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Cerebrovascular reactivity in depressed patients without vascular risk factors
JOURNAL OF PSYCHIATRIC RESEARCH
Journal of Psychiatric Research 42 (2008) 78–82
www.elsevier.com/locate/jpsychires
Cerebrovascular reactivity in depressed patients without vascular risk factors q A. Go´mez-Carrillo de Castro a, M. Bajbouj a, P. Schlattmann b, H. Lemke a, I. Heuser a,b, P. Neu a,* a b
Department of Psychiatry, Charite´ Berlin, Campus Benjamin Franklin, Eschenalle 3, 14050 Berlin, Germany Department of Biometry, Charite´ Berlin, Campus Benjamin Franklin, Eschenalle 3, 14050 Berlin, Germany Received 27 July 2006; received in revised form 4 October 2006; accepted 6 October 2006
Abstract Introduction: Cerebrovascular reactivity (CVR) seems to be gaining importance as a prognostic factor for stroke risk. CVR reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus; this mechanism plays an important role in maintaining a constant cerebral blood flow. Evaluating factors that influence CVR will help prevention or early detection of cerebrovascular disease (CVD). In this study we aimed to measure the CVR in vascular-risk free depressed individuals so as to evaluate the effect depression has on CVR and hence its role as a stroke risk factor. Methods: Using acetazolamid (ACZ) stimulation, CVR was assessed with a transcranial Doppler ultrasound in 25 non-smoking depressed patients (average age: 48.48 ± 14.40) and in 25 healthy non-smoking controls (average age: 46.76 ± 13.69) by calculating the difference between the maximal mean blood flow velocity at baseline and the maximal mean blood flow velocity after ACZ stimulation. Results: Basal Cerebral Blood flow in Patients was 50.6 cm/s (SD: 11.6) versus controls 52.80 cm/s (SD: 12.70) whereas after stimulation maximal blood flow velocity was 72.64 cm/s (SD: 15.75) in patients versus 80.20 cm/s (SD: 18.43) in controls. In an analysis of covariance we found that cerebrovascular reactivity was significantly reduced in the vascular-risk free depressed sample. Age had a significant influence whereas gender did not. Discussion: Major Depression appears to decrease cerebrovascular reactivity supporting the idea of increased risk for stroke in depressed patients. The mechanisms leading to this phenomenon and its subtle subgroup differences should be further investigated. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Cerebrovascular reactivity; Depression; Vascular risk factor; Metabolic syndrome; Non-smokers
1. Introduction The dilatory mechanism by which cerebral arterioles maintain a constant cerebral blood flow is reflected by the CVR. Since alterations in cerebral blood flow relate to stroke risk, CVR might play a role in stroke-risk prog-
q *
Note: The first two authors contributed equally to this article. Corresponding author. Tel.: +49 30 8445 8673; fax: +49 30 8445 8388. E-mail address: [email protected] (P. Neu). URL: www.charite.de/psychiatry (P. Neu).
0022-3956/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2006.10.001
nosis. Evaluating the factors that influence CVR could help detect, or even prevent, early stages of cerebrovascular disease (CVD). In the following text we expose the sequence of ideas behind this study. 1.1. From depression to cerebrovascular disease and vice versa Despite increasing evidence pointing towards a bidirectional relationship between depression and stroke, the relationship between these two entities has until now focused on depression as a consequence of stroke.
A. Go´mez-Carrillo de Castro et al. / Journal of Psychiatric Research 42 (2008) 78–82
79
Various interpretations of the etiological model relating cerebrovascular diseases and depression exist: a hierarchical, an interactive and a common etiological model. All of these are plausible, variable and not mutually exclusive (Ramasubbu, 2000). This study focuses on changes of CVR in major depression as a possible factor for increased stroke risk. We considered, the growing evidence suggesting depression as stroke a risk factor. First, prospective epidemiologic studies found that patients suffering depressive episodes have a higher prevalence of stroke (Jonas and Mussolino, 2000; Larson et al., 2001; Ohira et al., 2001; Everson et al., 1998; Colantonio et al., 1992). According to the authors, these findings remained statistically significant after adjusting for body mass index, smoking habits, diabetes, cholesterol, gender, blood pressure, alcohol consumption, physical activity, race and education. (Jonas and Mussolino, 2000; Larson et al., 2001; Ohira et al., 2001; Everson et al., 1998; Simonsick et al., 1995). Secondly, more and more evidence suggests that depression influences vascular risk factors (Eaton et al., 1996; Jonas et al., 1997), stroke recovery (Parikh et al., 1990) and increases the risk of cerebrovascular disease in patients with vascular risk factors (Simonsick et al., 1995).
cator of stroke risk and depressed patients have a higher risk of stroke, depression might also lead to a reduced CVR and thus contribute to increased stroke risk. We recently investigated a group of patients suffering from an acute depressive episode who were otherwise healthy and found a reduced CVR compared to the healthy control group (Neu et al., 2004). Due to the high prevalence of smokers among psychiatric patients, however, we had included smokers as well as non-smokers. Several reasons led us to carry out the present study with non-smoking depressed patients and controls. First, longterm effects of smoking could still have influenced our previously published results since we did find a negative correlation between number of pack years and CVR. Second, addiction to nicotine could be stronger in depressed than in healthy people, however there is, to date, no objective way of quantifying this. The present study evaluates our findings in a sample of non-smoking patients and controls without any vascular risk factors.
1.2. Cerebrovascular reactivity as an early indicator of cerebrovascular diseases?
Patients were recruited from in-patients at our university clinic. Inclusion criteria were major depression (of both unipolar or bipolar type disorders) as defined by DSMIV (structured clinical interview for DSM-IV, axis I disorder (First et al., 1997)), ages 18–70 years (48.48 ± 14.40) and right-handedness. Pregnancy, the presence of any vascular risk factors or history of neurological, cardiac, vascular or other psychiatric diseases led to exclusion from the sample.
It is suggested that perfusion imaging following vascular challenge tests, such as the CVR acetazolamide test (a carbonic anhydrase inhibitor), might provide a more sensitive measure of early CVD than structural MRI (Knop et al., 1992; Ringel Stein et al., 1992). The increase of blood flow velocity after stimulation with acetazolamide offers a reliable method for assessing CVR (Dahl et al., 1992). CVR reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus, which is important for maintaining constant cerebral blood flow. A normal CVR is of considerable importance for a physiological blood supply of the brain. The main factors modulating brain blood flow velocity are blood viscosity and vascular tone. Impaired autoregulation of vascular tone may contribute to increased risk of CVD. Furthermore, an impaired CVR has been found to be associated with a higher risk of stroke (Yonas et al., 1993; Silvestrini et al., 1996; Molina et al., 1999). Previous studies have shown a decreased vasodilatory capacity under various circumstances, for example in subjects with vascular risk factors such as long-term insulindependent diabetes (Fu¨lesdi et al., 1997) or non-controlled hypertension. 1.3. From depression to cerebrovascular reactivity However, the pathophysiologic mechanisms leading to this association between depression and stroke are not understood. We postulated that since CVR is a good indi-
2. Materials and methods 2.1. Patients
2.2. Controls The control group was made up of individuals who responded to a newspaper advertisement. All individuals were drug-free, between 18 and 70 years old (46.76 ± 13.69), right-handed, without vascular risk factors or history of neurological, cardiac, vascular or psychiatric disorders. Although controls were not matched for age or gender their epidemiologic parameters did not differ significantly from the patient group. 2.3. General procedure All patients and controls underwent a careful neurological and cardiologic examination, as well as ECG and blood chemistry tests. Clinical history was taken with particular attention to vascular risk factors. Any abnormalities in these examinations led to exclusion. Based on standard definitions, the presence of vascular risk factors was determined. Cardiac arrhythmia, coronary heart disease, hypertension (systolic blood pressure values >130 mmHg and/or diastolic blood pressure >90 mmHg
80
A. Go´mez-Carrillo de Castro et al. / Journal of Psychiatric Research 42 (2008) 78–82
on 2 out of 6 values taken on three different days or the use of antihypertensive medication), diabetes mellitus (when treated or with fasting glucose levels >5.7 mmol/L), hypercholesterolemia (when treated or with cholesterol levels >5.2 mmol/L or HDL–cholesterol <0.9 mmol/L or LDL– cholesterol >3.9 mmol/L), hypertriglyceridemia. (when treated or with levels >1.7 mmol/L) were all considered vascular risk factors and led to exclusion. Non-smoking was defined as continuous abstinence from smoking for at least 15 years. All subjects abstained from caffeine for at least 2 h before undergoing Doppler examination. Patients on antidepressant medication were only examined after a 7-day medication free window. When necessary short lasting benzodiazepines were given (1 mg lorazepam per day) and discontinued 24 h before the investigation. Depression was measured using the Hamilton depressionscale (HAMD) (Hamilton, 1980). All participants gave written informed consent. The local ethics committee approved the study. 2.4. Doppler protocol To exclude the presence of any intracranial stenosis that may have interfered with the CVR measurement, a complete Doppler examination of anterior, middle and posterior arteries, of both internal and external carotid arteries and of the basilar and vertebral arteries was performed on all patients and controls. Mean flow velocity (MFV) of the left middle cerebral artery was continuously monitored by means of a TC 2– 64 transcranial Doppler instrument (EME Medizinische Elektronik, Ueberlingen/Germany). A 2-MHz transducer fitted on a headband and placed on the left temporal bone window was used to obtain continuous measurements. The highest signal was sought at a depth ranging from 45 to 55 mm. MFV was calculated in centimetres per second. The investigation was carried out in a quiet windowless room, with patients and controls lying in a comfortable supine position without any visual or auditory stimulation. Maximum baseline mean flow velocity was obtained at rest by recording the continuous maximal MVF over 2 min during a 10-min period. Stimulation consisted of a 3-min intravenous administration of 15 mg/kg body weight acetazolamide (ACZ), as suggested elsewhere (Dahl et al., 1992). For 20 min after ACZ administration, MFV was measured every 2nd minute and the maximal continuous increase in MFV over 2 min was recorded. CVR was determined by calculating the difference between maximal mean flow velocity at baseline and the maximal mean flow velocity after stimulation. 2.5. Statistical analysis We performed an analysis of covariance to assess the effects of diagnosis while adjusting for age, gender and basal cerebral blood flow velocity. Model selection was
done based on F-tests using a stepwise selection approach. For all tests the significance level was set at 0.05, twotailed. Calculations were done with SPSS 9 for Windows. 3. Results A group of 25 non-smoking depressed patients and 25 non-smoking healthy controls underwent Doppler sonography exploration. The socio-demographic and clinical data are shown in Table 1. To adjust for baseline blood flow and to investigate the effects of gender and age, on cerebral blood flow velocity after stimulation, analysis of covariance was applied. The results of this model are shown in Table 2. As can be drawn from Table 2, the cerebral blood flow velocity (CBFV) at baseline – unsurprisingly – has a significant influence on CBFV after stimulation. Furthermore, belonging to the patient group had a significant effect on CBFV after stimulation. In other words depressed patients showed a significantly reduced cerebrovascular reactivity compared to healthy controls even after adjusting for maximal MFV at baseline. Maximal MFV after stimulation was also significantly affected by Age, but not by gender.
Table 1 Clinical, sociodemographic and hemodynamic data of patients and controls
Age (mean/sd) Female sex % (no.) Females age >50 years (no.) Hamilton Depression Scale (mean/sd) Height (cm, mean/sd) Weight (kg, mean/sd) Systolic blood pressure (mmHg, mean/ sd) Diastolic blood pressure (mmHg, mean/ sd) Heart rate (mean/sd) Maximal MFV at baseline (mean/sd) Maximal MFV after stimulation (mean/ sd)
Patients N = 25
Controls N = 25
48.48/14.40 60 (15) 5
46.76/13.69 24 (6) 2
24.43/5.13 170.68/8.48 70.90/14.58 122.60/12.83
2.80/0.91 179.71/6.99 73.38/10.33 124.55/9.60
75.40/7.76
80.00/5.91
73.68/7.45 50.64/11.16 72.64/15.75
78.60/9.707 52.80/12.70 80.20/18.43
cm = centimetres; MFV = mean flow velocity; sd = standard deviation; kg = kilogram.
Table 2 Analysis of covariance Model
Model coefficient B
Constant Mean flow velocity baseline controls patients Sex Age
T
Significance
Standard error 3.142 1.343
7.961 0.098
0.395 13.647
0.695 0.000
5.961 2.860 0.178
2.288 2.360 0.083
2.620 1.212 2.140
0.012 0.232 0.038
dependent variable: maximal mean flow velocity after stimulation.
A. Go´mez-Carrillo de Castro et al. / Journal of Psychiatric Research 42 (2008) 78–82
4. Discussion We studied the effect of acute depression on CVR in vascular risk free depressed patients and found that it was significantly reduced in comparison to healthy controls. The results of this study reaffirm our previous findings on CVR being reduced in depressed patients independently of vascular risk factors. In view of the fact that the patients included in this study were free of vascular risk factors, depression itself might contribute to a reduced CVR. The pathophysiological mechanisms underlying this finding remain unclear, but some hypotheses should be addressed. First of all, animal studies have shown that neuroadrenergic stimulation results in vasoconstriction of cerebral resistance vessels (Szabo et al., 1983; Kogure et al., 1979). Also, enhanced cerebral blood flow, induced by parasympathetic activity, was found to be normalized by the activation of sympathetic nerves, whereas the reverse phenomenon (i.e. parasympathetic activation normalizing the sympathetically induced cerebral blood flow reduction) did not occur (Morita-Tsuzuki et al., 1993). Thus, in a situation of sympathetic hyperactivity, autoregulation of cerebral blood flow might be reduced, resulting in an elevated cerebrovascular tone. In fact reports on autonomic imbalance in depressive patients exist (Tulen et al., 1996; Guinjoan et al., 1995) and this could contribute to the observed CVR reduction. Theoretically in a situation of neuroadrenergic stimulation, basal cerebral blood flow would be reduced. However this was not shown by our results. Secondly, numerous reports on hypothalamic-pituitaryadrenal deregulation and elevated basal cortisol levels in major depression exist (Catalan et al., 1998; Heuser et al., 1994). Glucocorticoids inhibit the expression of calcium dependent potassium channel proteins in vascular smooth muscle (Brem et al., 1999). In turn, potassium channels play a major role in vascular tone regulation. Activation of potassium channels in vascular smooth muscle cells leads to membrane hyperpolarization, closure of voltagedependent calcium channels and subsequent decrease in intracellular calcium, which results in vascular relaxation (Faraci and Donald, 1998). Consequently, elevated glucocorticoid levels during depression can lead to increased vascular tone by damaging potassium channels in vascular smooth muscle cells and could thus lead to increased vascular tone. Since vascular tone affects CVR, increased levels of cortisol would have a decreasing effect. Further studies are needed to confirm the influence of glucocorticoids on vascular tone in depression. The clinical relevance of the observed CVR reduction in depressed patients, in terms of contributing to cerebrovascular disease, yet remains to be fully elicited. From a clinical perspective the presence of one disorder may enhance the importance of identifying a coexisting or underlying disorder, as well as choosing a multifaceted treatment (Ramasubbu, 2000). It is also important to know the time course of CVR in patients suffering from depression in
81
order to further understand the interface of these two disorders. 5. Limitations Our sample consisted of major depression disorder of both unipolar and bipolar type. There is no data on the differences within depressive sub-diagnoses concerning vascular-linked pathophysiological changes and yet the heterogeneity of CVR within the patient group could point in that direction and should be a matter of future investigations. Furthermore, the groups were not homogenous in terms of gender. Although no influence of gender on CVR could be found, this remains a weakness of the study. Some studies reported a reduced CVR in postmenopausal women compared to premenopausal women (Kastrup et al., 1998; Olah et al., 2000). This difference might be mediated through increased production of prostacyclin, nitric oxide or by a direct effect of estrogens on the arterial wall (Matteis et al., 1998). It would be interesting to conduct within-subject follow-up studies evaluating pre- and postmenopausal CVR in women. Despite the fact that all patients included in this study were free of antidepressants for at least 7 days before Doppler examination, the effect antidepressants as well as benzodiazepines might have on CVR should be considered since it is possible that a serum drug level remained. Little is known of the effects of psychoactive medication on CVR. In a previous study we evaluated the effect that a 10-day treatment with mirtazapine had on the CVR of healthy males (Neu et al., 2006). No significant change of CVR was observed in that sample. It should be noted that our sample consisted of exclusively healthy individuals and that no other drugs were tested. The long-term effects of antidepressants and how and whether they have an impact on the CVR of depressed patients remain to be explored. References Brem AS, Bina RB, Mehta S, Marshall J. Glucocorticoids inhibit the expression of calcium-dependent potassium channels in vascular smooth muscle. Molecular genetics and metabolism 1999;67(1):53–7. Catalan R, Gallart JM, Castellanos JM, Galard R. Plasma corticotropinreleasing factor in depressive disorders. Biological Psychiatry 1998;44(1):15–20. Colantonio A, Kasi SV, Ostfeld AM. Depressive symptoms and other psychosocial factors as predictors of stroke in the elderly. American Journal of Epidemiology 1992;136:884–94. Dahl A, Lindegaard K-F, Russell D, Nyberg-Hansen R, Rootwelt K, Nornes H. A comparison of transcranial Doppler and cerebral blood flow studies to assess cerebral vasoreactivity. Stroke 1992;23:15–9. Eaton WW, Armenian H, Gallo J, Pratt L, Ford DE. Depression and risk for onset of type II diabetes. A prospective population based study. Diabetes Care 1996;19:1097–102. Everson SA, Roberts RE, Goldberg DE, Kaplan GA. Depressive symptoms and increased risk of stroke mortality over a 29 year period. Archives of Internal Medicine 1998;158:1133–8. Faraci FM, Donald GH. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiological Reviews 1998;78(1):53–115.
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First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSMIV axis I disorders (SCID I). Administration Booklet. Washington, DC: American Press; 1997. Fu¨lesdi B, Limburg M, Bereczki D. Impairment of cerebrovascular reactivity in longterm type 1 diabetes. Diabetes 1997;46:1840–5. Guinjoan SM, Bernabo JL, Cardinali DP. Cardiovascular tests of autonomic function and sympathetic skin responses in patients with major depression. Journal of Neurology, Neurosurgery and Psychiatry 1995;59:299–302. Hamilton M. Rating depressive patients. The Journal of Clinical Psychiatry 1980;41:21–4. Heuser I, Yassouridis A, Holsboer F. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. Journal of Psychiatry Research 1994;28(4):341–56. Jonas BS, Mussolino ME. Symptoms of depression as a prospective risk factor for stroke. Psychosomatic Medicine 2000;62(4):463–71. Jonas BS, Frank P, Ingram DD. Are symptoms of anxiety and depression risk factors for hypertension? Longitudinal evidence from the National Health and Nutrition Examination Survey I: Epidemiologic Follow-up Study. Archives of Family Medicine 1997;5:44–8. Kastrup A, Dichgans J, Niemeier M, Schabet M. Changes of cerebrovascular CO2 reactivity during normal aging. Stroke 1998;29(7):1311–4. Knop J, Thie A, Fuchs C, Siepmann G, Zeumer H. 99mTc-HMPOSPECT with acetazolamide challenge test to detect hemodynamic compromise in occlusive cerebrovascular disease. Stroke 1992;23: 1733–44. Kogure K, Scheinberg P, Kishikawa H, Utsunomiya Y, Busto R. Adrenergic control of cerebral blood flow and energy metabolism in the rat. Stroke 1979;10(2):179–84. Larson SL, Owens P, Ford D, Eaton W. Depressive disorder, dysthymia, and risk of stroke: thirteen-year follow-up from the Baltimore epidemiologic catchment area study. Stroke 2001;32(9):1979–83. Matteis M, Troisi E, Monaldo BC, Caltagirone C, Silvestrini M. Age and sex differences in cerebral hemodynamics: a transcranial Doppler study. Stroke 1998;29(5):963–7. Molina C, Sabin JA, Montaner J, Rovira A, Abillerra S, Codina A. Impaired cerebrovascular reactivity as a risk marker for first-ever lacunar infarction. Stroke 1999;30:2296–301. Morita-Tsuzuki Y, Hardebo JE, Bouskela E. Interaction between cerebrovascular sympathetic, parasympathetic and sensory nerves in blood flow regulation. Journal of Vascular Research 1993;30(5): 263–71.
Neu P, Schlattmann P, Schilling A, Hartmann A. Cerebrovascular Reactivity in major depression – a pilot-study. Psychosomatic Medicine 2004;66:6. Neu P, Schwertfeger N, Schlattmann P, Heuser I, Berman R. Cerebrovascular reactivity following administration of mirtazapine in healthy probands – a randomized, placebo controlled double-blind clinical study. Journal of Psychiatric Research. 2006. E-pub. Ohira T, Iso H, Satoh S, Sankai T, Tanigawa T, Ogawa Y, et al. Prospective study of depressive symptoms and risk of stroke among Japanese. Stroke 2001;32(4):903–8. Olah L, Valikovics A, Bereczki D, Fulesdi B, Munkasczy C, Csiba L. Gender-related differences in acetazolamide-induced cerebral vasodilatory response: a transcranial Doppler study. Journal of Neuroimaging 2000;10(3):151–6. Parikh RM, Robinson RG, Lipsey JR, Starkstein SE, Fedoroff JP, Price TR. The impact of poststroke depression on recovery in activities of daily living over a 2-year follow-up. Archives of Neurology 1990;47: 785–9. Ramasubbu R. Relationship between depression and cerebrovascular disease: conceptual issues. Journal of Affective Disorders 2000;57: 1–11. Ringel Stein EB, Van Eyck S, Mertens I. Evaluation of cerebral vasomotor reactivity by various vasodialating stimuli: comparison of CO to acetazolamide. Journal of Cerebral Blood Flow Metabolism 1992;12:162–8. Silvestrini M, Troisi E, Matteis M, Cupini LM, Bernardi G. Effect of smoking on cerebrovascular reactivity. Journal of Cerebral Blood Flow and Metabolism 1996;16(4):746–9. Simonsick EM, Wallace RB, Blazer DG, Berkman LF. Depressice symptomatology and hypertension associated morbidity and mortality in older adults. Psychosomatic Medicine 1995;57: 427–35. Szabo L, Kovach AG, Babosa M, Greenberg JH, Revich M. Effect of sustained norepinephrine infusion on local cerebral blood flow in the rat. Circulatory Shock 1983;10(2):101–17. Tulen JH, Bruijn JA, de Man KJ, van der Velden E, Pepplinkhuizen L, Man in ’t Veld AJ. Anxiety and autonomic regulation in major depressive disorder: an exploratory study. Journal of Affective Disorders 1996;40:61–71. Yonas H, Smith HA, Durham SR, Pentheny SL, Johnson DW. Increased stroke risk predicted by compromised cerebral blood flow reactivity. Journal of Neurosurgery 1993;79:483–9.
Journal of Psychiatric Research 42 (2008) 78–82
www.elsevier.com/locate/jpsychires
Cerebrovascular reactivity in depressed patients without vascular risk factors q A. Go´mez-Carrillo de Castro a, M. Bajbouj a, P. Schlattmann b, H. Lemke a, I. Heuser a,b, P. Neu a,* a b
Department of Psychiatry, Charite´ Berlin, Campus Benjamin Franklin, Eschenalle 3, 14050 Berlin, Germany Department of Biometry, Charite´ Berlin, Campus Benjamin Franklin, Eschenalle 3, 14050 Berlin, Germany Received 27 July 2006; received in revised form 4 October 2006; accepted 6 October 2006
Abstract Introduction: Cerebrovascular reactivity (CVR) seems to be gaining importance as a prognostic factor for stroke risk. CVR reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus; this mechanism plays an important role in maintaining a constant cerebral blood flow. Evaluating factors that influence CVR will help prevention or early detection of cerebrovascular disease (CVD). In this study we aimed to measure the CVR in vascular-risk free depressed individuals so as to evaluate the effect depression has on CVR and hence its role as a stroke risk factor. Methods: Using acetazolamid (ACZ) stimulation, CVR was assessed with a transcranial Doppler ultrasound in 25 non-smoking depressed patients (average age: 48.48 ± 14.40) and in 25 healthy non-smoking controls (average age: 46.76 ± 13.69) by calculating the difference between the maximal mean blood flow velocity at baseline and the maximal mean blood flow velocity after ACZ stimulation. Results: Basal Cerebral Blood flow in Patients was 50.6 cm/s (SD: 11.6) versus controls 52.80 cm/s (SD: 12.70) whereas after stimulation maximal blood flow velocity was 72.64 cm/s (SD: 15.75) in patients versus 80.20 cm/s (SD: 18.43) in controls. In an analysis of covariance we found that cerebrovascular reactivity was significantly reduced in the vascular-risk free depressed sample. Age had a significant influence whereas gender did not. Discussion: Major Depression appears to decrease cerebrovascular reactivity supporting the idea of increased risk for stroke in depressed patients. The mechanisms leading to this phenomenon and its subtle subgroup differences should be further investigated. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Cerebrovascular reactivity; Depression; Vascular risk factor; Metabolic syndrome; Non-smokers
1. Introduction The dilatory mechanism by which cerebral arterioles maintain a constant cerebral blood flow is reflected by the CVR. Since alterations in cerebral blood flow relate to stroke risk, CVR might play a role in stroke-risk prog-
q *
Note: The first two authors contributed equally to this article. Corresponding author. Tel.: +49 30 8445 8673; fax: +49 30 8445 8388. E-mail address: [email protected] (P. Neu). URL: www.charite.de/psychiatry (P. Neu).
0022-3956/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2006.10.001
nosis. Evaluating the factors that influence CVR could help detect, or even prevent, early stages of cerebrovascular disease (CVD). In the following text we expose the sequence of ideas behind this study. 1.1. From depression to cerebrovascular disease and vice versa Despite increasing evidence pointing towards a bidirectional relationship between depression and stroke, the relationship between these two entities has until now focused on depression as a consequence of stroke.
A. Go´mez-Carrillo de Castro et al. / Journal of Psychiatric Research 42 (2008) 78–82
79
Various interpretations of the etiological model relating cerebrovascular diseases and depression exist: a hierarchical, an interactive and a common etiological model. All of these are plausible, variable and not mutually exclusive (Ramasubbu, 2000). This study focuses on changes of CVR in major depression as a possible factor for increased stroke risk. We considered, the growing evidence suggesting depression as stroke a risk factor. First, prospective epidemiologic studies found that patients suffering depressive episodes have a higher prevalence of stroke (Jonas and Mussolino, 2000; Larson et al., 2001; Ohira et al., 2001; Everson et al., 1998; Colantonio et al., 1992). According to the authors, these findings remained statistically significant after adjusting for body mass index, smoking habits, diabetes, cholesterol, gender, blood pressure, alcohol consumption, physical activity, race and education. (Jonas and Mussolino, 2000; Larson et al., 2001; Ohira et al., 2001; Everson et al., 1998; Simonsick et al., 1995). Secondly, more and more evidence suggests that depression influences vascular risk factors (Eaton et al., 1996; Jonas et al., 1997), stroke recovery (Parikh et al., 1990) and increases the risk of cerebrovascular disease in patients with vascular risk factors (Simonsick et al., 1995).
cator of stroke risk and depressed patients have a higher risk of stroke, depression might also lead to a reduced CVR and thus contribute to increased stroke risk. We recently investigated a group of patients suffering from an acute depressive episode who were otherwise healthy and found a reduced CVR compared to the healthy control group (Neu et al., 2004). Due to the high prevalence of smokers among psychiatric patients, however, we had included smokers as well as non-smokers. Several reasons led us to carry out the present study with non-smoking depressed patients and controls. First, longterm effects of smoking could still have influenced our previously published results since we did find a negative correlation between number of pack years and CVR. Second, addiction to nicotine could be stronger in depressed than in healthy people, however there is, to date, no objective way of quantifying this. The present study evaluates our findings in a sample of non-smoking patients and controls without any vascular risk factors.
1.2. Cerebrovascular reactivity as an early indicator of cerebrovascular diseases?
Patients were recruited from in-patients at our university clinic. Inclusion criteria were major depression (of both unipolar or bipolar type disorders) as defined by DSMIV (structured clinical interview for DSM-IV, axis I disorder (First et al., 1997)), ages 18–70 years (48.48 ± 14.40) and right-handedness. Pregnancy, the presence of any vascular risk factors or history of neurological, cardiac, vascular or other psychiatric diseases led to exclusion from the sample.
It is suggested that perfusion imaging following vascular challenge tests, such as the CVR acetazolamide test (a carbonic anhydrase inhibitor), might provide a more sensitive measure of early CVD than structural MRI (Knop et al., 1992; Ringel Stein et al., 1992). The increase of blood flow velocity after stimulation with acetazolamide offers a reliable method for assessing CVR (Dahl et al., 1992). CVR reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus, which is important for maintaining constant cerebral blood flow. A normal CVR is of considerable importance for a physiological blood supply of the brain. The main factors modulating brain blood flow velocity are blood viscosity and vascular tone. Impaired autoregulation of vascular tone may contribute to increased risk of CVD. Furthermore, an impaired CVR has been found to be associated with a higher risk of stroke (Yonas et al., 1993; Silvestrini et al., 1996; Molina et al., 1999). Previous studies have shown a decreased vasodilatory capacity under various circumstances, for example in subjects with vascular risk factors such as long-term insulindependent diabetes (Fu¨lesdi et al., 1997) or non-controlled hypertension. 1.3. From depression to cerebrovascular reactivity However, the pathophysiologic mechanisms leading to this association between depression and stroke are not understood. We postulated that since CVR is a good indi-
2. Materials and methods 2.1. Patients
2.2. Controls The control group was made up of individuals who responded to a newspaper advertisement. All individuals were drug-free, between 18 and 70 years old (46.76 ± 13.69), right-handed, without vascular risk factors or history of neurological, cardiac, vascular or psychiatric disorders. Although controls were not matched for age or gender their epidemiologic parameters did not differ significantly from the patient group. 2.3. General procedure All patients and controls underwent a careful neurological and cardiologic examination, as well as ECG and blood chemistry tests. Clinical history was taken with particular attention to vascular risk factors. Any abnormalities in these examinations led to exclusion. Based on standard definitions, the presence of vascular risk factors was determined. Cardiac arrhythmia, coronary heart disease, hypertension (systolic blood pressure values >130 mmHg and/or diastolic blood pressure >90 mmHg
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on 2 out of 6 values taken on three different days or the use of antihypertensive medication), diabetes mellitus (when treated or with fasting glucose levels >5.7 mmol/L), hypercholesterolemia (when treated or with cholesterol levels >5.2 mmol/L or HDL–cholesterol <0.9 mmol/L or LDL– cholesterol >3.9 mmol/L), hypertriglyceridemia. (when treated or with levels >1.7 mmol/L) were all considered vascular risk factors and led to exclusion. Non-smoking was defined as continuous abstinence from smoking for at least 15 years. All subjects abstained from caffeine for at least 2 h before undergoing Doppler examination. Patients on antidepressant medication were only examined after a 7-day medication free window. When necessary short lasting benzodiazepines were given (1 mg lorazepam per day) and discontinued 24 h before the investigation. Depression was measured using the Hamilton depressionscale (HAMD) (Hamilton, 1980). All participants gave written informed consent. The local ethics committee approved the study. 2.4. Doppler protocol To exclude the presence of any intracranial stenosis that may have interfered with the CVR measurement, a complete Doppler examination of anterior, middle and posterior arteries, of both internal and external carotid arteries and of the basilar and vertebral arteries was performed on all patients and controls. Mean flow velocity (MFV) of the left middle cerebral artery was continuously monitored by means of a TC 2– 64 transcranial Doppler instrument (EME Medizinische Elektronik, Ueberlingen/Germany). A 2-MHz transducer fitted on a headband and placed on the left temporal bone window was used to obtain continuous measurements. The highest signal was sought at a depth ranging from 45 to 55 mm. MFV was calculated in centimetres per second. The investigation was carried out in a quiet windowless room, with patients and controls lying in a comfortable supine position without any visual or auditory stimulation. Maximum baseline mean flow velocity was obtained at rest by recording the continuous maximal MVF over 2 min during a 10-min period. Stimulation consisted of a 3-min intravenous administration of 15 mg/kg body weight acetazolamide (ACZ), as suggested elsewhere (Dahl et al., 1992). For 20 min after ACZ administration, MFV was measured every 2nd minute and the maximal continuous increase in MFV over 2 min was recorded. CVR was determined by calculating the difference between maximal mean flow velocity at baseline and the maximal mean flow velocity after stimulation. 2.5. Statistical analysis We performed an analysis of covariance to assess the effects of diagnosis while adjusting for age, gender and basal cerebral blood flow velocity. Model selection was
done based on F-tests using a stepwise selection approach. For all tests the significance level was set at 0.05, twotailed. Calculations were done with SPSS 9 for Windows. 3. Results A group of 25 non-smoking depressed patients and 25 non-smoking healthy controls underwent Doppler sonography exploration. The socio-demographic and clinical data are shown in Table 1. To adjust for baseline blood flow and to investigate the effects of gender and age, on cerebral blood flow velocity after stimulation, analysis of covariance was applied. The results of this model are shown in Table 2. As can be drawn from Table 2, the cerebral blood flow velocity (CBFV) at baseline – unsurprisingly – has a significant influence on CBFV after stimulation. Furthermore, belonging to the patient group had a significant effect on CBFV after stimulation. In other words depressed patients showed a significantly reduced cerebrovascular reactivity compared to healthy controls even after adjusting for maximal MFV at baseline. Maximal MFV after stimulation was also significantly affected by Age, but not by gender.
Table 1 Clinical, sociodemographic and hemodynamic data of patients and controls
Age (mean/sd) Female sex % (no.) Females age >50 years (no.) Hamilton Depression Scale (mean/sd) Height (cm, mean/sd) Weight (kg, mean/sd) Systolic blood pressure (mmHg, mean/ sd) Diastolic blood pressure (mmHg, mean/ sd) Heart rate (mean/sd) Maximal MFV at baseline (mean/sd) Maximal MFV after stimulation (mean/ sd)
Patients N = 25
Controls N = 25
48.48/14.40 60 (15) 5
46.76/13.69 24 (6) 2
24.43/5.13 170.68/8.48 70.90/14.58 122.60/12.83
2.80/0.91 179.71/6.99 73.38/10.33 124.55/9.60
75.40/7.76
80.00/5.91
73.68/7.45 50.64/11.16 72.64/15.75
78.60/9.707 52.80/12.70 80.20/18.43
cm = centimetres; MFV = mean flow velocity; sd = standard deviation; kg = kilogram.
Table 2 Analysis of covariance Model
Model coefficient B
Constant Mean flow velocity baseline controls patients Sex Age
T
Significance
Standard error 3.142 1.343
7.961 0.098
0.395 13.647
0.695 0.000
5.961 2.860 0.178
2.288 2.360 0.083
2.620 1.212 2.140
0.012 0.232 0.038
dependent variable: maximal mean flow velocity after stimulation.
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4. Discussion We studied the effect of acute depression on CVR in vascular risk free depressed patients and found that it was significantly reduced in comparison to healthy controls. The results of this study reaffirm our previous findings on CVR being reduced in depressed patients independently of vascular risk factors. In view of the fact that the patients included in this study were free of vascular risk factors, depression itself might contribute to a reduced CVR. The pathophysiological mechanisms underlying this finding remain unclear, but some hypotheses should be addressed. First of all, animal studies have shown that neuroadrenergic stimulation results in vasoconstriction of cerebral resistance vessels (Szabo et al., 1983; Kogure et al., 1979). Also, enhanced cerebral blood flow, induced by parasympathetic activity, was found to be normalized by the activation of sympathetic nerves, whereas the reverse phenomenon (i.e. parasympathetic activation normalizing the sympathetically induced cerebral blood flow reduction) did not occur (Morita-Tsuzuki et al., 1993). Thus, in a situation of sympathetic hyperactivity, autoregulation of cerebral blood flow might be reduced, resulting in an elevated cerebrovascular tone. In fact reports on autonomic imbalance in depressive patients exist (Tulen et al., 1996; Guinjoan et al., 1995) and this could contribute to the observed CVR reduction. Theoretically in a situation of neuroadrenergic stimulation, basal cerebral blood flow would be reduced. However this was not shown by our results. Secondly, numerous reports on hypothalamic-pituitaryadrenal deregulation and elevated basal cortisol levels in major depression exist (Catalan et al., 1998; Heuser et al., 1994). Glucocorticoids inhibit the expression of calcium dependent potassium channel proteins in vascular smooth muscle (Brem et al., 1999). In turn, potassium channels play a major role in vascular tone regulation. Activation of potassium channels in vascular smooth muscle cells leads to membrane hyperpolarization, closure of voltagedependent calcium channels and subsequent decrease in intracellular calcium, which results in vascular relaxation (Faraci and Donald, 1998). Consequently, elevated glucocorticoid levels during depression can lead to increased vascular tone by damaging potassium channels in vascular smooth muscle cells and could thus lead to increased vascular tone. Since vascular tone affects CVR, increased levels of cortisol would have a decreasing effect. Further studies are needed to confirm the influence of glucocorticoids on vascular tone in depression. The clinical relevance of the observed CVR reduction in depressed patients, in terms of contributing to cerebrovascular disease, yet remains to be fully elicited. From a clinical perspective the presence of one disorder may enhance the importance of identifying a coexisting or underlying disorder, as well as choosing a multifaceted treatment (Ramasubbu, 2000). It is also important to know the time course of CVR in patients suffering from depression in
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order to further understand the interface of these two disorders. 5. Limitations Our sample consisted of major depression disorder of both unipolar and bipolar type. There is no data on the differences within depressive sub-diagnoses concerning vascular-linked pathophysiological changes and yet the heterogeneity of CVR within the patient group could point in that direction and should be a matter of future investigations. Furthermore, the groups were not homogenous in terms of gender. Although no influence of gender on CVR could be found, this remains a weakness of the study. Some studies reported a reduced CVR in postmenopausal women compared to premenopausal women (Kastrup et al., 1998; Olah et al., 2000). This difference might be mediated through increased production of prostacyclin, nitric oxide or by a direct effect of estrogens on the arterial wall (Matteis et al., 1998). It would be interesting to conduct within-subject follow-up studies evaluating pre- and postmenopausal CVR in women. Despite the fact that all patients included in this study were free of antidepressants for at least 7 days before Doppler examination, the effect antidepressants as well as benzodiazepines might have on CVR should be considered since it is possible that a serum drug level remained. Little is known of the effects of psychoactive medication on CVR. In a previous study we evaluated the effect that a 10-day treatment with mirtazapine had on the CVR of healthy males (Neu et al., 2006). No significant change of CVR was observed in that sample. It should be noted that our sample consisted of exclusively healthy individuals and that no other drugs were tested. The long-term effects of antidepressants and how and whether they have an impact on the CVR of depressed patients remain to be explored. References Brem AS, Bina RB, Mehta S, Marshall J. Glucocorticoids inhibit the expression of calcium-dependent potassium channels in vascular smooth muscle. Molecular genetics and metabolism 1999;67(1):53–7. Catalan R, Gallart JM, Castellanos JM, Galard R. Plasma corticotropinreleasing factor in depressive disorders. Biological Psychiatry 1998;44(1):15–20. Colantonio A, Kasi SV, Ostfeld AM. Depressive symptoms and other psychosocial factors as predictors of stroke in the elderly. American Journal of Epidemiology 1992;136:884–94. Dahl A, Lindegaard K-F, Russell D, Nyberg-Hansen R, Rootwelt K, Nornes H. A comparison of transcranial Doppler and cerebral blood flow studies to assess cerebral vasoreactivity. Stroke 1992;23:15–9. Eaton WW, Armenian H, Gallo J, Pratt L, Ford DE. Depression and risk for onset of type II diabetes. A prospective population based study. Diabetes Care 1996;19:1097–102. Everson SA, Roberts RE, Goldberg DE, Kaplan GA. Depressive symptoms and increased risk of stroke mortality over a 29 year period. Archives of Internal Medicine 1998;158:1133–8. Faraci FM, Donald GH. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiological Reviews 1998;78(1):53–115.
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