PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jpnSubmit a ManuscriptEmail AlertsAbout JPNJournal of Psychiatry and Neuroscience
 
J Psychiatry Neurosci. Sep 2003; 28(5): 364–369.
PMCID: PMC193983
Beclomethasone-induced vasoconstriction in women with major depressive disorder
Nick J. Coupland, Kathleen M. Hegadoren, and Jessica Myrholm
Coupland — Department of Psychiatry, University of Alberta Hospital; Hegadoren, Myrholm — Faculty of Nursing, University of Alberta, Edmonton, Alta.
Objective
It has been hypothesized that abnormal negative feedback of cortisol release in major depressive disorder (MDD) may involve impaired central glucocorticoid receptor (GR) function. Beclomethasone-induced vasoconstriction (BIV) was recently used to test the hypothesis that impaired GR function generalizes to peripheral tissues, and it was reported that BIV was decreased in medicated patients with MDD. The objective was to test the hypothesis that BIV would be reduced in unmedicated women with MDD compared with healthy controls.
Design
Case–control.
Setting
A university womens' mental health research unit.
Participants
Women aged 18–65 years (n = 19) diagnosed, according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, with MDD after a structured interview and clinical assessment. Healthy women pair-matched for age, reproductive and smoking status.
Procedures
BIV was tested using a range of beclomethasone dipropionate concentrations (1–100 μg/mL) applied to the forearm, with vasoconstriction scored visually after 15–18 hours by raters blinded to diagnosis and the randomization of the application sites.
Outcome measure
Visual scores for BIV at each beclomethasone concentration.
Results
No significant differences between patients with MDD and controls were found. Postmenopausal women showed less of a response than premenopausal women or women taking sex-hormone preparations.
Conclusion
The study did not concur with the previous finding that BIV is decreased in MDD. Further research is needed to determine whether the difference in findings is due to medication or to other factors that may have distinguished the samples, including sex, age, reproductive status, illness severity, treatment resistance and setting.
Medical subject headings: beclomethasone, depressive disorder, glucocorticoid, hydrocortisone, receptors, vasoconstriction, women
Objectif
On a posé en hypothèse que dans le trouble dépressif majeur (TDM), le rétrocontrôle négatif anormal du cortisol pourrait venir d'un déficit fonctionnel du récepteur central des glucocorticoïdes (RG). Récemment, on a fait appel à la vasoconstriction induite par la béclométhasone (VIB) pour vérifier l'hypothèse selon laquelle le déficit fonctionnel du RG s'étend aux tissus périphériques, et on a signalé que la VIB était moindre chez les patients atteints d'un TDM qui recevaient des médicaments. L'objectif était de vérifier l'hypothèse selon laquelle la VIB serait réduite chez les femmes atteintes d'un TDM ne recevant pas de médicament, par rapport aux témoins en bonne santé.
Conception
Étude cas-témoins.
Contexte
Unité universitaire de recherche en santé mentale pour femmes.
Participants
Femmes de 18 à 65 ans (n = 19) chez lesquelles on a établi, suite à une entrevue structurée et à une évaluation clinique, un diagnostic de TDM fondé sur le Manuel diagnostique et statistique des troubles mentaux, 4e édition. Elles ont été jumelées, selon l'âge, l'état reproducteur et le statut de fumeuse, avec des femmes en bonne santé.
Interventions
Pour évaluer la VIB, on a appliqué sur l'avant-bras du dipropionate de béclométhasone suivant une gamme de concentrations (1 à 100 μg/mL), puis 15 à 18 heures plus tard, des évaluateurs qui ignoraient le diagnostic et la répartition aléatoire des sites d'application ont évalué visuellement la vasoconstriction.
Mesure de résultat
Résultats relatifs à la VIB établis visuellement pour chaque concentration de béclométhasone.
Résultats
On n'a pas relevé de différence importante entre les patientes atteintes d'un TDM et les témoins. Les femmes ménopausées ont présenté une réponse plus faible que les femmes non ménopausées ou celles recevant des préparations d'hormones sexuelles.
Conclusion
L'étude n'a pas corroboré la constatation antérieure selon laquelle la VIB est moindre dans les cas de TDM. Il faut effectuer d'autres recherches pour déterminer si la différence entre les constatations est attribuable aux médicaments ou à d'autres facteurs qui pourraient avoir différencié les échantillons, y compris le sexe, l'âge, l'état reproducteur, la gravité de la maladie, la résistance au traitement et le contexte.
Recent reviews suggest that abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis found in major depressive disorder (MDD) are important for understanding the pathogenesis of the disorder.1,2 Findings that include hypercortisolemia and a lack of suppression of cortisol in the dexamethasone-suppression test or the combined corticotropin-releasing hormone dexamethasone test have been postulated to involve an increase in the combined effects of the releasing factors, corticotropin-releasing hormone CRH and vasopressin, and a decrease in negative feedback control. Glucocorticoid receptors (GRs) are sensitive to changes in circulating cortisol and are thought to limit stress-induced increases in cortisol. A defect in GR-mediated feedback has been proposed as an explanation of HPA axis overactivity in depression, and on the basis of a lack of Cushingoid stigmata in hypercortisolemic depressed patients and of abnormalities in GRs in peripheral blood cells, some authors have suggested that GR dysfunction may generalize to tissues outside the HPA axis.1,2 It was recently reported that patients with MDD also showed reduced skin vasoconstriction in response to topical application of the potent glucocorticoid, beclomethasone (beclomethasone-induced vasoconstriction, BIV), further suggesting a peripheral GR abnormality in major depression.3 However, all of the patients studied were receiving antidepressants. The aim of the present study was therefore to test the hypothesis that BIV would be reduced in unmedicated women with MDD compared with healthy controls.
The study was approved by the university research ethics board. Women aged 18–65 years were recruited via notices and local contacts and gave written informed consent to participate. Subjects were screened for axis I diagnoses using the Mini-International Neuropsychiatric Interview.4 Patients were also fully assessed by an experienced clinician and were included if they met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for MDD. All cases scored in the moderate range of severity (17-item Hamilton Depression Rating Scale mean 21, range 17–27) and none met full criteria for atypical features. Controls were free of lifetime axis I disorders. Other exclusion criteria were: psychotic depression; depression or suicide risk of severity that would make it inappropriate to delay treatment until completion of testing in the follicular phase of the menstrual cycle; pregnancy or lactation; a lifetime history of schizophrenia, bipolar disorder or post-traumatic stress disorder (PTSD); history of an alcohol or substance use disorder within 3 months; use of corticosteroids within 3 months. None of the patients had been taking psychotropic medication more recently than 3 months before the study. Reproductive status and hormonal treatments are a source of variance in HPA axis function,5 and controls were therefore pair-wise matched for reproductive status, in addition to age and smoking (1 pair of subjects). Seven pairs were premenopausal, 6 postmenopausal and 6 were on hormonal treatments (birth control or hormone replacement). Subjects did not differ in weekly alcohol intake or body-mass index (Table 1).
Table thumbnail
Table 1
Procedures
Self-ratings were made for the last week on the Mood and Anxiety Symptoms Questionnaire short form (MASQ), a 62-item 5-point scale that discriminates depressive anhedonia, general distress and anxious arousal,6 and for the last month on the Perceived Stress Scale, a 14-item 5-point scale for rating non-specific appraisals of stress.7 Subjects refrained from alcohol for 48 hours before the tests, and BIV was tested in the follicular phase (day 6–10 after onset of menses), where appropriate. Tests used beclomethasone dipropionate (Sigma-Aldrich, Canada), dissolved in 95% ethanol to final concentrations of 0 μg/mL (vehicle control), 1 μg/mL, 3 μg/mL, 10 μg/mL, 30 μg/mL and 100 μg/mL. Solutions were prepared and stored under conditions known to give stable test responses.8 In the late afternoon, at least 2 hours after the last meal,9 subjects collected a salivary cortisol sample using a dental roll for 2 minutes (Salivette; Sarstedt Inc., Newton, NC). Six 2-cm grease rings were applied to the volar aspect of each forearm, and 10-μL aliquots of test solution were applied at random locations and then occluded with plastic wrap and tube gauze. After 15–18 hours, BIV was assessed visually on a 5-point scale under standard fluorescent lighting by the same 2 trained observers who underwent regular inter-rater assessment and feedback and who were blinded to the study design, diagnosis and randomization. The BIV scale was: 0 = no blanching, 1 = faint blanching, 2 = obvious blanching, 3 = intense blanching, 4 = intense blanching that extends outside test ring.8 The inter-rater rank correlation was 0.88, and BIV scores for each concentration were averaged from the 2 observers. To correspond with the analysis of Cotter et al,3 an additional “median BIV score” was calculated as the median score for each subject from the 3–100 μg/mL concentrations. Subjects collected a saliva sample 30 minutes after waking the next morning, before any vigorous activity, smoking, eating, tooth brushing or going outdoors, and after rinsing their mouth with plain water.10 Samples timed in relation to waking are correlated with diurnal cortisol and are more reliable than those collected at set time points.11 Saliva samples were centrifuged, stored at –80°C, and salivary cortisol was assayed in duplicate using a highly specific enzyme-linked immunosorbent assay kit (Alpco Milenia Cortisol; Dako Diagnostics Canada, Mississauga, Ont.), with inter-assay and intra-assay coefficients of variation ≤ 2% at 1.0 μg/dL and ≤ 8% at 5.0 μg/dL.
Statistics
Parametric data (including salivary cortisol and body mass index after log-normalization) were compared using paired t tests. BIV ratings at each beclomethasone concentration, median BIV scores, alcohol intake, MASQ general distress and anxious arousal were compared using Wilcoxon signed-rank tests. Spearman rank correlations were used to test for associations between salivary cortisol concentrations and BIV scores. Data are given as means (and standard deviations [SD] back-transformed for the normalized data), medians and quartiles; 95% confidence limits for the differences between means are given for the non-transformed parametric data.
BIV scores did not differ significantly between the MDD patients and controls at any beclomethasone concentration (Fig. 1). In addition, “median BIV scores” from the 3–100 μg/mL concentrations did not differ between depressed patients (mean 3.0, 95% confidence limits [CL] 2.5–3.5) and healthy controls (mean 2.75, 95% CL 2.5–3.5) (z = –1.02, p = 0.31). The number of subjects with at least faint blanching at each concentration did not differ significantly, and 100% of subjects showed obvious or greater blanching at 10 μg/mL beclomethasone or above. In the combined sample, there was a significant effect of reproductive status on the median BIV score (Kruskal-Wallis χ2 = 6.025, p = 0.049). Postmenopausal women (mean 2.5, 95% CL 2.25–2.9) showed less vasoconstriction than women who were premenopausal (mean 3.125, 95% CL 2.56–3.53) or taking hormones (mean 3.0, 95% CL 2.56–3.5).
figure 6FF1
Fig. 1: Median ratings of beclomethasone-induced vasoconstriction (BIV) in women with major depressive disorder (black bars) and healthy controls (white bars). Wilcoxon signed-ranks tests: 1 μg/mL: z = –0.44, p = 0.66; 3 μg/mL: (more ...)
There were no significant differences in salivary cortisol concentrations (Table 1). Median BIV scores were positively correlated with afternoon cortisol in MDD patients (r = 0.49, p = 0.035) but were not correlated with waking cortisol in patients (r = 0.29, p = 0.23) or with waking (r = –0.25, p = 0.31) or afternoon cortisol (r = 0.03, p = 0.92) in controls.
This study failed to replicate the finding of Cotter et al3 that MDD was associated with reduced BIV. Differences between the study populations or rating methods could be relevant to this discrepancy. The sample in the Cotter et al study was 41% male, whereas all of our subjects were female. Second, in the current study, subjects were matched for reproductive factors, including hormone treatments and cycle phase. Sex and reproductive factors may be relevant in view of the present finding that postmenopausal women showed reduced BIV and the literature on sex differences in HPA axis function.5 Third, patients were older in the Cotter et al study, and age may have contributed to the reduced response in postmenopausal women in this study. Fourth, all of the patients in this study were psychotropic-free, whereas Cotter et al's patients were all taking antidepressants. Although antidepressants have been reported to increase, not decrease, GR function,2 it is possible that BIV may be influenced by effects of antidepressants on vascular tone downstream from GRs. For example, glucocorticoids potentiate noradrenaline-induced vasoconstriction,12 and noradrenergic function may be increased by antidepressants.13 Fifth, the subjects in this study were moderately depressed outpatients recruited via public notices, whereas Cotter et al studied inpatients with major depression, half of whom were taking lithium. This suggests that factors such as severity, treatment-seeking, treatment-resistance, admission to hospital or suicide risk may be relevant, particularly because we excluded patients needing urgent treatment. Psychotically depressed patients, who may have more frequent or marked HPA axis abnormalities,14 were excluded from both studies. In the current study, patients with PTSD were excluded because of evidence that BIV may be increased in this population.15 In most of the patients in the Cotter et al study, but none in this study, blanching was undetectable at 3–10 μg/mL. A lower threshold of the current raters for detecting faint blanching could produce this result, but this would not explain the lack of group differences across the whole range of beclomethasone concentrations and on the “median BIV scores.”
Visual-ratings are the most sensitive method to detect faint steroid-induced vasoconstriction and are reliable within laboratories if consistent conditions and trained raters are used.16,17 However, comparisons between laboratories cannot be readily made without standardization. There is good evidence that BIV is mediated by GRs. First, steroid-induced vasoconstriction has shown clear dose–response relations,18 and vasoconstrictive potency is associated with clinical efficacy in the treatment of psoriasis, allergy and asthma.19,20,21 Second, vasoconstriction was inhibited by the nonselective GR antagonists, progesterone, deoxycorticosterone and mifepristone (RU486).8,22,23 Third, pharmacological blockade of the intracellular metabolism of cortisol by 11-β-hydroxysteroid dehydrogenase (11-β-HSD), using glycyrrhetinic acid, increased cortisol-induced vasoconstriction.24 11-β-HSD does not metabolize beclomethasone, and so differences in 11-β-HSD would not contribute directly to differences in BIV.25 Fourth, budesonide-induced vasoconstriction is influenced by genetic variants of GRs in healthy subjects26 that are also associated with risks for glucocorticoid-related disorders, including familial hypertension, hyperinsulinemia and abdominal obesity.27,28,29 Fifth, direct studies of BIV have also shown an association with familial hypertension and hyperinsulinemia30 and with clinical resistance to steroids in the treatment of asthma.8 These data also suggest that although GRs are differentially regulated in different tissues, alterations in GRs or in post-receptor mechanisms might exert effects across multiple tissues.
There was a mild increase in waking cortisol in patients compared with controls. Although this was not significant with 2-tailed tests selected a priori, it might be argued that 1-tailed tests would have been appropriate on the basis of prior evidence for cortisol hypersecretion in depression, although this may not be as common in outpatient or community populations as in patients in hospital.1,2,30 Waking cortisol was not correlated with BIV. Afternoon salivary cortisol and BIV were correlated, but in the opposite direction to that predicted for receptor down-regulation. This analysis was not the primary objective of the study and was uncorrected for multiple comparisons. The sample was small, and the timing of the saliva collection and control of the subjects' preceding activities were not as rigorous for the afternoon sample as for the waking sample.
The possibility that decreased BIV might be associated with more marked cortisol hypersecretion requires further study. Steroid-resistant asthma patients have shown lower BIV than steroid-sensitive patients taking long-term prednisone,8 and BIV was not correlated with plasma cortisol in hypertension,31 suggesting that reduced BIV may occur as a result of mechanisms other than GR down-regulation. In patients with MDD, impaired GR function may be a more consistent abnormality than reduced GR binding in peripheral blood cells.32
In conclusion, the present study did not find the predicted reduction in BIV in unmedicated patients with MDD, despite mild cortisol hypersecretion compared with the controls. Recent findings in PTSD15 and marked differences between the samples of patients with MDD studied to date suggest that further research is warranted. Although such samples may be difficult to recruit, MDD patients who are unmedicated, but also have severe, chronic, resistant depression may need to be studied.
Acknowledgments
Our thanks to raters Gail Rauw and Jordyce van Muyden, and to Jesse Chan, Heidi Choi, Evelyn Mitchell, Carla Morden, Kelly Shinkaruk, Sona Sihra for assistance with the study. Thanks to Brian Walker at the Western General Hospital, Edinburgh, Scotland for advice on the BIV method. Thanks to David Watson and Lee Anna Clark for permission to use the MASQ.
Footnotes
Funding is gratefully acknowledged from the Alberta Heritage Foundation for Medical Research (NC, KH), the NeuroScience Canada Foundation (NC) and the Canadian Institutes of Health Research (KH).
Competing interests: None declared.
Correspondence to: Dr. Nick J. Coupland, 1E7.16 WMC, Department of Psychiatry, University of Alberta Hospital, 8440–112 St., Edmonton AB T6G 2B7; fax 780 407-6672; nc2/at/ualberta.ca
Submitted July 24, 2002 Revised Dec. 4, 2002 Accepted Mar. 11, 2003
1. Checkley S. The neuroendocrinology of depression and chronic stress. Br Med Bull1996;52:597-617. [PubMed]
2. Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord2001;62:77-91. [PubMed]
3. Cotter PA, Mulligan OF, Landau S, Papadopoulos A, Lightman SL, Checkley SA. Vasoconstrictor response to topical beclomethasone in major depression. Psychoneuroendocrinol 2002;27:475-87. [PubMed]
4. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry1998;59:22-33. [PubMed]
5. Young EA, Korszun A. Women, stress and depression: sex differences in hypothalamic-pituitary-adrenal axis regulation. In: Leibenluft E, editor. Gender differences in mood and anxiety disorder, from bench to bedside. Washington: American Psychiatric Press; 1999. p. 31-52.
6. Watson D, Weber K, Assenheimer JS, Clark LA, Strauss ME, McCormick RA. Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. J Abnorm Psychol1995;104:3-14. [PubMed]
7. Cohen S, Kamarack T, Memelstein R. A global measure of perceived stress. J Health Soc Behav 1988;24:385-96. [PubMed]
8. Brown PH, Teelucksingh S, Matusiewicz SP, Greening AP, Crompton GK, Edwards CR. Cutaneous vasoconstrictor response to glucocorticoids in asthma. Lancet1991;337:576-80. [PubMed]
9. Gibson EL, Checkley S, Papadopoulos A, Poon L, Daley S, Wardle J. Increased salivary cortisol reliably induced by a protein-rich midday meal. Psychosom Med1999;61:214-24. [PubMed]
10. Pruessner JC, Wolf OT, Hellhammer DH, Buske-Kirschbaum A, von Auer K, Jobst S, et al. Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity. Life Sci1997;61:2539-49. [PubMed]
11. Edwards S, Clow A, Evans P, Hucklebridge F. Exploration of the awakening cortisol response in relation to diurnal cortisol secretory activity. Life Sci2001;68:2093-103. [PubMed]
12. Walker BR, Williams BC. Corticosteroids and vascular tone: mapping the messenger maze. Clin Sci (Lond)1992;82:597-605. [PubMed]
13. Checkley SA, Corn TH, Glass IB, Thompson C, Franey C, Arendt J. Neuroendocrine and other studies of the mechanism of antidepressant action of desipramine. Ciba Found Symp1986;123:126-47. [PubMed]
14. Schatzberg AF, Rothschild AJ. Psychotic (delusional) major depression: Should it be included as a distinct syndrome in DSM-IV? Am J Psychiatry1992;149:733-45. [PubMed]
15. Coupland NJ, Hegadoren KM, Myrholm J, Sihra S, Chan J, Mitchell E. Beclomethasone-induced vasoconstriction in posttraumatic stress disorder. Canadian College of Neuropsychopharmacology annual meeting; 2001 Jun 17–20; Banff (AB). p. 35.
16. Henry F, Fumal I, Pierard GE. Postural skin colour changes during the corticosteroid blanching assay. Skin Pharmacol Appl Skin Physiol1999;12:199-210. [PubMed]
17. Noon JP, Evans CE, Haynes WG, Webb DJ, Walker BR. A comparison of techniques to assess skin blanching following the topical application of glucocorticoids. Br J Dermatol1996; 134:837-42. [PubMed]
18. Demana PH, Smith EW, Walker RB, Haigh JM, Kanfer I. Evaluation of the proposed FDA pilot dose-response methodology for topical corticosteroid bioequivalence testing. Pharmaceut Res 1997;14:303-8. [PubMed]
19. Woodford R. Correlation of the vasoconstrictor assay and clinical activity in psoriasis [letter]. Arch Dermatol1986;122:1355. [PubMed]
20. Seidenari S, Di Nardo A, Mantovani L, Giannetti A. Parallel intraindividual evaluation of the vasoconstrictory action and the anti-allergic activity of topical corticosteroids. Exp Dermatol1997;6:75-80. [PubMed]
21. Johansson SA, Andersson KE, Brattsand R, Gruvstad E, Hedner P. Topical and systemic glucocorticoid potencies of budesonide and beclomethasone dipropionate in man. Eur J Clin Pharmacol1982;22:523-9. [PubMed]
22. Marks R, Barlow JW, Funder JW. Steroid-induced vasoconstriction: glucocorticoid antagonist studies. J Clin Endocrinol Metab1982;54:1075-7. [PubMed]
23. Gaillard RC, Poffet D, Riondel AM, Saurat JH. RU 486 inhibits peripheral effects of glucocorticoids in humans. J Clin Endocrinol Metab1985;61:1009-11. [PubMed]
24. Sandeep TC, Walker BR. Pathophysiology of modulation of local glucocorticoid levels by 11-beta-hydroxysteroid dehydrogenases. Trends Endocrinol Metab2001;12:446-53. [PubMed]
25. Walker BR, Best R, Shackleton CH, Padfield PL, Edwards CR. Increased vasoconstrictor sensitivity to glucocorticoids in essential hypertension. Hypertension1996;27:190-6. [PubMed]
26. Panarelli M, Holloway CD, Fraser R, Connell JM, Ingram MC, Anderson NH, et al. Glucocorticoid receptor polymorphism, skin vasoconstriction, and other metabolic intermediate phenotypes in normal human subjects. J Clin Endocrinol Metab1998;83:1846-52. [PubMed]
27. Rosmond R, Dallman MF, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab1998;83:1853-9. [PubMed]
28. Ukkola O, Perusse L, Chagnon YC, Despres JP, Bouchard C. Interactions among the glucocorticoid receptor, lipoprotein lipase and adrenergic receptor genes and abdominal fat in the Quebec Family Study. Int J Obes Relat Metab Disord2001;25: 1332-9. [PubMed]
29. Watt GC, Harrap SB, Foy CJ, Holton DW, Edwards HV, Davidson HR, et al. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure. J Hypertens1992;10:473-82. [PubMed]
30. Strickland P, Deakin JFW. Cortisol, stress and depression. Br J Psychiatry 2002;181:348-9.
31. Walker BR, Phillips DI, Noon JP, Panarelli M, Andrew R, Edwards HV, et al. Increased glucocorticoid activity in men with cardiovascular risk factors. Hypertension1998;31:891-5. [PubMed]
32. Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry2001;49:391-404. [PubMed]
Articles from Journal of Psychiatry & Neuroscience : JPN are provided here courtesy of
Canadian Medical Association