Introduction

Major depression is associated with an increased risk for cardiovascular diseases (CVDs) such as myocardial infarction (Yusuf et al. 2004) or stroke (O’Donnell et al. 2010; Pan et al. 2011). The magnitude of the increased risk due to depression is comparable to well-established cardiovascular risk factors such as obesity, metabolic syndrome, low high density lipoprotein (HDL), high cholesterol, or C-reactive protein (CRP) (Nicholson et al. 2006; Penninx et al. 2013; Seldenrijk et al. 2015). Major depression increases also the probability of CVD risk factors such as hypertension (Meng et al. 2012), type 2 diabetes (Mezuk et al. 2008), and obesity (Luppino et al. 2011). Furthermore, depressive symptoms predict mortality after an acute myocardial infarct (Frasure-Smith et al. 1993), heart failure (Fan et al. 2014), or in case of a preexisting CVD (Nicholson et al. 2006).

Biological and life style factors associated with major depression might contribute to the increased cardiovascular risk (Penninx et al. 2013; Whooley and Wong 2013). Furthermore, the use of antidepressants and its potentially adverse effects might also contribute to the increased CVD risk. However, due to equivocal findings, this is still a matter of debate. Some studies have reported adverse cardiovascular effects for tricyclic antidepressants (TCAs) (Cohen et al. 2000; Hamer et al. 2011; Jiang and Davidson 2005; Licht et al. 2015; Serodio et al. 2014; Smoller et al. 2009; Zimmermann-Viehoff et al. 2014) or serotonin reuptake inhibitors (SSRIs) (Licht et al. 2015; Rieckmann et al. 2013; Smoller et al. 2009; Weeke et al. 2012; Xiong et al. 2006). There is also evidence suggesting an unfavorable impact of antidepressant medication on prognostic cardiac markers such as heart rate variability (Kemp et al. 2014; Licht et al. 2010). Importantly, a partly recovery of heart rate variability was found when patients had stopped their medication (Licht et al. 2010). Another study reports an association of antidepressant use and increased risk for hypertension while a major depressive disorder without medication was rather associated with reduced blood pressure (Licht et al. 2009). Significant associations of a severe depressive episode and the use of TCAs with obesity have been reported (van Reedt Dortland et al. 2010). However, on the other hand, it is important to note that other studies did not find an increased morbidity or mortality risk or even found a reduced mortality risk for antidepressant medication with TCAs (Pratt et al. 1996; Rahman et al. 2013; Serodio et al. 2014) or SSRIs (Baumeister et al. 2011; Cohen et al. 2000; Glassman et al. 2002; Hamer et al. 2011; Lesperance et al. 2007; O’Connor et al. 2010; Rieckmann et al. 2013; Serodio et al. 2014; Weeke et al. 2012).

To further clarify the role of antidepressant medication for the increased CVD risk in depressed patients, we compared cardiovascular risk profiles between depressed patients with and without antidepressant medication and a healthy control group. Blood pressure, body mass index (BMI), as well as plasma levels of glucose, cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), and high sensitivity C-reactive protein (h-CRP) were measured as markers of CVD risk. We hypothesized that depressed patients with antidepressant medication would show the most pronounced adverse CVD risk profile, followed by depressed patients without medication, and with healthy controls exhibiting the most favorable CVD risk profile.

Material and methods

Participants

We recruited 44 depressed patients (without antidepressant medication, N = 24; with antidepressant medication, N = 20) from specialized depression clinics at the Department of Psychiatry and Psychotherapy and the Department of Psychosomatic Medicine, University Medical Center Hamburg, Germany, and 41 healthy subjects by public postings. Healthy subjects were matched for sex, age, and education.

Depression was assessed according to DSM-IV criteria using the Mini-International Neuropsychiatric Interview (MINI) conducted by two experienced psychiatrists (C.M and K.H.). To assess the severity of the depressive episode, two clinical depression interviews (17-Item Hamilton Depression Scale (HAMD-17; Hamilton 1960) and Montgomery-Asberg Depression Rating Scale (MADRS; Montgomery and Asberg 1979)) and a self-rating questionnaire (Beck’s Depression Inventory (BDI; Beck et al. 1961)) were conducted.

Criteria for exclusion were dementia, schizophrenia spectrum disorder, bipolar disorder, substance dependence, serious medical conditions associated with adrenal dysfunction, steroid use, pregnancy, and nursing.

All participants were examined by a physical exam, a blood count, and a clinical interview. In the clinical interview, also the use of medication (pharmaceutical agent, dosage, duration, and adherence), the number of past depressive episodes, and the length of the current episode were assessed. The examinations did not show an indication of a CVD neither in the patients nor in the healthy participants. All examinations were conducted by C.M. and K.H.

Twenty-four patients (15 women, 9 men) were free of psychotropic medication. One of these patients used medication of the group of AT blockers.

Twenty patients (13 women, 7 men) were treated with antidepressant medication: selective serotonin reuptake inhibitors (N = 8), selective norepinephrine reuptake inhibitor (N = 2), selective serotonin norepinephrine reuptake inhibitor (N = 3), mirtazapine (N = 3), agomelatine (N = 2), amitriptyline (N = 2), St. John’s wort (N = 2), tranylcypromine (N = 1), and opipramol (N = 1). The mean duration time of antidepressant use was 226 days (SD 345). All of the antidepressant medication was in the recommended dosage range. Six of these patients used medication of the group of α- or ß-blockers (N = 3), ACE-/AT-blockers (N = 3), or diuretics (N = 1).

Healthy participants (26 women, 15 men) were free of former and present DSM-IV axis I disorders as assessed by the MINI, had no physical illness, and were free of medication apart from two cases using medication of the group of ß-blockers (N = 2), ACE-/AT blockers (N = 1), statins (N = 1), or diuretics (N = 1).

The study was carried out in accordance with the latest version of the Declaration of Helsinki and approved by the responsible local ethics committee (ethics committee of the Medical Association of Hamburg). Informed consent of the participants was obtained after the nature of the procedures had been fully explained.

Markers of CVD risk

Blood samples for measurement of glucose, cholesterol, LDL, HDL, and h-CRP levels were taken under fasting conditions between 8 and 9:30 a.m. at the University Medical Center Hamburg by medical doctors. Additionally, weight and height for BMI calculations were assessed and blood pressure was recorded after 5 min of rest. All participants were requested to avoid physical activity such as biking before examination. All blood samples were analyzed as part of the routine assessment in the central laboratory of the University Medical Center Hamburg (Germany).

Statistical analysis

Differences in demographic characteristics between both patient groups and healthy participants were compared using one-way analyses of variance (ANOVAs) for continuous variables and χ 2 tests for dichotomous variables.

One-way analyses of covariance (ANCOVAs) were used to calculate the effect of group (patients without medication, patients with medication, healthy participants) for single risk CVD factors (systolic and diastolic blood pressure, BMI, levels of glucose, cholesterol, LDL, HDL, h-CRP). Post hoc tests (Bonferroni) were used to compare differences between groups. In a second step, for those variables that differed between groups, BMI was included as a covariate in one-way ANCOVAs of group (patients without medication, patients with medication, healthy participants) × blood pressure or glucose level, respectively, to disentangle the influence of BMI and depression on these variables.

A p value smaller than .05 was considered to indicate statistical significance.

Results

For most demographic characteristics (age (years), sex (female/male), education (length of education in years)), we found no significant differences between groups, but for “current smoking” (yes/no; χ 2 = 6.82, p = .03). Thus, “current smoking” was included as control variable in all ANCOVAs.

The mean age in the group of depressed patients without use of antidepressants was 40.0 years (SD 11.8), 43.1 years (SD 9.9) in the group of depressive patients using antidepressants, and 41.2 years (SD 11.6) in the group of healthy participants.

Variables related to psychopathology (first vs. recurrent depressive episode, number of past depressive episodes, mean BDI score, mean HAMD-17 score, and mean MADRS score) did not differ significantly between the two patient groups.

In the group of patients without use of antidepressants, the mean number of past depressive episodes was 2.2 (SD 2.5); for seven patients, the current episode was the first one. The length of the current episode was 12.4 months (SD 12.1).This patient group had a mean BDI score of 33.5 (SD 10.6), a mean HAMD score of 22.8 (SD 4.5), and a mean MADRS score of 29.5 (SD 5.8).

In the group of patients using antidepressants, the mean number of past depressive episodes was 2.5 (SD 5.1); for nine patients, the current episode was the first one. The length of the current episode was 11.4 months (SD 13.1).This patient group had a mean BDI score of 30.7 (SD 8.1), a mean HAMD score of 21.2 (SD 3.9), and a mean MADRS score of 30.7 (SD 5.9).

See Table 1 for demographic and psychopathological characteristics.

Table 1 Demographic variables and psychopathology
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Univariate ANCOVAs of group (patients without AD medication, patients with AD medication, healthy participants) × CVD risk factor, including smoking as a covariate, revealed a significant effect of group (F 2,78 = 4.30; p = .02) for systolic blood pressure. Post hoc tests revealed significant differences between patients with AD medication and healthy participants (p = .04) and at trend between patients without AD medication and healthy participants (p = .09), but no significant differences between both patient groups (see Fig. 1a).

Fig. 1
figure 1

Systolic (a) and diastolic (b) blood pressure in the groups of depressive patients without and with antidepressant medication and healthy control participants (*p < .10; **p < .05; AD antidepressant medication)

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For diastolic blood pressure, a significant effect of group (F 2,78 = 5.13; p < .01) was found. Post hoc tests revealed significant differences between patients with AD medication and healthy participants (p = .02) and at trend between patients without AD medication and healthy participants (p = .06), but no significant differences between both patient groups (see Fig. 1b).

For plasma glucose levels, a significant effect of group (F 2,77 = 9.56; p < .001) was found. Post hoc tests revealed significant differences between patients with AD medication and healthy participants (p < .01) and between patients without AD medication and healthy participants (p < .06), but no significant differences between both patient groups (see Fig. 2). For cholesterol, LDL, HDL, and h-CRP levels, there were no significant effects of group.

Fig. 2
figure 2

Plasma glucose levels in the groups of depressive patients without and with antidepressant medication and healthy control participants (*p < .10; **p < .05; AD antidepressant medication)

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For BMI, a significant effect of group (F 2,80 = 5.71; p < .01) was found. Post hoc tests revealed significant differences between patients with AD medication and healthy participants (p = .02) and between patients without AD medication and healthy participants (p < .05), but no significant differences between both patient groups.

See Table 2 for an overview, including means of each CVD risk factor according to group.

Table 2 CVD risk factors according to group (depressive patients with/without antidepressant medication and healthy participants)
Full size table

When BMI was included as an additional covariate, results for systolic blood pressure revealed a highly significant effect of BMI (F 1,77 = 14.03; p < .001). The effect of group was not significant in this ANCOVA. For diastolic blood pressure, a similar pattern was found: there was a significant effect of BMI (F 1,77 = 14.03; p < .01), but not for group. However, for plasma glucose levels, BMI had no significant effect as a covariate (as well as smoking), but the effect of group remained significant in this analysis (F 2,75 = 6.87; p < .01).

Discussion

In this study, we compared cardiovascular risk profiles among depressed patients with and without antidepressant medication and healthy individuals. Both patient groups differed, at least at trend level, from the healthy control group regarding systolic and diastolic blood pressure, plasma glucose levels, and BMI. In contrast, there were no significant differences between the two patient groups. These results clearly indicate an increased cardiovascular risk even in this group of relatively young depressed patients as assessed by the well-established CVD risk factors higher blood pressure, higher glucose levels, and higher BMI (Bogers et al. 2007; Mottillo et al. 2010). Interestingly, further analyses of the results for blood pressure revealed a highly significant effect of BMI as a covariate, which diminished the effect of group. However, the effect of MDD diagnosis on glucose was independent of BMI.

Our results confirm evidence from the literature indicating an increased cardiovascular risk in patients with depressive symptoms (Nicholson et al. 2006; Seldenrijk et al. 2015). The rather young age of the sample, being in their early 40s, further underlines the alarming impact of depression as a cardiovascular risk factor (Penninx et al. 2013).

Interestingly, there was no significant difference according to antidepressant medication regarding the CVD risk markers. This suggests that antidepressant medication did not play a prominent role for the cardiovascular risk in this sample. One reason for this finding might be the fact that only 2 out of 20 patients in our sample received a tricyclic antidepressant. Previous studies that examined the role of antidepressant medication as a cardiovascular risk factor in depression are heterogenous (Cohen et al. 2000; Glassman et al. 2002; Hamer et al. 2011; Jiang and Davidson 2005; Lesperance et al. 2007; Licht et al. 2015; O’Connor et al. 2010; Pratt et al. 1996; Rahman et al. 2013; Rieckmann et al. 2013; Serodio et al. 2014; Smoller et al. 2009; Weeke et al. 2012; Xiong et al. 2006; Zimmermann-Viehoff et al. 2014). However, in sum it appears from the literature that the use of SSRIs might be safer regarding the cardiovascular risk compared to TCA use, while other groups of antidepressants are not investigated sufficiently until now (Hare et al. 2014; Ho et al. 2014; Jiang and Davidson 2005; Schramm et al. 2014). Still, we cannot draw firm conclusions concerning this aspect from our sample since the size of the depressed group with antidepressants was too small to be divided into different classes of antidepressants. Furthermore, it is also important to note differences in study populations of depressed patients with regard to age or gender in previous studies that examined the role of antidepressants (Ho et al. 2014; Licht et al. 2015; Smoller et al. 2009) and preexisting cardiovascular risk (Glassman et al. 2002; Jiang and Davidson 2005; Lesperance et al. 2007; O’Connor et al. 2010; Rieckmann et al. 2013; Zimmermann-Viehoff et al. 2014).

Our results clearly indicate that the depressed patients with and without antidepressant medication exhibit an increased cardiovascular risk with no significant difference between both patient groups. That emphasizes the importance of biological factors increasing the cardiovascular risk which are associated with depression and rather independent from medication. In our study, especially sympathetic and metabolic factors seem to be important. Also, unfavorable life style factors associated with depressive symptoms (Bonnet et al. 2005; de Wit et al. 2010; Whooley et al. 2008; Ziegelstein et al. 2000) such as inactivity and unbalanced nutrition might play an important role and could explain the results.

Unfortunately, we have no data available regarding life style factors such as activities or nutrition, so that we cannot draw any firm conclusion about the impact of these factors. Furthermore, due to the sample size of the study, the depressed group with antidepressant medication cannot further be divided into different classes of antidepressants. Since many studies found a difference, especially between TCAs and SSRIs, it would be interesting to further clarify if the effects were more pronounced in one group of medication. Due to the sample size of the study, we cannot further divide the groups of depressed patients into subtypes of depression either. By now, there is accumulating evidence that the subtypes “melancholic” vs. “atypical” depression are associated with different risk profiles (Penninx et al. 2013). Especially for the atypical subtype, an increased risk for metabolic syndrome, obesity-related disturbances (Lamers et al. 2010; Seppala et al. 2012), and higher inflammation levels (Kaestner et al. 2005; Lamers et al. 2013; Yoon et al. 2012) was observed, whereas hypercortisolism is more often observed in the melancholic type (Kaestner et al. 2005; Karlovic et al. 2012; Lamers et al. 2013). Especially, the metabolic dysregulations appear plausible since weight gain is a cardinal symptom of atypical depression. Another important aspect might be the reasons why some depressed patients get a prescription of antidepressants and others do not. It is possible that patients with an already existing cardiovascular disease are less likely to get a prescription of antidepressants. However, since we did not find differences regarding the CVD risk factors between both patient groups (with vs. without antidepressant medication), this seems not a likely explanation in our sample.

Of note, also the inverse relationship of a CVD increasing the risk for depression has been reported (Lippi et al. 2009). Some mechanisms, such as subclinical inflammation, could have bidirectional effects and might enhance the risk for depression as well as for cardiovascular diseases. In addition, shared genetic effects, childhood maltreatment, or low socio-economic status could be a risk factor for both, depression and somatic diseases (Penninx et al. 2013). Because of the cross-sectional design of the study, we cannot draw any conclusion about the direction of the results.

Besides these limitations, an important strength of this study is the fact that the potentially confounding factor of medication was examined in the association between depression and CVD risk whereas many studies do not differentiate between the role of depression and antidepressant medication. Further strengths include the exact matching of the three groups and the rather young age of the sample.

In summary, our results confirm a significantly increased cardiovascular risk for depressed patients. Our results further point out that also rather young patients suffering from a major depression are exposed to an increased risk. This risk is also increased for patients without antidepressant medication.