The association between cardiovascular disease (CVD) and depression is well established and is suggested to be bidirectional. Numerous clinical and epidemiological studies investigating the association of depression and CVD have suggested that depression independently increases the risk of CVD 1.5-fold on average, and that patients with coronary artery disease and depression have a two- to threefold increased risk of future non-fatal and fatal cardiac events compared with those cardiac patients without depression.1, 2, 3, 4 Biological mechanisms that might link these two conditions together include the hypothalamic–pituitary–adrenal (HPA) axis, pro-inflammatory cytokines, changes of arterial elasticity and endothelial function (for reviews see refs 1,4,5,6,7,8,9,10,11,12,13,14).

Many epidemiological and clinical studies examining biological models of the relationship between CVD and depression have classified depression dichotomously either as yes/no or restricted analyses to major depression (MD) only. However, more recent research has begun to differentiate depressive subtypes such as dysthymia, melancholic MD (MMD), MD with typical or atypical features (see description of subtypes in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR); American Psychiatric Association15). Although differences in the strength of the association between various depression subtypes and CVD have been demonstrated,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 it remains unclear if these subtype-specific associations are caused by a subtype-specific biological mechanism. Surprisingly, studies directly addressing this question are lacking. If this assumption would be true one would expect firstly that subtypes of depression are characterized by specific biological models and secondly that these specific models are also relevant for the pathogenesis of CVD.

The aim of this review is to identify biological models and correlates of subtypes of depression that might be involved in the relationship with CVD. This review proposes a differential subtype model of depression relevant for the association with CVD as opposed to a unifying model of depression that is commonly used in the literature on CVD and depression comorbidity.

The literature search for this review was carried out according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines as they apply to systematic reviews.28 A systematic literature search was performed using the PubMed and PsycINFO databases covering articles from 1969–2011. The following search terms were used: (dysthymi* or (subsyndromal and depression) or (minor and depression) or (subthreshold and depression)) or bipolar disorder (BD) or MD or melanchol* or (depressi* and (melanchol* or atypical or psycho* or vascular)) and (immune or inflamm* or cytokine or glucocorticoid or cortisol or hypothalamus or endothelium or coag* or clotting or thrombosis). A second search was conducted as above, but with the addition of the following: and (CVD or stroke or ischemic heart disease or myocardial infarction or coronary heart disease or arterial stiffness or atherosclerosis). Articles were also obtained by reviewing reference lists of review and research articles. A total of 736 studies were found using these search terms. A total of 371 articles remained after assessment of abstracts for relevance to the aims of this review. Of these, 224 studies were excluded after review of the full text if they did not directly compare between subtypes of depression, did not provide data for individual subtypes, included child/adolescent populations or did not include measurement of relevant biomarkers. In most cases cross-sectional studies were also excluded; however, where studies of a longitudinal design were not available then cross-sectional studies were retained. In all, 147 studies were included in the final review (Figure 1).

Figure 1
figure 1

Study inclusion flowchart.

The bidirectional relationship between depression and CVD

The relationship between depression and CVD has been proposed to be bidirectional; existing depression increases the risk of incident CVD and a history of CVD increases the risk of depression. Many prospective and retrospective studies have investigated the association of existing depression and incident CVD.29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 Several meta-analyses of these studies have demonstrated a significant positive correlation with a moderate effect size of 1.5–2.7.3, 40, 41, 42

Similarly, several studies have investigated the role of depression status as a prognostic factor in patients with existing CVD.43, 44, 45, 46, 47, 48, 49, 50 Meta-analysis of these studies suggests that depressed patients have a 1.6–2.7-fold increased risk for further cardiovascular events within 24 months.42, 51, 52, 53 Conversely, relatively few studies have investigated the role of existing CVD in increasing the risk for the onset of depression (Supplementary Table).39, 43, 54 To our knowledge, this data has not been subjected to meta-analysis.

Analysis of the association between CVD and subtypes of depression reveals that the relationship with CVD appears to be particularly strong in patients with dysthymic disorder,16, 18, 19, 23 and BDs.16, 17, 22, 27 However, this literature is significantly limited by the paucity of prospective studies and studies that investigate a larger range of subtypes of depression (Table 1).

Table 1 Incidence, prevalence and associations between depression subtypes and cardiovascular diseases among clinical and community samples

In addition to its association with CVD, depression is also significantly associated with several other major cardiac risk factors including smoking, obesity and diabetes.55, 56 Many studies, however, have demonstrated that depression remains independently associated with CVD even after adjusting for these risk factors. This suggests that there are other mediators of this relationship including both biological and behavioral mediators.2, 55

Biological mechanisms involved in the CVD-depression association

The relationship between depression and CVD has been proposed to be bidirectional; that is, existing depression increases the risk of incident CVD and a history of CVD increases the risk of depression. Many prospective and retrospective studies have investigated the association of existing depression and incident CVD.29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 Several meta-analyses of these studies have demonstrated a significant positive correlation with a moderate effect size of 1.5–2.7.3, 40, 41, 42 Similarly, several studies have investigated the role of depression status as a prognostic factor in patients with existing CVD.43, 44, 45, 46, 47, 48, 49, 50 Meta-analysis of these studies suggests that depressed patients have a 1.6–2.7-fold increased risk for further cardiovascular events within 24 months.42, 51, 52, 53 Conversely, relatively few studies have investigated the role of existing CVD in increasing the risk for the onset of depression.39, 43, 54 To our knowledge, this data has not been subjected to meta-analysis.

The association with CVD appears to be particularly strong in patients with dysthymic disorder,16, 18, 19, 23 and BDs.16, 17, 22, 27 However, this literature is significantly limited by the paucity of prospective studies and by studies that investigate a larger range of subtypes of depression.

In addition to its association with CVD, depression is also significantly associated with several major cardiovascular risk factors, including smoking, obesity and diabetes.55 Many studies, however, have demonstrated that depression remains independently associated with CVD even after adjusting for these risk factors. This suggests that there are other factors impacting on this relationship, including both biological and behavioral mediators2, 55 (Figure 2).

Figure 2
figure 2

Biological mechanisms for the bidirectional relationship between depression and CVD.

Studies investigating immune system functioning in individuals with ‘depression’, irrespective of depressive subtypes, have found that many of these individuals manifest elevated inflammatory markers, particularly c-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α).57, 58 Several authors have suggested that this association of depression and inflammatory markers may be a key biological link in the comorbidity of depression and CVD (see for reviews refs 1,4,7,10,12,13,59). This may be mediated by interactions of inflammatory signaling cascades with several key processes implicated in the pathogenesis and pathophysiology of CVD. Key among these processes is atherosclerosis. It has been proposed that inflammatory mediators may accelerate the progression of atherosclerosis through several mechanisms, including chemoattraction of leukocytes to atherosclerotic lesions, inducing endothelial activation and expression of adhesion molecules and stimulating the expression of vascular endothelial growth factors (see for review ref. 60). Furthermore, inflammatory signaling cascades may amplify and accelerate the process of coagulation and thrombus formation.61

It has been suggested that the dysfunction of the HPA axis may also contribute to the pathogenesis of depression and comorbid CVD.1, 7 This contribution may be mediated, at least in part, by the loss of glucocorticoid receptor-mediated negative feedback on inflammatory signaling. It is also worth noting that the disruptions of the HPA axis may be reciprocally regulated by altered expression of pro-inflammatory cytokines constituting a complex bidirectional biological crosstalk.62 Dysregulation of the HPA axis may also lead to sympathoadrenal hyperactivity via central pathways. This hyperactivity may lead to an increase in vasoconstrictive tone, heart rate and platelet activation each of which have been implicated in the progression to CVD.7, 63 Furthermore, excess sympathetic drive may result in reduced heart rate variability, which may increase vulnerability to arrhythmia.64

Endothelial dysfunction is a recognized risk factor for CVD that is also often observed in patients with depression.65, 66, 67, 68 In both ‘healthy’ young volunteers and patients with CVD, depression status was associated with attenuated arterial dilatory responses to flow and nitroglycerin in addition to an increased expression of endothelial adhesion molecules and chemokines.69, 70 These factors may function to predispose these patients to atherosclerosis, thrombosis and vasospasm.

Biological mechanisms in depression subtypes relevant to CVD-depression comorbidity

More recent research has begun to investigate immune activation among depressed patients according to depression subtype, which might help to improve the understanding of the biological mechanisms underlying the relationship between CVD and depression.


Much research over the last decades has investigated whether the subtype of MMD may have a separate underlying pathophysiology to other non-melancholic forms of MD (NMMD) (Table 2a). Particularly relevant to CVDs are the investigation of immune alterations in MMD.

Table 2a Differential biological mechanisms in subtypes of depression—melancholic vs atypical vs non-melancholic/atypical

Many studies have investigated the profile of pro-inflammatory cytokines expressed in MMD as compared with NMMD; however, no consistent pattern has emerged. Of the pro-inflammatory cytokines IL-1β has been the most frequently investigated. Studies of serum IL-1β have variously reported increased,71 decreased72 or non-significantly different73, 74 levels in MMD relative to NMMD. Similarly, study of ex-vivo lipopolysaccharide stimulated whole blood IL-1β production have produced equivocal results.75 Other aspects of the IL-1 system have seldom been investigated, however, one study did report a decrease in the ratio of serum IL-1 receptor antagonist to IL-1β in NMMD compared with MMD, which normalized in clinical remission.72

Study of the cytokines IL-6 and TNF-α have also produced mixed results in similar investigations. No significant difference between MMD and NMMD was reported in serum;74 however, a study of ex-vivo mitogen-stimulated peripheral blood mononuclear cells did demonstrate an increase in IL-6 production in MMD relative to both NMMD and controls.21 There is also poor evidence of increased serum TNF-α in MMD relative to NMMD as reported by one study,73 yet others have found no significant difference in serum.71

In addition further aspects of the inflammatory response have also been investigated in MMD, including the acute phase proteins: CRP, haptoglobin and transferrin, and α-2-macroglobulin. Of these factors, CRP has been found to be elevated in NMMD relative to MMD and controls, whereas α-2-macroglobulin was higher in MMD relative to NMMD and controls.75 Haptoglobin and transferrin were found to be higher in both MMD and NMMD relative to controls but did not significantly vary between depressive groups.21 In contrast with these results, others have reported that serum haptoglobin was significantly higher in patients with MMD than NMMD,76 or else not different between MMD, NMMD or controls.75 Taken together, these consistently contradictory results in both pro-inflammatory cytokines and acute phase proteins suggest that the inflammatory system is unlikely to be differentially disordered in MMD as compared with NMMD.

Several authors have compared indices of adaptive immunity in MMD and NMMD. One study suggests an impairment of Th1-mediated immunity in MMD as these patients demonstrated reduced mitogen-stimulated whole blood IL-2 and interferon gamma (IFN-γ) production relative to both NMMD and controls at the untreated baseline.24 Other studies, however, have demonstrated an increase in the Th1 marker neopterin in serum relative to NMMD,73 and no significant difference in constitutive serum levels of the Th1 cytokine IFN-γ.74 A contrasting result has also been reported for IL-2 where MMD had greater ex-vivo peripheral blood mononuclear cell mitogen-stimulated production of IL-2 relative to NMMD and controls.77 This discrepancy from the earlier result may be explained by the reduction in absolute lymphocyte numbers observed in MMD patients in that study—thereby confounding the result in whole blood.24 In contrast to the Th1 cytokines no significant differences have been reported in the Th2 cytokines IL-4 and IL-10.24, 71, 77

Alterations in cell population numbers have also been observed in MMD relative to NMMD. One group noted an increase in the absolute CD4+ cell count in addition to an increased CD4+:CD8+ ratio that was not altered in clinical remission. This was not accompanied by any changes in absolute CD8+ cell count or other T-cell populations when comparing MMD and NMMD patients although natural killer cell activity was reduced in NMMD patients and significantly negatively correlated with depression severity.77 Another group reported an increased absolute monocyte count in NMMD relative to both MMD and controls,75 and the same group found no significant difference in absolute natural killer cell count between MMD and NMMD although the depressed groups were significantly higher than controls.24

HPA axis dysfunction has also been assessed as a potential differential biological marker for MMD. Several decades of studies utilizing the dexamethasone (DEX) suppression test as a potential discriminator between MMD and NMMD were included in a meta-analysis by Nelson and Davis,78 which found that there was no significant difference in rates of DEX suppression test non-suppression between MMD and NMMD after adjustment for inpatient/outpatient status. Other measures of HPA axis function such as serum adrenocorticotrophic hormone (ACTH) or cortisol have occasionally been reported in elevated levels in MMD as compared with NMMD,72 however, the majority of studies report no significant difference.21, 24, 74

It is also of particular relevance to note that a small study found no significant difference between MMD, NMMD, ‘minor depression’ or controls in regards to several indices of coagulation; prothrombin time, activated partial thromboplastin time and platelet aggregation to collagen or adenosine diphosphate.79

Atypical depression

Relatively few studies have assessed differentially disordered biomarkers in atypical depression. A study of whole blood lipopolysaccharide stimulated cytokine production found that patients with atypical depression expressed more IL-2 and less IL-4 resulting in an overall increased IL-2:IL-4 ratio as compared with typical depression. The same study found no significant difference for TNF-α or IL-6.80 Such a report would suggest a Th1 shift in the basal immune state associated with atypical depression relative to typical depression. Another study of mitogen-stimulated peripheral blood mononuclear cells found no significant difference in IL-1β or IL-2 production between the atypical and typical depressive subtypes.81 A single report has also identified increased serum leptin as a marker of atypical depression, which was significantly different from both typical depression and controls.82 The significance of this result is unclear as it awaits replication.

Some evidence also suggests differentially disordered cell populations in typical compared with atypical depression. Although there appears to be no significant difference in lymphocyte cell counts,83 one study found that lymphocyte proliferative response to mitogens differed slightly between the subtypes; typical MD showed an attenuated proliferative response to both concavalin A and low-dose phytohemagglutanin whereas atypical MD showed an attenuated response to phytohemagglutanin only.84 The (patho-) physiological significance of this result is questionable. A single report also found natural killer cell counts to be significantly higher in typical MD than atypical MD, which was in turn significantly higher than controls.83 Indices of HPA axis dysfunction also do not appear to be differentially disordered between atypical and typical depression81 (Table 2a).


The evidence for a differential biological profile in dysthymia is again inconsistent. Much of this investigation has focused on the pro-inflammatory cytokine IL-1β. One group investigated IL-1β in individuals with dysthymia and MD, and distinguished between typical and atypical features for both of these subtypes. Their results suggested that individuals with dysthymia, irrespective of whether typical or atypical features were present, had significantly elevated levels of IL-1β relative to controls. Although typical and atypical dysthymics had higher levels of IL-1β relative to typical and atypical major depressives, the authors did not report if these differences reached statistical significance. Additionally, concentrations of IL-1β increased with phytohemagglutinin dosage among all depressive subtypes but not for controls. Taken together, this study would seem to suggest that dysthymia, but not MD, is characterized by overexpression of IL-1β. Moreover, this overexpression was significantly and positively associated with baseline severity scores and duration of illness.81

More recent studies have also suggested that dysthymia may be characterized by higher overexpression of IL-1β than MD. In a study by Schlatter et al. the dysthymic group had significantly higher levels of IL-1β relative to controls, and 30% higher levels of IL-1β production relative to those with MD, however, this latter difference again did not reach significance. They also reported the absence of any associations between IL-1β and clinical characteristics of dysthymia such as severity or duration of illness.25, 26 Furthermore, they did not find significant differences in TNF-α expression between any of the depressive subtypes or between dichotomized depression and controls.25

These findings are somewhat complicated by those reported by Maes et al.20 In their study, Maes et al. found that MD patients had significantly higher IL-1β levels relative to controls, whereas intermediate levels of IL-1β were evident among patients with minor depression (dysthymia, adjustment disorder with depressed mood). However, as with the aforementioned studies, the differences in IL-1β levels between MD and dysthymia for IL-1β levels was not actually significant. However, comparison of these findings is difficult as in Maes et al. dysthymia and adjustment disorder with depressed mood were combined into the category of ‘minor depression’, and information regarding the duration of depressive symptoms among dysthymic and MD patients was not reported.20

These same studies suggest that MD and dysthymia do not differ significantly in the level of overexpression of IL-6.21, 25, 26 A more recent study also found no significant difference between MD and dysthymia in plasma IL-6 or serum brain-derived neurotrophic factor.85

A recent genotypic analysis of patients with post-stroke depression determined that several polymorphisms were differentially associated with major and minor post-stroke depression. The IL-4+33C/C genotype was associated with post-stroke MD only, whereas the IL-10-1082A/A genotype was found to be associated with both post-stroke MD and minor depression.86

In addition to these investigations of cytokines, a series of studies by Thomas et al. detail the lack any significant differences between MD, controls and ‘subsyndromal depression’ in serum levels of IL-1β, CRP, intercellular adhesion molecule-1 or vascular cell adhesion molecule-1.87, 88

Evidence of HPA axis dysfunction in dysthymia is also somewhat inconsistent. One group investigated cortisol levels in samples of patients with MD and minor depression, they found that with DEX and basal cortisol levels as covariates, MD patients had significantly higher post-DEX cortisol levels relative to controls, whereas patients with minor depression had intermediate levels.20 However, an earlier study by the same group found no significant difference between any subgroups of depression, including dysthymia and their controls.21

Little evidence suggests differential derangement of cellular indices in dysthymia. One study found natural killer cell counts to be higher in the atypical/typical subtypes of MD than the atypical/typical subtypes of dysthymia. The same study did not find any difference between MD and dysthymia in lymphocyte populations.83 No significant differences between MD and dysthymia were detected on mitogen-induced lymphocyte proliferation assays.84

A study investigating the indices of clotting prothrombin time, activated partial thromboplastin time and platelet aggregation to collagen or adenosine diphosphate found no significant difference between patients with minor depression and MD, or between depression groups and controls79 (Table 2b).

Table 2b Differential biological mechanisms in subtypes of depression—dysthymia vs major depressive disorders

Psychotic depression

In biomarker studies of the psychotic subtype of depression most attention has concentrated on differential dysregulation of the HPA axis. Meta-analysis of DEX suppression test studies suggests that patients with psychotic depression were significantly more likely to be non-suppressors in response to DEX (odds ratio: 3.0, 95% confidence interval, 2.2–4.1),78 however, DEX suppression test studies published since have continued to report inconsistent results.89, 90 Other indices of HPA axis functioning have also been shown to discriminate between psychotic and non-psychotic MD. Intensive monitoring of serum cortisol levels suggests that patients with psychotic MD may have a higher mean serum cortisol,91 a higher cortisol nadir and higher evening cortisol relative to both patients with non-psychotic MD and controls.92, 93 However, others have found that the mean serum cortisol and 24 h cortisol amplitude did not differ between psychotic and non-psychotic MD.89, 94 Similarly, opposing results for 24 h ACTH levels have also been reported.91, 94 Examination of other hormones in the hypothalamus–pituitary axis have also shown no significant differences between psychotic and non-psychotic MD in assays of thyroid-stimulating hormone response to thyrotrophin-releasing hormone or growth hormone response to growth hormone releasing factor.90 These results may be tentatively interpreted to suggest there may be some degree of differential dysregulation in the HPA axis related to the psychotic/non-psychotic distinction within MD.

Other differential mechanisms potentially relevant to CVD have been reported. One study suggests that platelet serotonin was increased in samples from patients with psychotic MD as compared with non-psychotic MD.89 Also, plasma dopamine β-hydroxylase (the enzyme converting dopamine to norepinephrine) activity has been reported to be lower in patients with psychotic relative to non-psychotic MD95 (Table 2c).

Table 2c Differential biological mechanisms in subtypes of depression—psychotic vs non-psychotic


Several studies in patients with BD observed an activation of the immune system during the manic, the depressed or the euthymic states of bipolar illness. Some authors suggested that certain markers may be specific to each state, however, no consistent pattern has emerged as of yet. Several pro-inflammatory cytokines have been investigated in BD. Investigating the ex-vivo mitogen-stimulated cytokine production of peripheral blood mononuclear cells from manic patients with BD, a reduced production of IFN-γ was observed that persisted in both acute mania and remission.96 These findings were replicated by others, who also observed an increase in plasma levels of IL-1 receptor antagonist, sCD4 and sCD8 in mania.97 In contrast, Kim et al.98 were unable to replicate the finding of increased IFN-γ in a cohort of medication free manic patients, however, they did note an increase in the IFN-γ/IL-4 ratio which is purported to be a more valid measure of the pro-inflammatory activities of IFN-γ than IFN-γ levels alone.

Other pro-inflammatory cytokines have also been found to be elevated in bipolar mania. Several authors have demonstrated an elevation of TNF-α levels,99, 100 and two studies demonstrated an increase in soluble TNF receptor 1 although they failed to replicate the finding of increased TNF-α.101, 102 Similarly, several authors have documented increased IL-6 during a manic phase of bipolar illness.98, 99, 103 Elevations in pro-inflammatory cytokines are not restricted to the manic state as TNF-α was increased in both manic and depressed patients,99 a finding also reported for IL-6.103 Other authors have demonstrated elevations in the production of pro-inflammatory cytokines and CRP as a trait marker of BD, independent of the current psychopathological state.104, 105, 106 Earlier studies had also demonstrated raised levels of serum sIL-2R among rapid cycling107 and manic108 bipolar patients with normalization in remission.107, 108, 109 In contrast, some studies found no significant association between pro-inflammatory cytokines and BD regardless of current state.102, 110, 111, 112

A dysregulation of the production of anti-inflammatory cytokines IL-4 and IL-10 has also been implicated in BD. For example, it was reported that IL-10 is increased in patients with BD irrespective of the current psychopathological state.100, 106, 112 However, studies in cohorts of exclusively manic96, 97 or euthymic113 patients found no significant association with IL-10 levels.99, 111 In support of an increase in anti-inflammatory cytokines in BD, elevated levels of the anti-inflammatory cytokine IL-4 were repeatedly reported in both the manic and euthymic states of bipolar illness.98, 103, 113 In contrast, an ex-vivo examination of IL-4 could not find an association with mania.97

Beyond the investigation of inflammatory proteins as markers of diagnostic subtypes of BD, these immunological factors appear to be positively correlated with the severity of bipolar symptoms. Although some reported that serum CRP was associated with scores of the Young Mania Rating Scale score, but not Hamilton Depression scale score,114 others found that a Young Mania Rating Scale score was positively correlated with IL-2 and IL-6, and the Hamilton Depression scale with IL-6 only.103 These findings are not uncontested, however, as several other studies found no association between several of these markers (CRP, IL-6, IL-8, TNF-α, IL-12 and IL-10) and symptom severity in BD.99, 110, 115

Beyond the innate immune markers discussed above, a recent study has demonstrated derangement of indices of adaptive immunity including T-cell subtypes and cytokines.111 An emerging body of literature proposes that disruptions of T-cell mediated immunity may interact with the aforementioned mechanisms of inflammatory markers and HPA axis to contribute to the progression of neuropsychiatric disorders.116, 117

A key complication of studies in bipolar patients is the purported immune effects of lithium and other mood stabilizers. Several studies have demonstrated differences in immune parameters between lithium-treated patients and un-medicated patients,104, 113, 118 however, this effect is not always replicated.101, 102, 109, 114 Any immune-modulatory effect appears to be related to chronic treatment with this agent and could not be replicated by in-vitro addition of lithium to samples from un-medicated patients.104 Additionally, it was suggested that the progressive nature of BD may act as a confounder as the early and late stages of the illness showed a differential profile of TNF-α, IL-6 and IL-10 expression.106

Several studies have reported dysfunction of the HPA axis in patients with BD. Similarly to unipolar depression, BD patients frequently demonstrate non-suppression of the cortisol response to DEX and/or corticotrophin releasing hormone in manic,119, 120 mixed120 and depressed states.121 It is notable, however, that the largest study of HPA axis functionality in BD did not find any significant difference in post-DEX cortisol between BD patients and controls.122 Overall, the study results remain inconclusive as both, a normalization119, 121 and a continued elevation123, 124 of post-DEX cortisol suppression was found in remitted BD patients.

BD has also been associated with increased basal cortisol levels119, 122, 124 and a greater cortisol awakening response and increased diurnal cortisol slope.122 In remission, though, basal cortisol secretion was not significantly different from controls, suggesting that this finding may be a marker of illness activity.125

It is also relevant to note that one study has demonstrated increased levels of serum von-Willebrand factor in patients with BD when compared with controls102 (Tables 2d and 3).

Table 2d Differential biological mechanisms in subtypes of depression—bipolar disorders vs major depressive disorders
Table 3 Differential biological mechanisms within bipolar disorders

Vascular depression

Vascular depression is associated with vascular disease, risk factors (e.g., diabetes mellitus, obesity) and late onset or change in the course of early-onset depression following the onset of vascular disease.126 The ‘vascular depression’ hypothesis proposed by Alexopoulos et al.126 suggests that characteristics of cerebrovascular disease and their risk factors are involved in the development of late-life depression. This hypothesis is based on the observed high comorbidity between depression and CVDs as well as risk factors such as hypertension, diabetes, coronary artery disease, stroke and the high rate of silent stroke and white matter hyperintensities among elderly individuals with depression.126, 127, 128 A study by Krishnan et al.129 reported that the crude and adjusted risks for vascular depression were associated with age and late-onset depression. Clinical features in patients with vascular depression are characterized by significant loss of interests (apathy), cognitive dysfunction and psychomotor retardation.130 The degree of cognitive dysfunction observed in patients with vascular depression is usually greater than in patients with non-vascular depression.131 Causative factors of depression in the elderly are not well understood, though a role of biological risk factors, such as decreased arterial elasticity contributing to this late-life depression has been discussed.132

Decreased arterial elasticity, which is an important biological marker of atherosclerosis, has been observed in depressed patients. Arterial elasticity is an indication of an artery's structural and functional properties, that is, the artery's ability to stretch when under stress.133, 134 Increased arterial stiffness (decreased arterial elasticity) is associated with cerebrovascular disease and death independent of atherosclerosis and other factors133, 135, 136, 137 as well as with depression in the elderly.135 The strongest associations were seen among those who met the criteria for a DSM-IV depressive disorder (major or minor depression, or dysthymia) compared with those who reached a clinical level of depressive symptoms (CES-D score 16) but did not meet the criteria for a depressive disorder. Those with a depressive disorder tended to have an increased risk for an abnormal distensibility coefficient of the common carotid artery and for an abnormal pulse wave velocity measurements, two markers of structural and functional vessel wall properties.138, 139, 140 Further studies support the hypothesis of arterial stiffness in depression.141 Arterial elasticity was examined in a sample of females with a lifetime DSM-IV-TR diagnosis of MD, currently depressed (onset 30 days) with very severe depressive symptoms (HDRS-17 score 24). Depressed patients had significantly higher baseline pulse wave velocity values relative to controls. Patients’ pulse wave velocity and HDRS scores significantly decreased following a 6-week antidepressant treatment period. Significantly greater vascular improvements were seen among full responders to treatment (HDRS scores reduced by 50%) as compared with partial responders indicating that patients’ degree of improvement in arterial stiffness was related to the degree of reduction of depressive symptoms. Interestingly, clinical features such as illness duration, number of previous episodes, melancholic or psychotic features or electroconvulsive therapy did not alter the results. Taken together, these results suggest that clinically acute MDE may have a short-term effect on the vascular wall, which results in increased arterial stiffness possibly explaining some of the associations observed between CVD and depression.141


The association between CVDs and depression using the latter as a single diagnostic entity is well established and suggested to be bidirectional.5 With regard to subtypes of depression the association is less clear, but seems to vary in its strength by subtype. Also, reviews investigating if biological mechanisms implicated in the association between CVD and depression defined as a single entity would also apply to the various subtypes of depression are lacking. Thus, the aim of this review was to determine if a differential involvement of biological mechanisms for subtypes of depression is evident in the published literature and if so, if this contributes to explain differences in the strength of the association between CVD and depression subtypes.

This review suggests a dose-response relationship between the increasing severity of depressive symptoms and immune activation as well as HPA axis hyperactivity. It also found evidence that these two mechanisms are differently involved in the relationship with CVD depending upon depression subtype.20, 21, 24, 25, 72, 81, 88, 89, 142, 143 However, the identification of a subtype-specific functional pattern for both mechanisms is not possible at this stage as study results are inconsistent. Other mechanisms such as arterial stiffness or endothelial dysfunction, which also are involved in the relationship between the disease entity depression and CVDs have not been investigated in subtypes of depression, with the notable exemption of BD.66 The inconsistent study results are likely to be explained by the respective studies’ limitations in terms of design factors and inconsistent methodologies. Many of the studies investigating biological mechanisms used samples that were small in number and heterogeneous in clinical and demographic participant characteristics such as severity of symptoms, duration of illness, number of comorbidities and histories of pharmacological and psychological therapies. They also varied significantly in the instruments and criteria used to classify depression, and techniques utilized in the measurement of biological markers. Another problem in the comparison of results is the variation in the delay between occurrence of CVD and assessment of depression and the heterogeneity in severity of CVDs. The paucity of longitudinal studies with a repeated assessment of both disease status is another limitation of reported studies.

On the other hand, and despite some overlap, the group of ‘CVDs’ is also heterogeneous with different clinical characteristics, risk factors and prognoses. The vast majority of studies examined myocardial infarction as an endpoint within the group of CVDs when studying the association with depression, and the number of studies reporting on other cardiovascular endpoints is considerably smaller. At least two of the biological mechanisms described above, arterial stiffness and endothelial dysfunction, are established steps in the pathophysiological cascade of disease development and could be considered endpoints in themselves. Thus, for a better understanding of a causal relationship it is not only necessary to differentiate between subtypes of depression but also between cardiovascular endpoints. An alternative approach for the latter is the analysis of the relationships of subtypes of depression with subclinical disease, for example, intima-media-thickness or vascular brain lesions such as white matter lesions and lacunar infarcts, or, to study the association between subtypes of depression and specific biological mechanisms directly. The latter is possible for some of the discussed mechanisms, for example, arterial stiffness, endothelial dysfunction and to some extent the activation of the immune system and dysfunction of the HPA axis. These analyses, however, have to be prospective in design with repeated assessments of the clinical disease status as well as the subclinical or biological surrogates. The differences in the strength of associations between specific subtypes of depression and CVDs, as reported in the literature, suggests that different biological mechanisms might be involved in mediating these associations. This assumption would enable researchers to describe distinct (patho-) physiological profiles for subtypes of depression.

The implications for psychological treatment in reducing CVD mortality have also been raised. It has been suggested that if depression does indeed cause an increase in CVD mortality, then one would expect to see a reduction in mortality following psychological intervention. However, recent studies have not confirmed this expectation.144, 145 Additionally, although depression may be a factor that predisposes a patient to the development of CVD, it may not necessarily be the factor that maintains the development of CVD. Systemic immune activation may be stimulated by one depressive episode and ongoing regardless of the episode going into remission through treatment. Very little research has investigated inflammation and depression longitudinally. Moreover, a different concept may be required for elderly patients among whom vascular depression is commonly seen.

A concept that applies a differential model of CVD and depressive subtypes may be more appropriate compared with a unifying model of depression used in the past. Research moving beyond the unifying model and assessing both single CVDs and depressive subtypes longitudinally may enhance efforts to unravel causes and mechanisms of the bidirectional relationship between CVD and depression. Such research would potentially lead to the development of timely and appropriate measures for detection, prevention and treatment for CVD and depression.