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Gender-specific association of galanin polymorphisms with HPA-axis dysregulation, symptom severity, and antidepressant treatment response.

ABSTRACT: Galanin (GAL) is an estrogen-inducible neuropeptide, highly expressed in brain regions reported to be involved in regulation of mood and anxiety. GAL possibly has a direct modulatory effect on hypothalamic-pituitary-adrenal (HPA)-axis regulation. Recent data from pharmacological and genetic studies indicate a significant function of GAL in stress-related disorders. By using a tag SNP approach covering the locus encoding preprogalanin (PPGAL), earlier findings of female-specific associations of polymorphisms in this locus with panic disorder were expanded to a larger sample of 268 outpatients with anxiety disorders (ADs). Within a larger sample of 541 inpatients with major depressive disorder (MDD), we then tested associations of one PPGAL tag SNP with specific depression symptom clusters and HPA-axis activity assessed by the combined dexamethasone-suppression/CRH-stimulation test both at inpatient admission and discharge (n=298). Gender specificity as well as dependence of the association on levels of circulating estrogens was analyzed. Genotyping revealed high linkage disequilibrium in the promoter area of the PPGAL gene, which includes several estrogen-response elements. Confirming earlier results, rs948854, tagging this promoter region, was associated with more severe anxiety pathology in female AD patients, but not in males. In premenopausal female MDD patients, the same allele of rs948854 was associated with more severe vegetative but not cognitive depressive symptoms at discharge and worse treatment response on antidepressant medication. Furthermore, this allele was associated with higher HPA-axis activity at admission. No significant case-control associations could be observed. However, because of power limitations of both patient samples, small effects cannot be excluded. The reported associations in independent samples of AD and MDD support an estrogen-dependent function of GAL in pathophysiology of anxiety and depression, affecting response to antidepressant treatment.

SUBMITTER: Unschuld PG

PROVIDER: S-EPMC3055457 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Gender-specific association of galanin polymorphisms with HPA-axis dysregulation, symptom severity, and antidepressant treatment response.

Unschuld Paul G PG Ising Marcus M Roeske Darina D Erhardt Angelika A Specht Michael M Kloiber Stefan S Uhr Manfred M Müller-Myhsok Bertram B Holsboer Florian F Binder Elisabeth B EB

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20100317 7

Galanin (GAL) is an estrogen-inducible neuropeptide, highly expressed in brain regions reported to be involved in regulation of mood and anxiety. GAL possibly has a direct modulatory effect on hypothalamic-pituitary-adrenal (HPA)-axis regulation. Recent data from pharmacological and genetic studies indicate a significant function of GAL in stress-related disorders. By using a tag SNP approach covering the locus encoding preprogalanin (PPGAL), earlier findings of female-specific associations of p ...[more]

PMID: 20237460

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Project description:Childhood trauma is among the most potent contributing risk factors for depression and is associated with poor treatment response. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been linked to both childhood trauma and depression, but the underlying mechanisms are poorly understood. The present study aimed to investigate the link between childhood trauma, HPA axis activity and antidepressant response in patients with depression. As part of the Wellcome Trust NIMA consortium, 163 depressed patients and 55 healthy volunteers were included in this study. Adult patients meeting Structured Clinical Interview for Diagnostic and Statistical Manual Version-5 criteria for major depression were categorised into subgroups of treatment responder (n = 42), treatment non-responder (n = 80) and untreated depressed (n = 41) based on current depressive symptom severity measured by the 17-item Hamilton Rating Scale for Depression and exposure to antidepressant medications established by Antidepressant Treatment Response Questionnaire. Childhood Trauma Questionnaire was obtained. Baseline serum C-reactive protein was measured using turbidimetric detection. Salivary cortisol was analyzed at multiple time points during the day using the ELISA technique. Glucocorticoid resistance was defined as the coexistence of hypercortisolemia and inflammation. Our results show that treatment non-responder patients had higher exposure to childhood trauma than responders. No specific HPA axis abnormalities were found in treatment non-responder depressed patients. Untreated depressed showed increased diurnal cortisol levels compared with patients on antidepressant medication, and higher prevalence of glucocorticoid resistance than medicated patients and controls. The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. Therefore, our findings suggest that the severity of childhood trauma experience contributes to a lack of response to antidepressant treatment. The effects of childhood trauma on increased cortisol levels are specifically evident in patients with glucocorticoid resistance and suggest glucocorticoid resistance as a target for the development of personalized treatment for a subgroup of depressed patients with a history of childhood trauma rather than for all patients with resistance to antidepressant treatment.

Project description:BackgroundSexual assault is implicated in several adverse psychological and physical health outcomes, including posttraumatic stress disorder (PTSD) and depression. Neurobiological research has shown variations related to the hypothalamic-pituitary-adrenal (HPA) axis, immune alterations, metabolic function, and brain circuitry. Although these mechanisms have been extensively studied, the results have demonstrated different outcomes in PTSD.MethodsWe compared the plasma adrenocorticotropin (ACTH) and salivary cortisol levels of fifty-eight women with PTSD developed after sexual assault to those of forty-four female controls with no history of trauma. We also evaluated the psychiatric diagnosis and symptom severity of PTSD and depression. The participants' clinical conditions were associated with their hormonal levels to assess whether symptom severity was related to hormonal imbalance.ResultsA large percentage of sexually assaulted women had PTSD and comorbid depression. The ACTH levels were higher in the PTSD group than the control group and increased as PTSD severity increased, considering depressive symptoms, measured by the Beck Depression Inventory (BDI) (p < 0.0001), as well as PTSD symptoms, measured by subscale D of the Clinician-Administered PTSD Scale (CAPS-5) (p = 0.045) and the CAPS-5 total scale (p = 0.026). Cortisol levels measured at 10 pm were higher for the PTSD group than the control group (p = 0.045, p = 0.037, respectively), and the cortisol awakening response showed elevated cortisol levels for the PTSD group.ConclusionsThese results show a correlation between symptom severity and HPA axis imbalance in patients with PTSD. Elevated ACTH and an elevated cortisol response in patients with comorbid depressive symptoms were the opposite of the expected response for patients with PTSD only. This association leads to the hypothesis that the neurobiological alterations of PTSD are related to the type of symptoms presented and their severity. These manifestations likely influence the disease course, prognosis and response to treatment. These outcomes highlight the need to discuss particular neurobiological alterations in patients with PTSD developed after sexual assault, mainly those with severe depressive symptoms.

Dataset Information

Gender-specific association of galanin polymorphisms with HPA-axis dysregulation, symptom severity, and antidepressant treatment response.

Publications

Gender-specific association of galanin polymorphisms with HPA-axis dysregulation, symptom severity, and antidepressant treatment response.

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