واکنش پذیری عروق مغزی در بیماران افسرده بدون عوامل خطر عروقی

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.

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 prognosis. 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. 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 and 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 and Simonsick et al., 1995). Secondly, more and more evidence suggests that depression influences vascular risk factors (Eaton et al., 1996 and 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). 1.2. Cerebrovascular reactivity as an early indicator of cerebrovascular diseases? 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 and 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 and 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 insulin-dependent diabetes (Fülesdi 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 indicator 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, long-term 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.

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. Table 1. Clinical, sociodemographic and hemodynamic data of patients and controls Patients N = 25 Controls N = 25 Age (mean/sd) 48.48/14.40 46.76/13.69 Female sex % (no.) Females age >50 years (no.) 60 (15) 5 24 (6) 2 Hamilton Depression Scale (mean/sd) 24.43/5.13 2.80/0.91 Height (cm, mean/sd) 170.68/8.48 179.71/6.99 Weight (kg, mean/sd) 70.90/14.58 73.38/10.33 Systolic blood pressure (mmHg, mean/sd) 122.60/12.83 124.55/9.60 Diastolic blood pressure (mmHg, mean/sd) 75.40/7.76 80.00/5.91 Heart rate (mean/sd) 73.68/7.45 78.60/9.707 Maximal MFV at baseline (mean/sd) 50.64/11.16 52.80/12.70 Maximal MFV after stimulation (mean/sd) 72.64/15.75 80.20/18.43 cm = centimetres; MFV = mean flow velocity; sd = standard deviation; kg = kilogram. Table options Table 2. Analysis of covariance Model Model coefficient T Significance B Standard error Constant 3.142 7.961 0.395 0.695 Mean flow velocity baseline 1.343 0.098 13.647 0.000 controls patients −5.961 2.288 −2.620 0.012 Sex −2.860 2.360 −1.212 0.232 Age 0.178 0.083 2.140 0.038 dependent variable: maximal mean flow velocity after stimulation. Table options 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.