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Cerebrovascular Reactivity in Major Depression: A Pilot Study

Departments of Psychiatry (P.N., P.S.), Radiology (A.S.), and Neurology (A.H.), Charité—Hochschulmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.

Address correspondence and reprint requests to Dr. Peter Neu, Charité—Hochschulmedizin Berlin, Campus Benjamin Franklin, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Eschenallee 3, 14050 Berlin, Germany. E-mail: peter.neu{at}medizin.fu-berlin.de

	ABSTRACT

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OBJECTIVE: There are a growing number of reports that depression may increase the risk of stroke. Little is known, however, about the pathophysiologic mechanisms underlying this association. Cerebrovascular reactivity (CVR) reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus and is an important mechanism to provide constant cerebral blood flow. We hypothesized that CVR is reduced in patients with major depression, thus contributing to the association between depression and stroke.

METHODS: We assessed CVR in 33 patients with unipolar depression and 26 healthy controls by calculating the increase in cerebral blood flow velocity after stimulation with acetazolamide. Blood flow velocities were measured by transcranial Doppler ultrasound.

RESULTS: Cerebrovascular reactivity was significantly reduced in depressed patients. Smoking was also associated with a significant reduction in CVR, whereas age and gender had no significant influence.

CONCLUSIONS: Cerebrovascular reactivity appears to be impaired in major depression. Further studies should clarify the mechanisms leading to this reduced CVR.

Key Words: cerebrovascular reactivity, • ultrasound, • major depression.

Abbreviations: ACZ = acetazolamide;; CVR = cerebrovascular reactivity;; MFV = mean flow velocity.

	INTRODUCTION

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There is growing evidence that depression may increase the risk of stroke. Some large, prospective epidemiologic studies have found a higher rate of cerebral infarction among people with depressive episodes. The higher risk remained statistically significant even after adjustment for confounding factors such as body mass index, smoking habits, diabetes, cholesterol, gender, blood pressure, alcohol consumption, physical activity, gender, race, and education (1–5). Thus, depressive disorder may be a risk factor for stroke that appears to be independent of traditional cardiovascular risk factors. However, the pathophysiologic mechanisms leading to this association between depression and stroke are not understood.

The main factors modulating cerebral blood flow velocity are blood viscosity and vascular tone. Impaired autoregulation of vascular tone may contribute to a higher risk of developing cerebrovascular disease. Cerebrovascular reactivity (CVR) reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus and is important for maintaining constant cerebral blood flow. Previous studies have shown a decreased vasodilatory capacity under various circumstances—for example, in subjects with long-term insulin-dependent diabetes (6) or noncontrolled hypertension. Moreover, impaired CVR in young hypertensive subjects appears to improve after the initiation of antihypertensive treatment (7).

In the absence of major arterial stenosis, impaired CVR has been associated with a higher risk of stroke (8,9). Because depressive patients have a higher risk of stroke, we hypothesize that CVR is reduced in these patients.

The increase of blood flow velocity after stimulation with acetazolamide (ACZ) offers a reliable method for assessing CVR (10). We therefore studied CVR in a group of patients suffering from a depressive episode and in a healthy control group.

	METHODS AND MATERIALS

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Patients
Inclusion criteria were unipolar major depression, melancholic subtype, as defined by DSM-IV (Structured Clinical Interview for DSM-IV, Axis I Disorder (11)); age 18 to 70 years, and right-handedness. Pregnancy; the presence of any vascular risk factor (except smoking); or a history any neurologic, cardiac, vascular or other psychiatric disease led to exclusion from the sample. Smoking did not lead to exclusion from the study because of the high prevalence of smoking among psychiatric patients. We evaluated smoking habits by calculating pack years. One pack year was defined as the mean number of packs of cigarettes smoked per day multiplied by years. Nonsmoking was defined as continuous abstinence from smoking for at least the past 15 years.

Controls
All controls were drug-free, between 18 and 70 years old, and right-handed, and had no vascular risk factors (except smoking) and no history of any psychiatric disorder. The control group included people from a wide variety of professions, including gardeners, nurses, craftspeople, and subjects with academic qualification. The control group was selected from the general population. No matching of patients and control was performed.

All patients and controls underwent a careful neurologic and cardiologic examination, electrocardiogram, and blood chemistry analysis. A clinical history was taken with particular attention to vascular risk factors.

We determined the presence of vascular risk factors using standard definitions. The risk factors included cardiac arrhythmia, coronary heart disease, hypertension, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia. Hypertension was defined by systolic blood pressure values greater than 130 mm Hg and/or diastolic blood pressure greater than 90 mm Hg on two of six different determinations on 3 different days or use of antihypertensive medication; diabetes mellitus was defined by being treated for the condition or fasting glucose levels greater than 5.7 mmol/l; hypercholesterolemia was defined by being treated for the condition or cholesterol levels greater than 5.2 mmol/l or high-density lipoprotein cholesterol less than 0.9 mmol/l or low-density lipoprotein cholesterol greater than 3.9 mmol/l; and hypertriglyceridemia was defined as being treated for the condition or levels greater than 1.7 mmol/l.

Fifteen patients were not treated with any drugs when admitted to our hospital. Eighteen were already taking one antidepressant (either fluvoxamine, venlafaxine, dibenzepin, moclobemide, or nefazodone), which was gradually reduced and then discontinued 3 days before investigation. Depression was measured using the Hamilton Depression Scale (12). All participants gave written informed consent. The study was approved by the local ethics committee.

Doppler Protocol
Cerebrovascular reactivity investigations were performed by the same physician at the same time of day, between 4 and 6 PM. Before the examination, all patients and controls abstained from caffeine for at least 2 hours and smoking for at least 1 hour.

To exclude the presence of any intracranial stenosis that might interfere with the measuring of CVR, a complete Doppler examination of anterior, middle, and posterior arteries, both internal and external carotid arteries, and the basilar and vertebral arteries was performed in all patients and controls.

Mean flow velocity (MFV) of the left middle cerebral artery was continuously monitored by means of a TC2-64 transcranial Doppler instrument. One 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 centimeters per second. The investigation was performed in a quiet, windowless room. The patients and controls lay in a comfortable supine position and kept their eyes closed. Baseline MFV was obtained at rest by recording the continuous maximal MVF for 2 minutes during a 10-minute period. Stimulation consisted of a 3-minute intravenous administration of 15 mg/kg body weight ACZ, as suggested elsewhere (13). For 20 minutes after ACZ administration, MFV was measured every second minute, and the maximal continuous increase in MFV over a period of 2 minutes was recorded. CVR was determined by calculating the difference between maximal baseline MFV and maximal MFV after stimulation.

Statistics
We performed an analysis of covariance to assess the effects of diagnosis while adjusting for age, gender, smoking, and basal cerebral flow. Model selection was performed based on F tests using a stepwise selection approach. For all tests, the significance level was set at .05, two-tailed. Calculations were performed with SPSS 9 for Windows.

	RESULTS

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A group of 33 unipolar depressed patients and 26 healthy controls were investigated by Doppler sonography. Sociodemographic and clinical data are shown in Table 1. The groups did not differ significantly in age and pack-years of smoking. Both groups had comparable numbers of women and nonsmokers.

View larger version (14K): [in this window] [in a new window]   Fig. 1. Estimated MFV (centimeters/second) after stimulation with 95% confidence interval adjusted for smoking and baseline flow volume in patients and controls.

	DISCUSSION

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Our main finding is that a group patients suffering from a current depressive episode had a reduced CVR compared with a healthy control group. None of the patients or controls had any vascular risk factor except smoking. The findings on the acute effects of smoking are controversial. Morioka et al. (14) found that most of the acute effects on cerebral blood flow vanish within 20 seconds after cessation of smoking. Thus, an abstinence of 1 hour from smoking as in our study was sufficient to avoid acute effects. Still, long-term effects of smoking may negatively influence vascular reactivity. We found a negative association between the number of pack-years and CVR, which supports this assumption, but this was true for both groups. However, because there was no difference in pack-years between patients and controls, the finding remains that CVR is reduced in depression. It could be argued that a person suffering from depression may be more strongly addicted to nicotine (15) than an otherwise healthy person, which cannot be quantified exactly by the pack-year calculation. This issue should be addressed in future studies by including nonsmokers only. All patients and controls in our study were drug-free at the time of investigation, although 18 of the patients had received medication 3 days before the investigation. Theoretically, it is possible that there was a serum drug level left that might have affected CVR. Nothing is known about the influence of antidepressants on cerebral vascular tone and blood flow in humans. One study postulates that fluoxetine increases cerebral blood flow in rats (16), but this assumption has yet to be investigated in humans. Further studies should therefore investigate whether antidepressants may influence CVR in humans.

We do not yet know whether the observed reduced CVR has clinical importance in terms of leading to an cerebrovascular insult in these patients. It would be important to know whether CVR improves after remission from a depressive episode. It would therefore be of high interest to follow these patients after remission.

Finally, there was heterogeneity of the CVR in the patient group. Some patients presented a normal CVR comparable with that of the controls, and some did not. This result suggests that there may be a subset of depressive patients who have a reduced CVR. This subgroup, however, is still to be specified.

This study indicates that further investigation of CVR in depression may benefit our understanding of the association of depression and cerebrovascular disease. Further studies should try to clarify the pathophysiologic mechanisms leading to a reduced CVR during depression.

	NOTES

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We thank Professor Isabella Heuser and Mr. Steven Langdon for critically reviewing this paper.

Received for publication January 14, 2003.

Revision received July 23, 2003.

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