HANNES BOHMAN 1, ULF JONSSON 1,2, ANNE-LIIS VON KNORRING 1, LARS VON KNORRING 2, GUNILLA OLSSON 1, AIVAR PÄÄREN 1, MARITA LARSSON 3 & TORD NAESSEN 3

Transcription

1 The World Journal of Biological Psychiatry 2009, 15, ifirst article BRIEF REPORT Thicker carotid intima layer, thinner media layer and higher intima/ media ratio in women with recurrent depressive disorders: A pilot study using non-invasive high frequency ultrasound HANNES BOHMAN 1, ULF JONSSON 1,2, ANNE-LIIS VON KNORRING 1, LARS VON KNORRING 2, GUNILLA OLSSON 1, AIVAR PÄÄREN 1, MARITA LARSSON 3 & TORD NAESSEN 3 1 Department of Neuroscience, Child and Adolescent Psychiatry, Uppsala University, Uppsala, Sweden, 2 Department of Neuroscience, Psychiatry, Uppsala University, Uppsala Sweden, and 3 Department of Women s and Children s Health, Uppsala University, Uppsala Sweden Abstract Background. Growing evidence indicates that depression is an important risk factor for coronary heart disease. Thus, the aim of the present study has been to investigate if young women with adolescent onset and recurrent depressive disorders have signs of carotid intima and media changes already at the age of 30. Methods. Fifteen subjects with adolescent onset recurrent depressive disorders, mean age 31.5 years, were compared to 20 healthy women with a mean age of 39.6 years. The thickness of carotid artery intima and media was assessed, using non-invasive high-frequency ultrasound (25MHz). Results. The subjects with recurrent depressive disorders had significantly thicker carotid intima, significantly thinner carotid media and significantly higher intima/media ratio despite the fact that they were about 10 years younger than the healthy women. Hypertension, obesity or smoking could not explain the results. Conclusion. Already at the age of 30, subjects with recurrent depressive disorders with adolescent onset do have early signs of carotid intima and media changes, indicating a less healthy artery wall, despite otherwise no clinical signs of cardiovascular disease. Key words: Recurrent depression, adolescent onset, cardiovascular disease, carotid intima, carotid media Introduction Growing evidence indicates that depression is an important risk factor for coronary heart disease (Blumenthal 2008). Depression is a predictor of mortality in patients following myocardial infarction. Also in the general population, depression is a predictor of having an acute cardiac event (Lesperance and Frasure-Smith 2007). In a recent study, Davis et al. (2008) could demonstrate that patients with major depressive disorders in the past year were 50100% more likely than controls to develop hypertension or dyslipidemia. Furthermore, transition rates to coronary artery disease or congestive heart failure were increased 50100% among patients with diabetes, hypertension and dyslipidemia. The associations remained equally strong when depression 12 years in the past was taken into account as with depression in the past year (Davis et al. 2008). In a meta-analysis (Rugulies 2002), it was demonstrated that subjects with clinical depression had more than 2.5 times the risk of myocardial infarction or coronary death as subjects in the general population. Subjects with symptoms of depression who did not meet the full criteria of clinical depression had about 1.5 times increased risk of a future cardiac event. However, the exact mechanism by which depression increases the risk of coronary heart disease is not known. Risky behaviours, autonomic dysregulation, inflammation as well as coincidence models in which dietary factors affecting both depression and heart disease have been suggested (Lesperance and Frasure-Smith 2007). To follow the process to the development of atherosclerosis, the thickness of the combined carotid Correspondence: Professor Lars von Knorring, MD, PhD, Department of Neuroscience, Psychiatry, University Hospital, SE Uppsala, Sweden. Tel.: Fax: Lars.von_Knorring@UASPsyk.uu.se (Received 29 August 2008; accepted 22 January 2009) ISSN print/issn online # 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: /

2 2 H. Bohman et al. artery intimamedia layers estimated using ultrasound is the gold standard (Wendelhag et al. 1991). However, with advancing age and development of atherosclerosis, the intima and media layers change in different directions, i.e. the intima becomes thicker and the media becomes thinner (Gussenhoven 1991). Thus, separate assessment of carotid artery intima and media thickness using noninvasive high-frequency ultrasound appears to be more valuable, as we have previously shown a striking difference in intima thickness and the intima/media thickness ratio between subjects with and without cardiovascular disease (Rodriguez-Macias et al. 2006). Thus, the aim of the present pilot study has been to elucidate if changes in the intima and the intima/ media thickness ratio of the carotid artery can be detected already in young women with adolescent onset recurrent depressive disorders but without clinical signs of cardiovascular disease. Methods Selection and description of participants In a total population of high-school students aged 1617 years in a Swedish town was screened for depression and previous suicide attempts, and 2300 subjects (93.3%) participated (Olsson and von Knorring 1999). Those with high depression scores (12.3%) and previous suicide attempts (2.4%), as well as controls matched for gender and education, were interviewed for a diagnosis, and 88.8% participated. The diagnoses were based on a structured interview, the Diagnostic Interview for Children and Adolescents, (DICA- R-A), assessing diagnoses according to DSM-III-R. Since the DICA-R-A is designed to assess lifetime diagnoses, questions were added to determine the age at the latest episode of depression (Olsson and von Knorring 1999). The 1-year prevalence of major depression was 5.8% and the lifetime prevalence was 11.4%, with four girls being represented for every boy. In total, 363 subjects were identified as depressed, either at the screening or at the interview and 252 subjects were collected as controls. Fifteen years later, the same subjects have been reinvestigated by means of clinical interviews. Furthermore, weight, length, BMI, waist, hip, waist/hip ratio, systolic blood pressure, diastolic blood pressure and pulse were recorded. From this sample, a subgroup of 15 women with at least three recurrent depressive episodes with adolescent onset has been selected due to availability and willingness to participate in the study. However, all patients invited agreed to participate in the study. They are not representative of the whole sample but representative of a group of patients with recurrent depressive disorders with early onset. The mean age was 31.5 years. The control group included 20 healthy young women with a mean age of 39.6 years. In this pilot study, the control group was selected due to availability and age-matched controls were not included. As the controls are about 10 years older than the subjects with adolescent depression all found differences between the groups ought to have a high validity. Technical information Carotid total wall thickness and the thickness of the individual artery layers were assessed noninvasively using high-resolution ultrasonographic equipment (Osteoson Minhorst GmbH, Meudt, Germany), fitted with a broad-banded probe with 25 MHz center frequency. Briefly, the scan converter enables the image to be frozen at a selected scan-time (2 s) and the unit permits two-dimensional data acquisition, presenting the results as scans A and B. About 128 lines of echo data were detected as an A-echo signal, sampled by an eight-bit analog-to-digital converter, converted by scanning to a rectangular format and viewed as B-mode images on a 32-colour scale monitor. Image resolution is approximately 0.07 mm axially along the ultrasonographic beam and the depth of focus is in the range of mm in front of the tip of the probe. The system recognizes objects of about mm in size, and the software-driven cursors permit a minimal digital display of 0.02 mm. The left common carotid artery (LCCA) was examined at the point of the strongest pulse, in front of the sternocleidomastoid muscle, with the subjects sitting in an upright position and looking straight ahead. The three-layer image showed the pulsating artery near wall and the artery lumen. Ten B scans (point estimates) were carried out and measurements of the thickness of the whole arterial wall and its layers were performed off-line. Means of the 10 measurements were calculated and used in the analysis. The total thickness of the carotid wall was measured from the leading edge of the adventitia to the far edge of the intima. Measurements of the adventitia and intima were made using only the brightest echoes from leading edge to far edge, and the thickness of the media layer was measured as the distance between the two brightest echoes. The coefficient of variation (CV%) was about 2.4% for total carotid wall, 4.2% for media layer and about 8% for the intima layer. The values for artery wall layer given in this study

3 Carotid intima in recurrent depression 3 were mean values based on 10 or more measurements (Rodriguez-Macias et al. 2006). The assessor was blinded to the clinical data of the study subjects. The validity of the technique has been demonstrated in subjects with cardiovascular diseases (Rodriguez- Macias et al. 2006) and in normal aging (Naessen and Rodriguez-Macias 2006). Statistics Although, parametric data were obtained and although the data seemed to be normally distributed, a conservative approach was taken and non-parametric statistical tests were used. Thus, differences between means have been tested by the MannWhitney U-test. Correlations were tested by the Spearman correlation coefficient. The conservative approach was chosen due to the small sample size and the fact that age-matched controls were not available. However, in separate analyses, the Student s t-test and linear correlation coefficients were used and almost identical results were obtained. Frequency distributions were tested by means of the Fisher exact test. Two tailed tests were used and the level of significance was set a PB0.05. Ethics The study has been approved by the Regional Board of Ethics and has been conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Results In patients with recurrent depressive disorders, compared to control women, the carotid intima was significantly thicker (0.17 vs mm, z4.83, PB0.0001), the carotid media significantly thinner (0.49 vs mm, z2.40, PB0.02) and the resulting intima/media ratio was significantly higher (0.38 vs. 0.20, z4.40, PB0.0001) (Figure 1). As a matter of fact, three out of 20 healthy volunteers and all women with recurrent depressive disorders had carotid intima thickness above the mean1sd of the thickness of the healthy volunteers Fisher exact test, P0.0001). The mean BMI was 24.9, the median was Only one subject had a BMI between 25 and 30 and only two subjects had a BMI above 30. Twelve of the 15 subjects had normal BMI values. After exclusion of the three subjects with obesity, the subjects with recurrent depressive disorders (n12), compared to control women (n20), were found to have significantly thicker carotid intima (0.17 vs. Figure 1. Carotid intima and media thickness as well as intima/ media ratio in healthy women (N20) and women with recurrent depressive disorders (N15). MannWhitney U-test. *PB0.05, ***PB mm, z4.58, PB0.0001), somewhat thinner carotid media (0.53 vs mm, z1.71, n.s.) and significantly higher intima/media ratio (0.36 vs. 0.20, z4.01, PB0.0001). The mean systolic blood pressure was mmhg and the mean diastolic blood pressure was mmhg. The mean waist circumference was cm and the mean hip circumference was cm. The mean waist/hip ratio was The intima thickness, the media thickness, and the intima/media ratio did not correlate significantly with weight, length, BMI, waist, hip, waist/hip ratio, systolic blood pressure, diastolic blood pressure or pulse in the women with recurrent depressive disorders, except for a significant negative correlation between hip circumference and the carotid intima thickness (r 0.53, PB0.05)(Table I). Within the group of women with recurrent depressive disorders, only two out of 15 women were regular smokers. They had somewhat thicker intima (0.19 vs mm), thinner media (0.37 vs mm) and higher intima/media ratio (0.52 vs. 0.35), although the differences did not reach statistical significance. However, also with these two women omitted, the women with recurrent depressive disorders had significantly thicker carotid intima (z4.60, PB0.0001), thinner carotid media

4 4 H. Bohman et al. Table I. Spearman rank correlation coefficients between weight, length, BMI, waist, hip, waist/hip ratio, systolic blood pressure, diastolic blood pressure, pulse and carotid intima thickness, carotid media thickness and intima/media ratio in the women with recurrent depressive disorders (N15). Intima thickness Media thickness Intima/Media ratio Weight Length BMI Waist Hip 0.53* Waist/Hip ratio Systolic blood pressure Diastolic blood pressure Pulse (z1.99, PB0.05) and higher intima/media ratio (z4.13, PB0.0001). Eleven of the 15 women with recurrent depressive disorders had used antidepressant drugs, at least for a period of time. The carotid intima thickness (z 0.07, n.s.), the carotid media thickness (z1.38, n.s.) or the intima/media ratio (z1.24, n.s.) did not differ significantly between the subjects who had or had not had any antidepressant drugs. Discussion The most remarkable finding in the present pilot study is that young women with recurrent depressive disorders with adolescent onset, around 30 years old, without any clinical signs of cardiovascular disease have significantly thicker carotid intima, significantly thinner carotid media and significantly higher intima/media ratio than healthy women about 10 years older. The findings indicate a less healthy carotid artery wall, according to previous documentation (Rodriguez-Macias et al. 2006). Risky behaviours and life style factors have been suggested as one possible mechanism to explain the increased risk of cardiovascular disease in patients with recurrent depressive disorders (Lesperance and Frasure-Smith 2007). In the present study, the changes in carotid intima and media thickness do not seem to be related to life style factors, at least not to smoking. Only two out of 15 women were smokers and although they had somewhat thicker carotid intima and somewhat thinner carotid media, the findings are robust also without these two women. Furthermore, the changes in the carotid intima and media do not seem to be related to known risk factors for cardiovascular disease such as hypertension or obesity as there were almost no significant correlations between weight, length, BMI, waist, hip, waist/ hip ratio, systolic blood pressure, diastolic blood pressure or pulse and any of the carotid artery wall variables. This is in contrast to results in a previous study on elderly subjects showing significant correlations between the carotid artery wall variables and cardiovascular risk factors (Rodriguez-Macias et al. 2006). However, there are other risk factors not taken into account in the present study. Thus, the World Federation of Societies of Biological Psychiatry (WFSBP) task force on biological markers in depression (Mössner et al. 2007) concluded that hypercholesterolemia, cortisol hypersecretion and low blood folate levels are robust findings in subjects with recurrent depressive disorders. Also inflammation might be a risk factor for cardiovascular disease in subjects with recurrent depressive disorders (Lesperance and Frasure-Smith 2007). Furthermore, Danese et al. (2008) and Piletz et al. (2008) have reported elevated inflammation levels in subjects with recurrent depressive disorders. Furthermore, only women are included in the present study. Current knowledge points to important gender differences in age of onset, symptom presentation, management, outcome as well as traditional and psychosocial risk factors. Compared to men, the risk for cardiovascular disease in women is more strongly increased by some traditional factors (diabetes, hypertension, hypercholesterolemia, obesity), and socioeconomic and psychosocial factors seem to have a higher impact in women (Möller-Leimkühler 2008). Thus, our results cannot automatically be generalised to men with recurrent depressive disorders. Thus, although the women in the present study were selected due to adolescent onset and recurrent depressive disorders thereafter, the findings indicate the importance of controlling patients with recurrent depressive disorders for early signs of cardiovascular disease, also when there are no clinical signs of such diseases.

5 Conflict of interest statement The authors have no conflict of interest with any commercial or other associations in connection with the submitted article. References Blumenthal JA Depression and coronary heart disease: association and implications for treatment. Cleve Clin J Med 75(Suppl 2):S4853. Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry 65: Davis J, Fujimoto RY, Juarez DT, Hodges KA, Asam JK Major depression associated with rates of cardiovascular disease state transitions. Am J Manage Care 14: Gussenhoven EJ, Frietman PA, The SH, van Suylen RJ, van Egmond FC, Lancée CT, et al Assessment of medial thinning in atherosclerosis by intravascular ultrasound. Am J Cardiol 68: Lespérance F, Frasure-Smith N Depression and heart disease. Cleve Clin J Med 74(Suppl 1):S6366. Möller-Leimkühler AM Women with coronary artery disease and depression: a neglected risk group. World J Biol Psychiatry 9: Carotid intima in recurrent depression 5 Mössner R, Mikova O, Koutsilieri E, Saoud M, Ehlis AC, Müller N, et al Consensus paper of the WFSBP Task Force on Biological Markers: biological markers in depression. World J Biol Psychiatry 8: Naessen T, Rodriguez-Macias K Menopausal estrogen therapy counteracts normal aging effects on intima thickness, media thickness and intima/media ratio in carotid and femoral arteries. An investigation using noninvasive high-frequency ultrasound. Atherosclerosis 189: Olsson GI, von Knorring AL Adolescent depression: prevalence in Swedish high-school students. Acta Psychiatr Scand 99: Piletz JE, Halaris A, Iqbal O, Hoppensteadt D, Fareed J, Zhu H, et al Pro-inflammatory biomarkers in depression: Treatment with venlafaxine. World J Biol Psychiatry 31:111. Rodriguez-Macias KA, Lind L, Naessen T Thicker carotid intima layer and thinner media layer in subjects with cardiovascular diseases. An investigation using noninvasive highfrequency ultrasound. Atherosclerosis 189: Rugulies R Depression as a predictor for coronary heart disease. a review and meta-analysis. Am J Prev Med. 23:5161. Wendelhag I, Gustavsson T, Suurküla M, Berglund G, Wikstrand J Ultrasound measurement of wall thickness in the carotid artery: fundamental principles and description of a computerized analysing system. Clin Physiol 11: