis for understanding the mechanisms by which the changing hormonal environment of the menopause transition may interact with the psychosocial environment of midlife to contribute to perimenopausal depression risk. Future research investigating this model may inform the development of novel pharmacological treatments for perimenopausal depression and related disorders, such as postpartum depression and premenstrual dysphoric disorder.

The Association of 5-HTTLPR XLL Genotype with Higher Cortisol Levels in African Americans

Genetic variants of the human serotonin transporter (SERT) may contribute to HPA axis dysregulation. SERT has two promoter region polymorphisms (5-HTTLPR: VNTR and SNP: rs25531), which may alter levels of SERT protein and its function. Combining these polymorphisms creates a functional polymorphism (FN) which may modulate mRNA expression. This study examines the relationship between these genetic variants and morning and evening salivary samples of both cortisol and dehydroepiandrosterone sulfate (DHEAS) concentrations in 269 African American (AA) adults. Resultant allele frequencies for the VNTR, SNP, and FN genotypes were 70% L (2% XLL), 84% A, and 54% LA (2% XLLA), respectively. The XLL genotype was associated with significantly higher concentrations of cortisol (~3X) and DHEAS (~2X) for both VNTR and FN polymorphisms. No significant differences were found for SNP genotypes. Conclusions were that persons with VNTR and FN XLL polymorphisms had significantly higher cortisol and DHEAS concentrations than other genotypes. AAs also appear to have a higher frequency of the rare XL allele than Caucasians. Whether the XLL genotype predisposes AAs to greater health challenges will require further research to determine the implications of these findings.

Longitudinal effects of the SSRI paroxetine on salivary cortisol in Major Depressive Disorder

Hypothalamic-pituitary-adrenal (HPA)-axis dysregulation is a prominent finding in more severe Major Depressive Disorder (MDD), and is characterized by increased baseline cortisol levels at awakening (BCL), blunted cortisol awakening response (CAR) and increased area under the cortisol curve (AUC). Selective serotonin reuptake inhibitors (SSRIs) appear to normalize HPA-axis dysfunction, but this is hardly investigated longitudinally. We studied salivary BCL, CAR and AUC at awakening and 30min thereafter. We compared measurements in initially drug-free MDD-patients with healthy controls (HCs) at study-entry. In patients, we repeated measures after 6 and 12 weeks' treatment with the SSRI paroxetine. Non-responding patients received a randomized dose-escalation after six weeks' treatment. We found no significant study-entry differences in BLC, CAR or AUC between MDD-patients (n=70) and controls (n=51). In MDD-patients, we found general decreases of BCL and AUC during paroxetine treatment (p≤0.007), especially in late and non-responders. Importantly, while overall CAR did not change significantly over time, it robustly increased over 12 weeks especially when patients achieved remission (p≤0.041). The dose-escalation intervention did not significantly influence CAR or other cortisol parameters. In conclusion, paroxetine seems to interfere with HPA-axis dysregulation, reflected in significant overall decreases in BCL and AUC during treatment. Paroxetine appears to decrease HPA-axis set-point in MDD, which might result in increased HPA-axis activity over time, which is further improved when patients achieve remission (ISRCTN register nr. ISRCTN44111488).