Impact of Gene-Gender Effects of Adrenergic Polymorphisms on Hypothalamic-Pituitary-Adrenal Axis Activity in Depressed Patients

Abstract

Objective: There is overwhelming evidence that activation of the hypothalamic-pituitary-adrenal (HPA) system plays a major role in depression and cardiovascular disease in genetically susceptible individuals. We hypothesized that due to the multiple interactions between the sympathetic and the HPA systems via adrenoceptors, polymorphisms in these genes could have an impact on HPA axis activity in major depression. Methods: Using the dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test, we investigated the association of α₂-adrenoceptor (ADRA2A –1291C→G) and the β₂-adrenoceptor gene (ADRB2 Arg16Gly) in 189 patients with major depression during the acute state of the disease and after remission. Results: Male ADRA2A –1291G allele homozygotes showed significant pretreatment HPA axis hyperactivity, with increased adrenocorticotropin (ACTH; F = 4.9, d.f. = 2, p = 0.009) and cortisol responses (F = 6.4, d.f. = 2, p = 0.003). In contrast, female ADRB2 Arg/Arg homozygotes had increased pretreatment ACTH (F = 7.17, d.f. = 2, p = 0.001) and cortisol (F = 8.95, d.f. = 2, p = 0.000) levels. Interestingly, in the respective genotypes, the stress hormones remained elevated in the second DEX/CRH test, despite a reduction in depressive symptoms. Conclusions: This study provides evidence that, depending on gender and polymorphisms, there is continuous HPA axis overdrive in a proportion of patients irrespective of the status of depression. Considering the importance of stress hormones for cardiovascular disorders, our data might suggest that these patients are at high risk of comorbidity between depression and cardiovascular disorders.

Genome-wide association studies in ADHD

“…Another example is gender; given the difference between sexes, certain genetic risk factors can be expected to affect males and females differently. That this affects association studies has already been shown in ADHD (Biederman et al 2008; Guimaraes et al 2007; Rommelse et al 2008b) as well as other (related) psychiatric disorders (Craig et al 2004; Diamond 2007; Haefner et al 2008; Kendler 1998; Lang et al 2008; Okamura et al 2007; Rucci et al 2009). An additional potentially important factor is age at diagnosis.…”

Fetal hormonal programming of sex differences in depression: linking women's mental health with sex differences in the brain across the lifespan

“…Study inconsistencies may be related to timing of cortisol assessments or may reflect methodological confounds, such as age of study subjects (e.g., post-menopausal women differ from premenopausal women and thus sex differences differ), chronicity of illness (e.g., sustained illness may produce blunted cortisol response rather than hypercortisolemia), or low statistical power to detect sex differences which may vary in effect size, depending on characteristics of the sample (details next paragraph). Further, genetic background likely affects HPA axis dysregulation, as demonstrated in studies showing increased ACTH and cortisol in males (but not females) homozygotic for the alpha (2)-adrenoreceptor gene and females (but not males) homozygotic for the beta (2)-adrenoreceptor gene (Haefner et al, 2008). Collectively, these findings offer initial evidence of sex differences in the role of HPA axis in MDD pathophysiology and emphasize the importance of considering genetic variation in HPA axis-associated genes.…”

A placebo-controlled study of sertraline’s effect on cortisol response to the dexamethasone/corticotropin-releasing hormone test in healthy adults

“…Our unexpected findings lead us to speculate about contributions from the many complex effects involved in HPA axis reactivity and to conclude that the Dex/CRH test cortisol response may not be a useful tool for evaluating the potential effectiveness of antidepressants on HPA axis downregulation in healthy volunteers. Recent data describing gene–gender effects on Dex/CRH test response (Haefner et al 2008) suggest a further avenue of research inquiry for understanding our results.…”

“…These findings are important, given the extensive use of the Dex/CRH test for assessing HPA axis function in a variety of pathological conditions and for studying the mechanism of action of numerous therapeutic agents. A growing literature has identified a collection of clinical and demographic variables exerting significant effects on the cortisol response to the Dex/CRH test, including age (Kunugi et al 2006), sex (Haefner et al 2008), temperament (Tyrka et al 2008b), coping style (Hori et al 2010), early life adversity (Carpenter et al 2009b; Heim et al 2008), quality of parental care (Tyrka et al 2008a), adult trauma exposure (Klaassens et al 2009), social support (Tsuru et al 2008), psychiatric comorbidity (Veen et al 2009), and genotype (Binder et al 2010; Tyrka et al 2009; Zobel et al 2010). Assumptions about qualitatively similar cellular and system-level responses to receptor activation by sertraline across depressed and healthy subjects supported the rationale for this investigation.…”