The major finding in this study was that serum content of both AEA and 2-AG were positively correlated with both diastolic and mean arterial pressure in ambulatory, medication-free, women with depression. We also found that diastolic pressure was positively correlated with 2-AG in minor depression but with AEA in major depression, hinting at a differential role of the eCBs in depression. Our data also confirm previous suggestions that depression is accompanied by elevated blood pressure, which is a major risk factor for cardiovascular diseases. To our knowledge, this is the first report of a correlation between eCBs and blood pressure in clinical depression. This correlation, however, does not necessarily imply a casual relationship. It is also important to note that it is too early to generalize our data to a larger population. Notably, the current data were obtained in relatively young, female volunteers. Therefore it remains to be determined if similar results also occur in older subjects and in men.
By still unknown mechanisms, depression seems to have a negative impact on basic cardiovascular functions. For instance, reductions in heart rate variability [15
] and baroreflex sensitivity [17
] as well as increases in blood pressure or hypertension [29
] have been reported in depressed patients. These changes might explain why depression is a risk factor for cardiovascular diseases, and increases mortality and morbidity in patients with myocardial infarction or heart failure [14
]. In this study, we found that depressed women have significantly higher systolic pressure (by an average of 6.5 mmHg) and also tend to have a higher mean arterial pressure (by an average of 4.2 mmHg). Interestingly, increases in systolic and mean arterial blood pressure are more evident in individuals with minor, as compared to major, depression. For the majority of depressed subjects, their systolic and diastolic pressures remain within the normotensive range [30
]. Nevertheless, it is noteworthy that several epidemiological studies have suggested a continual and gradual increase in cardiovascular risks with increased systolic and diastolic blood pressure, even when pressures remain within normal range [31
There is strong evidence from laboratory animals that eCBs are involved in the regulation of blood flow and blood pressure, especially in pathophysiological conditions such as hypertension [18
]. Exogenous addition of AEA or 2-AG can reduce cardiac contraction, vascular tone and arterial blood pressure [19
]. Importantly, Kunos and colleagues [22
] have demonstrated that the hypotensive effects of AEA are more pronounced in hypertensive, anaesthetized animals. Indeed, in Spontaneously Hypertensive Rats, a commonly used model for genetic hypertension, inhibition of enzymatic degradation of endogenous AEA is sufficient to reduce blood pressure [33
]. Notably, modulation of eCB signaling, by using AEA enzyme inhibitors or CB1
receptor antagonist, regulates blood pressure in hypertensive, but not normotensive rats. These results suggest that an eCBs tone limits the extent of hypertension under pathophysiological conditions. This might explain our observed correlations of eCBs and blood pressure in the depressed (hypertensive) but not in healthy subjects. On the other hand, increases in blood pressure have recently been shown to elevate AEA content in the regulatory center for baroreceptor reflex [35
]. It has been proposed that AEA enhances baroreflex function, which might be compromised in depression [17
], by increasing neuronal activity at the nucleus tractus solitarius [35
Our data that serum contents of AEA and 2-AG are strongly and positively correlated with diastolic and mean arterial blood pressure in depressed but not healthy women, suggest that serum eCBs could function to compensate for an elevated blood pressure in depression. If this is true, the data also suggest that this feedback mechanism fails to normalize the systolic pressure, which remains elevated in depressives. This hypothesis is consistent with the animal data available; however, the possibility that eCBs somehow contribute to the increase in blood pressure cannot be ruled out. It is interesting that serum eCB content and blood pressure are not correlated in control subjects. Furthermore, despite opposing changes of averaged, serum eCB content in minor and major depression [10
], either AEA or 2-AG remains positively correlated with diastolic blood pressure in both depression groups. Taken together, the present findings suggest that a positive correlation between serum eCBs and blood pressure could be a common feature of depression at different levels of severity. It is conceivable that biochemical changes in depression, or its associated increase in blood pressure, play a facilitatory role in the positive correlation between eCBs and blood pressure.
Emerging evidence suggests changes in eCB signaling are involved in depression and anxiety disorders. In the same cohort of female subjects as in the current study, we observed that serum 2-AG content is negatively correlated with the duration of current depressive episode and AEA content is negatively correlated with Hamilton ratings for cognitive and somatic anxiety in depressed subjects [10
]. However, there is no correlation between these parameters and blood pressure (data not shown). Together, our results point to the complex interrelationships among serum content of eCBs, depression and blood pressure. In this study, there is also evidence that AEA and 2-AG could play a differential role in minor vs major depression since diastolic pressure was positively correlated with 2-AG in minor depression and with AEA in major depression. The synthesis and degradation of the two eCBs involve distinct enzymes [6
] and eCB levels are often differentially regulated in stress and anxiety [3
]. Alterations of eCBs signaling in depression and hypertension of different severity remain unclear but our data might indicate that 2-AG is the predominant eCB involved in blood pressure control in minor depression, whereas AEA plays a more important role in major depression. Such differential roles also highlight the need for measurements of both eCBs in future studies on subtypes of depression.
Depression is sometimes associated with an increased prevalence of obesity and smoking, which could act as confounding factors in the association between blood pressure and eCBs. In this study, depressed subjects are more likely to be obese (with BMI ≥ 30 kg/m2
) compared to their matched controls. Whilst this might contribute to the increased blood pressure in depressives, a direct link between BMI and serum eCBs is not evident. In addition, tobacco smoking, the waist-to-hip ratio, serum total cholesterol also fail to explain the correlations between eCBs and blood pressure in depression. It is noteworthy that the absence of correlation between BMI and eCBs in the current study (in women; average age of 29 years) contrasts with the observation that BMI is positively correlated with plasma 2-AG, but not AEA, in men with an average age of 42 years [37
]. The discrepancy could also be due to the limited number of subjects with advanced obesity in our sample [38
]. Interestingly, however, there is indication that 2-AG, but not AEA, is positively correlated with serum total cholesterol levels in our female subjects. Since subfractions of cholesterol content were not determined in this study, it is unknown if high-density lipoproteins (HDL)-cholesterol or low-density lipoproteins (LDL)-cholesterol, or both, are involved. This is of particular interest in light of the finding that the CB1
receptor antagonist, rimonabant, improves serum HDL-cholesterol of overweight or obese subjects in a randomized, double-blinded clinical trial [39
]. Further analysis also revealed that correlations between 2-AG and total serum cholesterol, and between BMI and blood pressure, occurred predominantly in individuals with minor depression. At present, the significance of these subtle differences of cardiovascular and metabolic variables between minor and major depression is unclear.
To conclude, our study shows that serum contents of eCBs are positively correlated with blood pressure in depressed women but not in their matched control subjects. We speculate that eCBs play a role in regulation of blood pressure in depression, perhaps acting to buffer an increase in blood pressure. In this study, depressed women also have a higher systolic blood pressure, body mass index, waist-to-hip ratio and higher prevalence of tobacco smoking, all of which are associated with increased risk of cardiovascular diseases. Since eCBs are likely involved in both cardiovascular and neuronal functions, the interrelationships among these agents, cardiovascular parameters and depression warrant further attention.
Given the negative impact of depression on patients who have ischemic heart disease or have recently had myocardial infarction, it has been suggested that effective treatment of depression can not only improve the quality of life but also the clinical outcome of patients with heart diseases. A few, although not all, clinical trials have indeed shown that treating depression with selective serotonin reuptake inhibitors (SSRI) significantly improve the prognosis of patients recovering from myocardial infarction [40
]. In this regard, it is interesting to note that inhibitors of fatty acid amide hydrolase have been proposed to reduce the symptoms of anxiety and depression [43
]. Perhaps increasing eCBs signaling by these inhibitors could also help normalize blood pressure homeostasis in depression. However, this approach could also be detrimental to depressive individuals with obesity-related co-morbidities since a recent clinical study has reported that plasma eCBs is inversely related to coronary blood flow in advanced obesity [38
]. More clinical studies examining the role of eCBs in depression and cardiovascular functions are required.