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| |  Salivary Cortisol Response to Prednisolone Challenge Helps Understand Treatment-Resistant Depression: Presented at ECNP By Chris Berrie PARIS, FRANCE -- September 19, 2006 -- The suppression of salivary cortisol levels by prednisolone provides a physiological assessment of the status of the hypothalamic-pituitary-adrenal (HPA) negative-feedback axis through significant differences between control subjects and patients with treatment-resistant depression (TRD), according to research presented here at the 19th Congress of the European College of Neuropsychopharmacology (ECNP). The non-randomised, single-blind, placebo-controlled, repeated-measure study was presented on September 17th by principal investigator Mario F. Juruena, MD, clinical researcher, affective disorders unit, South London and Maudsley Trust, London, United Kingdom. Major depression is the most prevalent of all of the psychiatric disorders but 50% to 70% of cases respond to currently available antidepressants, Dr. Juruena said. Patients with TRD have reduced glucocorticoid receptor (GR) function and a hyperactive HPA, leading to high cortisol levels. This led to the use of the dexamethasone test to investigate the HPA axis status in these depressed patients. However, dexamethasone has pharmacodynamics and pharmacokinetics that are distinct from those of the endogenous glucocorticoids, and binds only to the GR. In contrast, cortisol binds to both the GR and the mineralocorticoid receptor. According to Dr. Juruena, prednisolone is a better corticosteroid than dexamethasone to assess the HPA axis because it binds to 2 different receptors, not only the glucocorticoid receptors but also the mineralocorticoid receptors, providing a more physiological approach. Therefore he and his colleagues conducted a study to evaluate GR function and the relative contributions of biological and physiological factors in patients with TRD to their level of disability, with the hypothesis that control subjects and patients with TRD differ in response to this prednisolone-suppression test. "This is not a therapeutic issue, this is just a [prednisolone challenge] to understand what happens when the people get depressed and do not respond to different treatments and become resistant to treatments, and so we are trying to assess this in a physiological way, and trying to define and characterise the depression patients regarding their biological HPA axis after prednisolone [dosing]," Dr. Juruena explained. The study enrolled 34 healthy control subjects and 33 patients diagnosed with recurrent major depression according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revision IV and had shown resistance to treatment with at least 2 different classes of antidepressants at minimum therapeutic doses. All patients were challenged with both placebo and prednisolone 5 mg and salivary cortisol levels were measured at 9, 12 and 17 hours after treatment. The demographic characteristics of controls and TRD patients at baseline were similar for age (44.8 vs 50.9 years), gender (male, 41% vs 18%) and body mass index (BMI, 26.2 vs 29.1 kg/m2). Mean psychometric measures and scores of the TRD patients were: age at onset of depression, 28.5 years; number of depressive episodes, 7.6; duration of current episode, 32.6 months; duration of depressive illness, 21.1 years; Beck Depression Inventory-II (BDI-II), 38.5 (controls, 2.3); 21-item Hamilton Rating Scale for Depression (HRSD-21), 21.8 (controls, 5.2); Beck Hopelessness Scale (BHS), 16.3, Mini-Mental State Examination (MMSE), 27.8; Pittsburgh Sleep Quality Index (PSQI), 12.3; and Recent Life Changes (RLC), 308.8. Patients in the TRD group had higher salivary cortisol levels compared with controls, and in both groups the prednisolone challenge led to significant decreases on challenge (P < .001) and over time (P < .001). Linear regression analysis with the area under the curve (AUC) for salivary cortisol concentration after prednisolone treatment, age, BMI, age at onset, and duration of depression showed non-significant relationships. Significant correlations were seen for: number of depressive episodes (R = 0.31; P < .05); BDI-II (R = 0.71; P < .05); HAMD-21, (R = 0.30; P < .05); BHS, (R = 0.48; P < .05); MMSE, (R = 0.48; P < .05); PSQI, (R = 0.74; P < .05); and RLC, (R = 0.55; P < .05). When directly compared as AUC measures for salivary cortisol, suppression sensitivity to the prednisolone challenge was not significantly different between controls and TRD patients (53% vs 39%, respectively; P = .120). However, significant differences between controls versus TRD patients were seen for: AUC after placebo (26.6 vs 36.7; P = .017); AUC after prednisolone (11.4 vs 24.2; P = .013); plasma cortisol after placebo (285.8 vs 429.8 nmol/L; P < .001); and plasma cortisol after prednisolone (222.1 vs 319.2 nmol/L; P = .048). The researchers concluded that the prednisolone suppression test demonstrated significant difference between controls and TRD patients in their salivary cortisol response to prednisolone challenge versus placebo, with correlation between salivary cortisol after prednisolone in TRD patients indicating less suppression than controls after prednisolone and placebo. Dr. Juruena also noted the very interesting correlations they found between salivary cortisol response to prednisolone and psychometric measures, showing that severity of depression, hopelessness, stressful events, cognitive function and sleep disorders are associated with HPA axis impairment in these TRD patients. "So," he said, "by correlating this area under the curve of the salivary cortisol with the psychometric measures, we can ultimately define which kind of patient will become resistant to treatment." On a more speculative note, he said that differences in the ratio of mineralocorticoid receptor to GR could explain some of these abnormalities, which would indicate the potential for a new target for antidepressant action.
[Presentation title: Treatment-Resistant Depression: Response to Prednisolone Suppression Test. Abstract P.2.a.003]
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