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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 35-46

The depressed heart


1 Department of Psychiatry and Neuroscience & Physiology, College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
2 Department of Psychiatry and Neuroscience & Physiology, College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA; Department of Psychiatry, School of Medicine, Flinders University, Australia

Date of Submission25-Jul-2019
Date of Acceptance28-Aug-2019
Date of Web Publication25-Nov-2019

Correspondence Address:
Dr. Seth W Perry
College of Medicine, SUNY Upstate Medical University, Syracuse, NY
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/hm.hm_13_19

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  Abstract 

Our appreciation and understanding of the interrelationships between disrupted metabolic function and depression have increased significantly over the last few decades. This review focuses still more specifically on the intersections between cardiovascular disease (CVD) and major depressive disorder (MDD). General pathophysiological mechanisms implicated in both diseases include inflammation, cytokine and hypothalamic–pituitary–adrenal axis dysregulation, oxidative stress, neurotransmitter disruptions, neuroplasticity, and the microbiome. Here, we explore these mechanistic overlaps of depression and CVD, including some discussion of related and frequently comorbid disorders, such as obesity and diabetes, and the closely related “metabolic syndrome.” Finally, we discuss integrated therapeutic strategies for treating MDD comorbid with CVD.

Keywords: Cardiovascular disease, depression, diabetes, hypothalamic–pituitary–adrenal axis, inflammation, metabolic syndrome, microbiota, monoamines, obesity


How to cite this article:
Perry SW, Licinio J, Wong ML. The depressed heart. Heart Mind 2019;3:35-46

How to cite this URL:
Perry SW, Licinio J, Wong ML. The depressed heart. Heart Mind [serial online] 2019 [cited 2022 Oct 2];3:35-46. Available from: http://www.heartmindjournal.org/text.asp?2019/3/2/35/271525


  Introduction Top


Until recently, the etiopathogeneses and treatment of seemingly disparate conditions such as major depressive disorder (MDD) and cardiovascular disease (CVD) were primarily considered separately. At least as early as the 1950s or 1960s, there was US and international literature suggesting possible relationships between depression and cardiovascular function or CVD. One interesting early study found altered blood–brain barrier (BBB) permeability in depressed cases that returned to normal as the depression resolved.[1] A 1953 case report in the New England Journal of Medicine drew possible connections between depression and cardiac failure.[2] Moreover, some classes of antidepressants, particularly the tricyclic antidepressants (TCAs), have long been understood to have cardiac effects and risks,[3],[4],[5],[6] particularly in those with CVD.[4],[7],[8] (Herein, we define CVD broadly, to encompass any aberrant or pathologic condition or function of the heart or cardiovascular system).

However, a more complete picture of the scope and significance of the functional interrelationships and shared mechanisms between MDD and CVD has only begun to emerge over the last decade or two, as evidenced by a PubMed default keyword search for “depression” and “cardiovascular.” Indeed, depression is associated with increased risk of CVD, and vice versa, leading to increased morbidity and mortality when the conditions are comorbid, with many expected shared pathophysiologic mechanisms.[9],[10],[11],[12],[13],[14],[15] We refer the reader to a number of excellent reviews that have covered the depth and breadth of this topic in more detail than we can here.[10],[11],[16],[17],[18] In this review, we highlight some key concepts and discuss the epidemiological and functional links between MDD and CVD, organized around shared genetics, obesity and type 2 diabetes mellitus (T2D), the various components of metabolic syndrome (MetS) (e.g., dyslipidemia and hypertension), the gut microbiota, and integrated therapeutic strategies, as they relate to comorbid CVD and MDD.


  Shared Genetics of Cardiovascular Disease and Major Depressive Disorder Top


Meta-analyses of numerous genome-wide association studies have associated depression or mood disorders with many genes linked to particular aspects of CVD, a few of which include the genes for methylenetetrahydrofolate reductase (blood pressure); calcium voltage-gated channel subunit alpha 1 D (blood pressure and hypertension); RE1-silencing transcription factor (coronary artery disease); FTO (high-density lipoprotein [HDL] cholesterol or triglycerides); neurocan (NCAN) (total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol); GSK-3β (HDL cholesterol); and apolipoprotein E (HDL, LDL, and total cholesterol).[19] In addition to the above genes associated with both depression and particular aspects of cardiovascular function, other genes were identified that are more broadly associated with both risk of cardiometabolic diseases such as obesity and T2D and mood disorders.[19] All of these genes and the biological pathways in which they were enriched are shown in [Figure 1]. These identified genes highlight the many known and yet-to-be-discovered mechanistic overlaps between the pathophysiologies of MDD, CVD, obesity, and T2D, as well as potential targets for integrated therapies.
Figure 1: Network of genes and enriched canonical signaling pathways implicated in cardiometabolic depressive disorders and disease risks. The list of 24 CMMDh genes (left), genes enriched to the top canonical signaling pathways (middle), and the network of these genes with mood disorders and the CMD-Rs (right) are depicted. In the right, it illustrates the ingenuity IPA-generated network of the CMMDh genes with coronary artery diseases, hypertension, diabetes mellitus, obesity, depressive disorder, and bipolar disorder. The colored dotted lines highlight CMMDh genes that were related to bipolar disorder (orange) and depression (red). The figure and legend are reprinted without modification from[19] under a Creative Commons Attribution 4.0 International License (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/). CMMDh = Cardiometabolic Mood Disorders hub genes, IPA = Ingenuity Pathway Analysis, CMD-R = Cardiometabolic Diseases Risk

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  Common Biology of Obesity, Type 2 Diabetes Mellitus, Cardiovascular Disease, and Major Depressive Disorder Top


Depression has been most consistently and strongly linked to three significant cardiometabolic disease states: obesity, T2D, and CVD. Numerous pathophysiologic mechanisms are shared between these prevalent metabolic conditions and depression, i.e., inflammation, cytokine and hypothalamic–pituitary–adrenal (HPA) axis dysregulation, oxidative stress, neurotransmitter disruptions, neuroplasticity, and the gut microbiota, a few of which are highlighted here.

Shared risk factors and common comorbidities

Reciprocal meta-analyses of 8 and 9 longitudinal studies, respectively, showed that obesity at the baseline was associated with a 1.55-fold increase in MDD incidence at follow-up, and depression at the baseline was associated with 1.58 times increased risk of developing obesity.[20] Similarly, depressed individuals are more likely to have T2D,[21] and those with T2D are more likely to be depressed,[22] which may establish a similar self-amplifying feedback loop. T2D is also associated with a two-fold increase in clinical MDD risk, and MDD comorbid with T2D is linked to poor glycemic control, higher mortality rates, and perhaps increased CVD risk.[23] Obesity and MetS are known risk factors for developing insulin resistance and T2D, as well as for CVD, and T2D and obesity are frequently associated with and often likely contribute significantly to CVD. Individuals with CVD are also more likely to be depressed,[11] and those with MDD have increased risk of CVD with higher mortality and morbidity and poorer treatment responses.[10],[11] These four conditions are seemingly so intertwined as to render the “chicken or egg” question irrelevant, with many common pathobiological mechanisms likely contributing to all four conditions.

Molecules and pathways

[Figure 1] depicts many of the molecules and pathways that have been implicated in both MDD and one or more cardiometabolic disorders, with many expected to play roles in all four discussed here [Table 1].[19] Excluding those genes/molecules and pathways already shown in [Figure 1], other molecules of interest implicated (in human and/or animal models) in both depression and one or more cardiometabolic disorders include norepinephrine, neuropeptide Y (NPY), melanocortin-4 receptor (MC4), urocortin, melanin-concentrating hormone, galanin, adiponectin, ghrelin, cocaine- and amphetamine-regulated transcript, orexins, cholecystokinin, bombesin, growth hormone, glucagon-like peptide-1, uncoupling proteins 2 and 3, beta-adrenergic receptors, nuclear factor kappa B and other transcription factors, beta-catenin, tumor necrosis factor (TNF, also known as TNF alpha), interleukins (ILs), and insulin.[24] These and the molecules and pathways depicted in [Figure 1] are involved in HPA axis, neuroimmune, and endocrine regulation; central nervous system (CNS) and peripheral pro- and anti-inflammatory effects; synaptic transmission and function; appetite regulation; immune cell and system responses; gene transcription; energy production; respiration; and protein packaging and transport. There is considerable cross talk between these molecules and systems, and on the whole, self-amplifying feedback loops may develop at the molecular and behavioral levels.{Table 1}

To highlight one example, insulin resistance and glucose dysregulation may have direct functional and metabolic consequences both on the brain, impacting depression, and on the periphery, impacting CVD. Glucose is the critical fuel for the brain and synaptic transmission; either too little or too much of this crucial nutrient in the brain has been linked to MDD, dementia, and a variety of neurodegenerative and peripheral diseases.[25],[26] Similarly, insulin, the key molecule involved in systemic glucose homeostasis, regulates both brain function and systemic metabolism, and insulin resistance or dysregulation in the brain has likewise been linked to MDD, cognitive dysfunction, and other neurologic diseases.[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40] In the periphery, insulin dysregulation is expected to be a direct contributor to the primary and secondary effects of CVD and related cardiometabolic pathologies.[41]

The monoamines in major depressive disorder and cardiovascular disease

The monoaminergic neurotransmitters (monoamines) include: the catecholamines dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline); the tryptamine serotonin; and histamine. Monoamines are key mediators of both neurologic and cardiovascular function in health and disease and have long been understood to play critical roles in MDD (and more recently in cardiometabolic disorders). The vast majority of antidepressant drugs are believed to exert their therapeutic effect via one or more of these circuits. Moreover, at various points in the CNS, HPA axis, and microbiota–gut–brain axis, the monoaminergic circuits act either directly or in concert with many of the immune and endocrine molecules discussed herein to regulate food intake, adiposity, metabolism, and body weight.[42],[43],[44],[45] Cardiometabolic disorders are also associated with inflammatory responses and higher levels of circulating cytokines, which, in turn, play significant roles in modulating monoamine and other neurotransmitter signaling linked to both MDD and obesity.[46] The monoamines are likewise key modulators of cardiac and cardiovascular function,[47],[48] and thus aberrant monoamine signaling can impact cardiovascular and cardiometabolic function, and may conceivably contribute to the pathophysiology of CVD. Accordingly, monoamine oxidase (MAO) inhibitors, a class of antidepressants, are generating interest as attractive potential therapies for CVD.[49]

Finally, one major theory of depression, the “network” theory, posits that reduced neurogenesis and/or neuroplasticity are significant contributors to depression and that antidepressants' therapeutic action results from increasing monoamine levels, which, in turn, enhances neurogenesis and neuroplasticity to reduce MDD.[50] Intriguingly, neuroplasticity has been emerging recently as a likely mediator of diabetic[51] and CVD[52] pathophysiologies, and many of the molecules and pathways identified in [Figure 1] and section “molecules and pathways” have known roles in neuroplasticity. BDNF, for example, is a well-known regulator of neurogenesis and neuroplasticity that is implicated in the regulation of food intake and obesity,[53] MDD,[54] MDD comorbid with obesity,[55],[56],[57] cardiovascular function and CVD,[58] and T2D.[59] Fat mass and obesity-associated (FTO) gene variants have been linked with the risk of depression and comorbid obesity[60],[61],[62] as well as T2D,[63] CVD,[64],[65] and other cardiometabolic conditions,[66],[67] and FTO is expressed in adult neural stem cells and neurons and regulates adult neurogenesis in mice,[68] which presents an intriguing link to the neurogenesis theory of depression. Together these studies make FTO an attractive therapeutic target candidate for treating depression comorbid with CVD and cardiometabolic disorders. These many pleiotropic connections highlight mechanisms by which monoamines and other signaling pathways may contribute to the shared pathology of depression, CVD, and cardiometabolic diseases.

Hypothalamic–pituitary–adrenal axis

The HPA axis is one of the four major neuroendocrine systems and, along with the sympathetic nervous system (SNS), is one of two major neuroimmune interfaces that bi-directionally mediate the physiologic and functional responses to stress, and participate in the regulation of cardiovascular function.[69] A detailed overview of the HPA axis is beyond the scope of this review, but it has been expertly covered elsewhere,[70],[71],[72] as have the mechanistic and functional links between the HPA axis, MDD, obesity,[73],[74],[75],[76] cardiovascular regulation,[69] and cardiovascular risk in those with mood disorders.[12],[17],[70],[77]

For this review, the critical point is that many of the molecules evidenced to participate in the shared biology of depression, CVD, and cardiometabolic diseases will act, at least in part (and sometimes exclusively), via the HPA axis. Hyperactivation of the HPA axis can occur through numerous mechanisms including physical or emotional stressors and leads to elevated cortisol levels, which, in turn, have been shown to promote depression, obesity, and other cardiometabolic diseases and various cardiovascular risks and disorders. Some of the earliest evidence that excess cortisol was related to comorbid depression, obesity, and cardiovascular dysfunction comes from clinical observations of Cushing's syndrome, which is caused by a pathological hypercortisolemia and typically accompanied by symptoms of obesity, MDD, and other metabolic disruption including glucose intolerance, dyslipidemia, and hypertension. There are numerous pleiotropic and tightly intertwined downstream mediators in these effects, and we discuss a few of them briefly in sections “adipose system, glucocorticoids, leptin, and inflammation in depression and cardiovascular disease” and “gut microbiota.”

Adipose system, glucocorticoids, leptin, and inflammation in depression and cardiovascular disease

Far from being a passive depot for fat storage, the adipose system is now understood to be a complex and dynamic array consisting of adipocytes (fat cells), immune cells, blood vessels, and other architectural components that act in concert to regulate metabolic and inflammatory processes as they impact health and disease.[78],[79] Inflammatory mechanisms originating from adipose tissue and obesity phenotypes have earned newfound importance as likely contributors to conditions ranging from cancer to psychiatric disease, including depression and CVD. In the periphery, elevated cortisol is believed to contribute to obesity by glucocorticoid-mediated upregulation of pathways involved in adipogenesis and fat deposition.[80] In the brain, glucocorticoids stimulate food intake by interacting with several appetite-regulating targets in the arcuate nucleus of the hypothalamus: in this region, they increase adenosine monophosphate-activated protein kinase signaling and upregulate expression of the orexigenic NPY and agouti-related peptide (AGRP).[81] This dysregulation of adipose tissue and consequent adipo-inflammatory mechanisms are increasingly shown to play critical roles in the development of CVD,[82],[83],[84],[85],[86],[87] although with complex and sometimes paradoxical effects depending on the location and type of adipose tissue, together with the type and state of the CVD.[86],[88],[89],[90]

Glucocorticoids also help regulate leptin, the first identified “adipokine,” i.e., cytokine-like hormones produced by adipose tissue that regulate physiologic processes such as food intake, energy metabolism, insulin sensitivity, reproduction, stress responses, bone growth, and inflammation,[91] with known roles in obesity, MDD, and CVD. Leptin released into the circulatory system by adipose tissue crosses the BBB, after which it binds to leptin receptors in the hypothalamus, the primary brain center for regulating food intake and body weight.[92] Typically, leptin acts as an anorexigenic adipokine, serving to decrease food intake (it signals satiety and suppresses appetite) and increase energy expenditure to maintain body fat stored at normal levels.[92] However, activated hypothalamic leptin receptors can either directly or indirectly induce downstream expression of various anorexigenic (e.g., POMC, CRH, and BDNF) and orexigenic (e.g., NPY, AGRP, and orexin) peptides,[92] so leptin may have pleiotropic effects that are ultimately dependent on the net result of all activated pathways. Glucocorticoids stimulate leptin release from adipocytes, yet also promote leptin resistance in the brain,[81] so they too can also exert opposing effects on leptin pathways. The anorexigenic hormone ghrelin, secreted by the stomach and produced by some neurons in the brain, is one of the primary appetite-stimulatory signals and likely interplays bidirectionally with leptin pathways to regulate food intake and body fat.[92],[93]

In 1997, Montague etal. discovered that congenital leptin deficiency in humans was associated with severe early-onset obesity,[94] and innate or acquired leptin resistance is associated with more common forms of obesity.[95] Obese individuals without congenital leptin deficiency (a rare condition) have high circulating leptin levels which are directly correlated with adiposity (fat mass) and develop leptin resistance (akin to the insulin resistance that develops in pre-Type 2 diabetes).[96] For this reason, leptin-replacement therapy has been astonishingly effective at normalizing weight and metabolic profiles in those with congenital leptin deficiency, but less so in patients with common obesity.[95] We and others have since discovered that leptin mediates or influences all components of MetS including obesity, dyslipidemia, insulin sensitivity, glucose homeostasis, and blood pressure,[96],[97],[98] and leptin is now recognized as a significant player in cardiovascular health and disease.[99],[100],[101],[102],[103],[104] Leptin deficiency is linked to depression and antidepressant resistance in humans and animals, and leptin has antidepressant effects that have been shown to involve glucocorticoids, GSK-3β, β-catenin, synaptic plasticity, neurogenesis, glutamate, and dopamine.[105],[106],[107],[108],[109],[110],[111]

Beyond leptin, our understanding of how the HPA axis and these other molecular players impact MDD and cardiometabolic disease comorbidities is expanding. Cortisol, glucocorticoids, leptin, ghrelin, NPY, AGRP, BDNF, and numerous pro- and anti-inflammatory cytokines have all been implicated in the pathophysiology of both depression and cardiometabolic diseases. Numerous studies have demonstrated that individuals with MetS have a higher prevalence of depression, and individuals with depression are more likely to have MetS.[112],[113],[114] Depression may lead to a vicious cycle of HPA axis hyperactivation and consequent hypercortisolemia, leading to increased MetS, which further amplifies depression and CVD. Cortisol itself may promote depression directly via inhibitory actions on serotoninergic systems in the brain.[70] Obesity is characterized by a chronic, low-grade inflammatory state and release of pro-inflammatory cytokines and adipokines from adipose tissue, which can promote depression via stimulation of the HPA axis or by direct molecular actions.[74],[75] For example, pro-inflammatory cytokines such as IL6 and TNF are known players in synaptic regulation, mediate sickness behavior, and are increasingly believed to contribute to both depression pathology[54] and CVD.[115],[116],[117] These and similar molecules are also implicated in neurodegeneration and neurodegenerative disorders and thus may contribute to the hippocampal neurodegeneration found in depressed subjects.[50],[54] We refer the reader to other reviews for detailed coverage of these topics.[46],[73],[113],[118],[119],[120],[121],[122],[123],[124]

Gut microbiota

The gut microbiota, i.e., the sum of all microorganisms in the gut, is a chief component of the microbiota–gut–brain axis, a bidirectional communication network consisting of the microbiota, gut, CNS (brain and spinal cord), autonomic and enteric nervous systems, and HPA axis, that serves to regulate metabolic and physiologic processes, and in recent years, it has become a significant topic of interest as a previously unappreciated mediator of both peripheral and CNS health and disease. A detailed appreciation of the microbiota–gut–brain axis is beyond the scope of what we can cover here (instead see[125],[126],[127],[128],[129] for recent coverage of this topic), but it involves many of the same hormonal, immune, and molecular neural signals as described throughout herein. [Figure 2] illustrates the various components of the microbiota–gut–brain axis and provides a top-level overview of the key bidirectional signaling networks [Figure 2]a, which when disrupted can lead to a variety of metabolic and psychiatric conditions including depression, CVD, and cardiometabolic disorders [Figure 2]b.
Figure 2: The microbiota–gut–brain axis in depression and cardiometabolic disease. (a) Direct and indirect pathways comprise the bidirectional interactions between the gut microbiota and the central nervous system, involving endocrine, immune, and neural signaling. Afferent pathways signaling to the brain (up arrows) include (1) peripheral lymphocytes or other immune cells that release pro- or anti-inflammatory cytokines which can have endocrine or paracrine actions; (2) sensory nerve terminals, such as on the vagus nerve, may be activated by gut peptides released by enteroendocrine cells; and (3) neurotransmitters emanating from the gut, such as serotonin synthesized and released by enterochromaffin cells (an enteroendocrine cell subtype), also have endocrine and paracrine effects in both the central nervous system and periphery; (4) in the central nervous system, after the brainstem relays (e.g., the solitary nucleus), the amygdala (Am) and insular cortex integrate visceral inputs and hypothalamic activation initiates the efferent arm (down arrows) whereby (5) hypothalamic–pituitary–adrenal axis activation releases corticosteroids (e.g., cortisol) which effect many actions as described in this review, and can also modulate gut microbiota composition; and (6) activation of neuronal efferents releases neurotransmitters with a variety of effects on the periphery, including modulation of the gut microbiome. (b) Loss of homeostasis in one or more of these pathways is believed to contribute to numerous disease conditions, including but not limited to depression, obesity, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease, as we detail herein. The figure and legend are reprinted with modifications from[152] under the Creative Commons Attribution License (CC BY) (https://creativecommons.org/ licenses/by/3.0/)

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With these many shared effector pathways, the microbiota has recently been ascribed putative roles in obesity, T2D,[130] CVD,[131],[132],[133],[134],[135],[136],[137],[138],[139],[140] and MDD, as well as numerous other neurologic, psychiatric, and peripheral diseases.[141],[142],[143],[144],[145] For example, colleagues and we recently reported that the gut microbiota mediates depressive-like behavior in a mouse model,[146] effects which may be regulated by inflammasome signaling via caspase-1.[147] Another mouse study demonstrated that consumption of Lactobacillusrhamnosus bacteria reduced anxiety- and depression-related behavior and stress-induced corticosterone levels and altered gamma-aminobutyric acid receptor expression (mRNA levels) in several brain regions relevant to depression.[148] Moreover, as the authors state very nicely: “Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus nerve as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the microbiota-gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.”[148] This study illustrates one of the many ways by which gut microbiota may contribute to the functional and synaptic pathophysiology of depression via these closely intertwined pathways. Likewise, the gut microbiota has generated much attention in recent years for its role in cardiovascular function and disease, and we refer readers to several reviews for much more comprehensive coverage of this complex topic.[131],[132],[133],[134],[135],[136],[137],[138],[139],[140] Also linked closely with CVD, and a common MDD comorbidity, is obstructive sleep apnea (OSA). Recent studies are connecting changes in the gut and nasal microbiomes with OSA and altered immunoinflammatory pathways.[149],[150],[151] Thus, the microbiome and inflammation and their consequent downstream effects on neurovascular and synaptic function may be common mechanisms and pathways that link depression, the microbiome, CVD, and OSA.


  Metabolic Syndrome and Depression Top


Closely intertwined with obesity and T2D, and also strongly linked with depression, is “MetS” – a collection of aberrant physiologic parameters including obesity, unfavorable lipid profiles (e.g., high triglyceride and/or low HDL cholesterol levels), high blood pressure, and high blood glucose (insulin resistance) – that when present together or in combination significantly increase one's risk for developing diabetes, CVD, and related conditions.[153],[154],[155],[156],[157],[158],[159],[160],[161],[162],[163],[164] Several additional connections have been made between depression and the CVD-specific elements of MetS.

Cholesterol and lipids

The links between depression and genes related to lipid metabolism are particularly intriguing, because cholesterol and lipids are central components of cellular and neuronal membranes, and thus are critical regulators of neuronal and synaptic health and function.[165],[166],[167],[168],[169],[170] Not surprisingly then, there is substantial evidence that dyslipidemia can, at minimum, be correlated with depression, suicidality, and other psychiatric diseases.[171] However, the findings in this area are too nuanced to allow for simplistic conclusions such as “any dyslipidemia associated with MetS, e.g., high total cholesterol, high triglycerides, low HDL/LDL, or HDL/total cholesterol ratios, is positively correlated with depression.” In fact, albeit with some exceptions that have reported positive or no associations between lipid levels and depression or suicide, most reports have found that total and individual serum lipid levels (i.e., cholesterol, triglycerides, HDL, and LDL) are negatively correlated with depression and suicidality, that is, lower across the board in depressed or suicidal patients versus controls.[171],[172] This general finding is consistent with substantial other literature that has reported deficits in key synaptic lipids, e.g., multiple species of phosphatidylcholine and sphingomyelin in one example,[173] associated with depression and other psychiatric diseases.[171],[174],[175] In other words, lower levels of various broad lipid types appear to correlate with deficits in key lipid subspecies that are critical to maintaining synaptic homeostasis.

At the same time, although low HDL (“good”) cholesterol levels have consistently been linked to depression and suicidality (consistent with this model), the picture for LDL cholesterol and depression has been far more heterogeneous.[176] We expect, and there is some evidence[177] to suggest that these inconsistencies likely result from the immune-inflammatory response seen in depression, which would tend to drive HDL levels down and LDL levels up.

Many studies have linked deficits in key neuronal and synaptic lipid species to changes in neurotransmitter signaling.[171],[174],[175] In animal models, lower brain levels of polyunsaturated fatty acids such as docosahexaenoic acid (DHA) correlate with lower serotonin (5-HT), and higher 5-HT2A receptor levels, which is consistent with reduced 5-HT and increased 5-HT2A found in postmortem brains of depressed patients and individuals dying by suicide.[174] Likewise, other human studies have consistently found lower DHA levels in depression- or suicide-relevant areas of the brains of depressed individuals.[174] 5-Hydroxyindoleacetic acid (5-HIAA, a 5-HT metabolite that correlates with 5-HT levels) levels were lower in suicide attempters versus controls.[178] Similar results have been found for multiple other types of lipid or fatty acid compounds, and other neurotransmitter systems involved in MDD.[174],[175] Overall, the data support the general principles that deficits of key neuronal and synaptic lipids may casually contribute to depression and other psychiatric diseases, as one might anticipate given lipids' critical roles in neuronal function.

Blood pressure

Blood pressure control is influenced by the SNS, HPA-axis, and immune-inflammatory molecules and mechanisms. Recent evidence also implicates the microbiota in hypertension[179],[180] and hypertension comorbid with obesity.[181] Studies on the relationships between depression and blood pressure or hypertension have shown variable results. Some reports have found increased hypertension risk for MDD subjects, whereas others have found the opposite. Conversely, some longitudinal studies have reported that low BP at the baseline is predictive for later depressive symptoms, whereas other such studies concluded that high BP at the baseline predicts later depression. Hypertension is a significant risk factor for CVD, and the studies of connections between depression and CVD have been less dichotomous. However, whether hypertension promotes depression or vice versa and whether similar mechanisms promote both independently remain open questions.

Several observations may help explain these often conflicting findings. First, activation of the SNS is a hallmark of hypertension,[182] and Barton etal. reported a distinctly bimodal distribution of SNS activity in MDD patients, with one subset having lower SNS activity versus nondepressed individuals and the other MDD subset having higher SNS activity versus normal controls.[183] This finding alone could explain the apparent variable associations between depression and hypertension. Furthermore, different types of antidepressants[184] can have opposing effects on blood pressure, which makes medication status another critical factor that likely contributes to this observed variability. While further research is needed to clarify precisely how blood pressure and hypertension relate to depression risk, the critical point is that as for other elements of CVD, cross talk between the same molecular pathways of the SNS, HPA axis, immuno-inflammation, and the gut microbiota, can be expected to influence both hypertension and depression morbidity in ways that are likely reciprocal, and may be causal.

Depression and noncardiovascular disease cardiac risk

Depression also increases the risk for several acute cardiac abnormalities not related to CVD or coronary artery disease – such as Takotsubo cardiomyopathy (also known as “broken heart syndrome”) and sudden cardiac death – likely through similar triggers, mechanisms, and pathways that include extreme (and often acute) emotional or physical stress or distress, SNS hyperactivity, and/or catecholamine overload.[185],[186] Hence, similar mechanisms may also link depression with non-CVD-related cardiac risks.


  Are Integrated Therapies the Future? Top


Based on existing knowledge, some have already suggested integrated therapeutic strategies for treating MDD comorbid with various metabolic diseases, including CVD.[54],[187] Here, we define “integrated therapies” as a single drug or combination of drugs expressly indicated to simultaneously benefit two or more conditions, such as MDD comorbid with CVD (obesity and T2D). For example, SSRIs (selective serotonin reuptake inhibitors) may be an optimal pharmacological treatment for depression in patients with CVD, for their apparent beneficial (and fewer adverse) effects on myocardial infarction risk, ischemia–reperfusion injury, reduced platelet aggregation, and atherosclerosis compared to other antidepressants such as tricyclics.[54] More specifically, it has been suggested that “Due to its low risk of drug-drug interactions, adverse effect profile and potential for beneficial antiplatelet activity, sertraline could be considered the choice antidepressant for patients with ischemic heart disease.”[188] Similarly, SSRIs may be a good option for diabetes comorbid with depression, for their favorable effects on glycemic control compared to other types of antidepressants.[54],[189],[190] On the other hand, these effects must be monitored closely, as in some cases, SSRIs or other antidepressants may contribute to hypoglycemia in people with diabetes.[191],[192]

SSRIs may also induce weight loss in the short term,[42] but may lead to long-term weight gain, especially in conjunction with a sedentary lifestyle.[193] The 5-HT2C selective serotonin receptor agonist lorcaserin,[194] and the norepinephrine–dopamine reuptake inhibitor antidepressant bupropion in combination with the opioid receptor antagonist naltrexone,[195] are both believed to have anorexigenic actions in the hypothalamus, and are two of the relatively few drugs that have been Food and Drug Administration approved for weight loss.[196] Alternate emerging drug classes such as triple reuptake inhibitors may present new opportunities for simultaneously treating depression, eating disorders, obesity, and T2D,[197] but the need for development of additional novel integrated therapeutics remains. Herein we have highlighted numerous genetic and molecular targets evidenced to be involved in the pathophysiology of both depression and comorbid conditions─such as FTO's involvement in MDD, obesity, and CVD─thus making them attractive potential hits for the future development of integrated drug therapies.

In addition to weight gain, another frequent side effect with SSRIs, that is also common to and therefore may be further exacerbated by depression comorbidities such as T2D and CVD, is sexual dysfunction. In such cases, the comorbidities themselves and the side effects or exacerbations brought on by pharmacotherapies may arise by common mechanisms and pathophysiology. For example, both male and female sexual dysfunctions are common with obesity, CVD, MetS, and T2D,[198] and nitric oxide is one of many signaling mechanisms common to all these disorders. Intriguingly and perhaps not surprisingly in this context, while most drugs related to CVD (e.g., antihypertensives, diuretics, and beta-blockers) negatively impact sexual function, the beta-blocker nebivolol – which, like most erectile dysfunction (ED) drugs, increases nitric oxide availability and thus has favorable impacts on sexual function – has recently been demonstrated to protect against depressive-like behavior in rats.[199] Indeed, nitric oxide signaling is attracting increasing interest as a target for antidepressant therapies[200] and thus may be an attractive, newly developing integrated therapy for CVD comorbid with depression. Similarly, the hypoglycemic drugs such as metformin, pioglitazone, and liraglutide have shown favorable results for ED[198] and are all currently being evaluated as antidepressant therapies in humans and/or animal models.[201],[202],[203] These and similar studies highlight the growing need to harness and understand the complex interactions between MDD, its many comorbidities, and the drugs that treat them, to develop novel integrated therapies for comorbid depression, CVD, and metabolic disorders.

At the same time, we must pay close attention to the potential risks for adverse drug interactions that may arise with integrated therapies. MDD's long list of comorbidities, including CVD, means that many individuals are concomitantly taking numerous drugs. This rise in polypharmacy has led to growing evidence for relevant and nontrivial drug interactions with antidepressants that may have been previously unappreciated, particularly with drugs for depression's significant metabolic comorbidities.[188],[191] For example, SSRIs or other antidepressants may sometimes contribute to diabetic hypoglycemia.[191],[192] Some antidepressants can increase the risk for or exacerbate several aspects of CVD.[188],[191] For example, “Hypertension can be significant with serotonin norepinephrine reuptake inhibitors (SNRIs) and MAOIs. The potential for QT prolongation is present with TCAs, certain selective serotonin reuptake inhibitors (SSRIs), certain SNRIs and mirtazapine.”[188] These and similar findings[188],[191] highlight both the need for being acutely aware of potential drug interactions when prescribing other drugs concomitant with antidepressants and the clear need for more deliberately tailored integrated therapies for depression and its comorbidities.


  Conclusions Top


There is a tremendous need for novel therapies to treat depression comorbid with CVD and other cardiometabolic diseases. Herein, we have highlighted multiple new and emerging potential target molecules and pathways common to depression and comorbid pathologies that are ripe for further exploration, so that we may develop the most effective and comprehensive pharmacotherapies for treating depression in the context of CVD and cardiometabolic disorders, to help reduce morbidity and mortality from these significant and growing global health burdens.

Financial support and sponsorship

This work was supported by institutional funds from the State University of New York (SUNY) Upstate Medical University. This paper is subject to the SUNY Open Access Policy.

Conflicts of interest

There are no conflicts of interest.

Copyright Notice and Acknowledgement

This paper includes overlapping content and substantial portions of the text reproduced verbatim from our own previously written book chapter: Perry SW, Wong ML, Licinio J. General medical conditions: Metabolic disorders. In: Trivedi M, editor. Primer on Depression. Copyright 2019, Oxford University Press (online and in print). Reproduced with permission of the Licensor through PLSclear.

 
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