The depressed heart

Seth W Perry; Julio Licinio; Ma-Li Wong

doi:10.4103/hm.hm_13_19

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Year : 2019 | Volume : 3 | Issue : 2 | Page : 35-46

The depressed heart

Seth W Perry¹, Julio Licinio², Ma-Li Wong²
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 Submission	25-Jul-2019
Date of Acceptance	28-Aug-2019
Date of Web Publication	25-Nov-2019

Correspondence Address:
Dr. Seth W Perry
College of Medicine, SUNY Upstate Medical University, Syracuse, NY
USA

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/hm.hm_13_19

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 2023 Jun 6];3:35-46. Available from: http://www.heartmindjournal.org/text.asp?2019/3/2/35/271525

Introduction

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

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

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

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-HT_2A receptor levels, which is consistent with reduced 5-HT and increased 5-HT_2A 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?

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-HT_2C 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

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.

References

1.	Coppen AJ. Abnormality of the blood-cerebrospinal fluid barrier of patients suffering from a depressive illness. J Neurol Neurosurg Psychiatry 1960;23:156-61.
2.	Fish DJ, Dillon JA. Symptoms of depression in cardiac failure; report of a case. N Engl J Med 1953;249:493-4.
3.	Biamino G, Fenner H, Schüren KP, Neye J, Ramdohr B, Lohmann RW, et al. Cardiovascular side effects of tricyclic antidepressants – A risk in the use of these drugs. Int J Clin Pharmacol Biopharm 1975;11:253-61.
4.	Biamino G, Fenner H, Neye J, Schuren KP, Ramdohr B. Comparativein vitro andin vivo studies on the effects of tricyclic antidepressants on myocardial contractility. Recent Adv Stud Cardiac Struct Metab 1975;10:59-69.
5.	Glassman AH, Bigger JT Jr. Cardiovascular effects of therapeutic doses of tricyclic antidepressants. A review. Arch Gen Psychiatry 1981;38:815-20.
6.	Carney MW. Tricyclics and the heart. Br J Psychiatry 1979;134:637-9.
7.	Coull DC, Crooks J, Dingwall-Fordyce I, Scott AM, Wier RD. Amitriptyline and cardiac disease. Risk of sudden death identified by monitoring system. Lancet 1970;2:590-1.
8.	Kantor SJ, Glassman AH, Bigger JT Jr., Perel JM, Giardina EV. The cardiac effects of therapeutic plasma concentrations of imipramine. Am J Psychiatry 1978;135:534-8.
9.	Nemeroff CB, Goldschmidt-Clermont PJ. Heartache and heartbreak – The link between depression and cardiovascular disease. Nat Rev Cardiol 2012;9:526-39.
10.	Seligman F, Nemeroff CB. The interface of depression and cardiovascular disease: Therapeutic implications. Ann N Y Acad Sci 2015;1345:25-35.
11.	Hare DL, Toukhsati SR, Johansson P, Jaarsma T. Depression and cardiovascular disease: A clinical review. Eur Heart J 2014;35:1365-72.
12.	Halaris A. Co-morbidity between cardiovascular pathology and depression: Role of inflammation. Mod Trends Pharmacopsychiatry 2013;28:144-61.
13.	Bradley SM, Rumsfeld JS. Depression and cardiovascular disease. Trends Cardiovasc Med 2015;25:614-22.
14.	Whooley MA, Wong JM. Depression and cardiovascular disorders. Annu Rev Clin Psychol 2013;9:327-54.
15.	Elderon L, Whooley MA. Depression and cardiovascular disease. Prog Cardiovasc Dis 2013;55:511-23.
16.	Zhang Y, Chen Y, Ma L. Depression and cardiovascular disease in elderly: Current understanding. J Clin Neurosci 2018;47:1-5.
17.	Halaris A. Inflammation-associated co-morbidity between depression and cardiovascular disease. Curr Top Behav Neurosci 2017;31:45-70.
18.	Raič M. Depression and heart diseases: Leading health problems. Psychiatr Danub 2017;29 Suppl 4:770-7.
19.	Amare AT, Schubert KO, Klingler-Hoffmann M, Cohen-Woods S, Baune BT. The genetic overlap between mood disorders and cardiometabolic diseases: A systematic review of genome wide and candidate gene studies. Transl Psychiatry 2017;7:e1007.
20.	Samaan Z, Lee YK, Gerstein HC, Engert JC, Bosch J, Mohan V, et al. Obesity genes and risk of major depressive disorder in a multiethnic population: A cross-sectional study. J Clin Psychiatry 2015;76:e1611-8.
21.	Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan: A meta-analysis. Diabetes Care 2008;31:2383-90.
22.	Nouwen A, Winkley K, Twisk J, Lloyd CE, Peyrot M, Ismail K, et al. Type 2 diabetes mellitus as a risk factor for the onset of depression: A systematic review and meta-analysis. Diabetologia 2010;53:2480-6.
23.	Nouwen A. Depression and diabetes distress. Diabet Med 2015;32:1261-3.
24.	Licinio J, Wong ML. The interface of obesity and depression: Risk factors for the metabolic syndrome. Braz J Psychiatry 2003;25:196-7.
25.	van Praag H, Fleshner M, Schwartz MW, Mattson MP. Exercise, energy intake, glucose homeostasis, and the brain. J Neurosci 2014;34:15139-49.
26.	Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: The role of glucose in physiological and pathological brain function. Trends Neurosci 2013;36:587-97.
27.	Banks WA, Owen JB, Erickson MA. Insulin in the brain: There and back again. Pharmacol Ther 2012;136:82-93.
28.	Moulton CD, Pickup JC, Ismail K. The link between depression and diabetes: The search for shared mechanisms. Lancet Diabetes Endocrinol 2015;3:461-71.
29.	Straub RH. Insulin resistance, selfish brain, and selfish immune system: An evolutionarily positively selected program used in chronic inflammatory diseases. Arthritis Res Ther 2014;16 Suppl 2:S4.
30.	Ghasemi R, Dargahi L, Haeri A, Moosavi M, Mohamed Z, Ahmadiani A, et al. Brain insulin dysregulation: Implication for neurological and neuropsychiatric disorders. Mol Neurobiol 2013;47:1045-65.
31.	Detka J, Kurek A, Basta-Kaim A, Kubera M, Lasoń W, Budziszewska B, et al. Neuroendocrine link between stress, depression and diabetes. Pharmacol Rep 2013;65:1591-600.
32.	Holden RJ. The role of brain insulin in the neurophysiology of serious mental disorders: Review. Med Hypotheses 1999;52:193-200.
33.	Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Häring HU, et al. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol Rev 2016;96:1169-209.
34.	Werner H, LeRoith D. Insulin and insulin-like growth factor receptors in the brain: Physiological and pathological aspects. Eur Neuropsychopharmacol 2014;24:1947-53.
35.	Kullmann S, Heni M, Fritsche A, Preissl H. Insulin action in the human brain: Evidence from neuroimaging studies. J Neuroendocrinol 2015;27:419-23.
36.	Kleinridders A, Ferris HA, Cai W, Kahn CR. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 2014;63:2232-43.
37.	Gray SM, Meijer RI, Barrett EJ. Insulin regulates brain function, but how does it get there? Diabetes 2014;63:3992-7.
38.	Cetinkalp S, Simsir IY, Ertek S. Insulin resistance in brain and possible therapeutic approaches. Curr Vasc Pharmacol 2014;12:553-64.
39.	Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: Sources, localization and functions. Mol Neurobiol 2013;47:145-71.
40.	Derakhshan F, Toth C. Insulin and the brain. Curr Diabetes Rev 2013;9:102-16.
41.	Rask-Madsen C, Kahn CR. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2012;32:2052-9.
42.	Lee SH, Paz-Filho G, Mastronardi C, Licinio J, Wong ML. Is increased antidepressant exposure a contributory factor to the obesity pandemic? Transl Psychiatry 2016;6:e759.
43.	Halford JC, Cooper GD, Dovey TM. The pharmacology of human appetite expression. Curr Drug Targets 2004;5:221-40.
44.	Harrold JA, Dovey TM, Blundell JE, Halford JC. CNS regulation of appetite. Neuropharmacology 2012;63:3-17.
45.	Halford JC, Harrold JA. Neuropharmacology of human appetite expression. Dev Disabil Res Rev 2008;14:158-64.
46.	Felger JC, Lotrich FE. Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience 2013;246:199-229.
47.	Head GA. Central monoamine neurons and cardiovascular control. Kidney Int Suppl 1992;37:S8-13.
48.	McCall RB. Role of neurotransmitters in the central regulation of the cardiovascular system. Prog Drug Res 1990;35:25-84.
49.	Deshwal S, Di Sante M, Di Lisa F, Kaludercic N. Emerging role of monoamine oxidase as a therapeutic target for cardiovascular disease. Curr Opin Pharmacol 2017;33:64-9.
50.	Dean J, Keshavan M. The neurobiology of depression: An integrated view. Asian J Psychiatr 2017;27:101-11.
51.	Zheng Z, Wu J, Wang R, Zeng Y. Diabetes mellitus may induce cardiovascular disease by decreasing neuroplasticity. Funct Neurol 2014;29:7-13.
52.	Zheng Z, Zeng Y, Wu J. Increased neuroplasticity may protect against cardiovascular disease. Int J Neurosci 2013;123:599-608.
53.	Rosas-Vargas H, Martínez-Ezquerro JD, Bienvenu T. Brain-derived neurotrophic factor, food intake regulation, and obesity. Arch Med Res 2011;42:482-94.
54.	Lang UE, Borgwardt S. Molecular mechanisms of depression: Perspectives on new treatment strategies. Cell Physiol Biochem 2013;31:761-77.
55.	Lee IT, Fu CP, Lee WJ, Liang KW, Lin SY, Wan CJ, et al. Brain-derived neurotrophic factor, but not body weight, correlated with a reduction in depression scale scores in men with metabolic syndrome: A prospective weight-reduction study. Diabetol Metab Syndr 2014;6:18.
56.	Numakawa T, Richards M, Nakajima S, Adachi N, Furuta M, Odaka H, et al. The role of brain-derived neurotrophic factor in comorbid depression: Possible linkage with steroid hormones, cytokines, and nutrition. Front Psychiatry 2014;5:136.
57.	Kurhe Y, Mahesh R. Mechanisms linking depression co-morbid with obesity: An approach for serotonergic type 3 receptor antagonist as novel therapeutic intervention. Asian J Psychiatr 2015;17:3-9.
58.	Pius-Sadowska E, Machaliński B. BDNF – A key player in cardiovascular system. J Mol Cell Cardiol 2017;110:54-60.
59.	Eyileten C, Kaplon-Cieslicka A, Mirowska-Guzel D, Malek L, Postula M. Antidiabetic effect of brain-derived neurotrophic factor and its association with inflammation in type 2 diabetes mellitus. J Diabetes Res 2017;2017:2823671.
60.	Samaan Z, Anand SS, Zhang X, Desai D, Rivera M, Pare G, et al. The protective effect of the obesity-associated rs9939609 A variant in fat mass – And obesity-associated gene on depression. Mol Psychiatry 2013;18:1281-6.
61.	Milaneschi Y, Lamers F, Mbarek H, Hottenga JJ, Boomsma DI, Penninx BW, et al. The effect of FTO rs9939609 on major depression differs across MDD subtypes. Mol Psychiatry 2014;19:960-2.
62.	Rivera M, Locke AE, Corre T, Czamara D, Wolf C, Ching-Lopez A, et al. Interaction between the FTO gene, body mass index and depression: Meta-analysis of 13701 individuals. Br J Psychiatry 2017;211:70-6.
63.	Jiménez-Osorio AS, Musalem-Younes C, Cárdenas-Hernández H, Solares-Tlapechco J, Costa-Urrutia P, Medina-Contreras O, et al. Common polymorphisms linked to obesity and cardiovascular disease in Europeans and Asians are associated with type 2 diabetes in mexican mestizos. Medicina (Kaunas) 2019;55. pii: E40.
64.	Franczak A, Kolačkov K, Jawiarczyk-Przybyłowska A, Bolanowski M. Association between FTO gene polymorphisms and HDL cholesterol concentration may cause higher risk of cardiovascular disease in patients with acromegaly. Pituitary 2018;21:10-5.
65.	Liu C, Mou S, Pan C. The FTO gene rs9939609 polymorphism predicts risk of cardiovascular disease: A systematic review and meta-analysis. PLoS One 2013;8:e71901.
66.	Ganeff IM, Bos MM, van Heemst D, Noordam R. BMI-associated gene variants in FTO and cardiometabolic and brain disease: Obesity or pleiotropy? Physiol Genomics 2019;51:311-22.
67.	De Luis DA, Aller R, Izaola O, Primo D, Romero E. Association of the rs9939609 gene variant in FTO with insulin resistance, cardiovascular risk factor and serum adipokine levels in obese patients. Nutr Hosp 2016;33:573.
68.	Li L, Zang L, Zhang F, Chen J, Shen H, Shu L, et al. Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Hum Mol Genet 2017;26:2398-411.
69.	Burford NG, Webster NA, Cruz-Topete D. Hypothalamic-pituitary-adrenal axis modulation of glucocorticoids in the cardiovascular system. Int J Mol Sci 2017;18: pii: E2150.
70.	Haddad JJ, Saadé NE, Safieh-Garabedian B. Cytokines and neuro-immune-endocrine interactions: A role for the hypothalamic-pituitary-adrenal revolving axis. J Neuroimmunol 2002;133:1-9.
71.	Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 2006;8:383-95.
72.	Mitrovic I. Introduction to the Hypothalamo – Pituitary-Adrenal (HPA) Axis (Lecture). Availkable from: https://www.yumpu.com/en/document/view/5383668/introduction-to-the-hypothalamo-pituitary-adrenal-hpa-axis/8. [Last accessed on 2019 Oct 30].
73.	Bornstein SR, Schuppenies A, Wong ML, Licinio J. Approaching the shared biology of obesity and depression: The stress axis as the locus of gene-environment interactions. Mol Psychiatry 2006;11:892-902.
74.	Milaneschi Y, Simmons WK, van Rossum EF, Penninx BW. Depression and obesity: Evidence of shared biological mechanisms. Mol Psychiatry 2019;24:18-33.
75.	Bose M, Oliván B, Laferrère B. Stress and obesity: The role of the hypothalamic-pituitary-adrenal axis in metabolic disease. Curr Opin Endocrinol Diabetes Obes 2009;16:340-6.
76.	Lemche E, Chaban OS, Lemche AV. Neuroendorine and epigentic mechanisms subserving autonomic imbalance and HPA dysfunction in the metabolic syndrome. Front Neurosci 2016;10:142.
77.	Jokinen J, Nordström P. HPA axis hyperactivity and cardiovascular mortality in mood disorder inpatients. J Affect Disord 2009;116:88-92.
78.	Hotamisligil GS. Foundations of immunometabolism and implications for metabolic health and disease. Immunity 2017;47:406-20.
79.	Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature 2017;542:177-85.
80.	Lee MJ, Pramyothin P, Karastergiou K, Fried SK. Deconstructing the roles of glucocorticoids in adipose tissue biology and the development of central obesity. Biochim Biophys Acta 2014;1842:473-81.
81.	Sominsky L, Spencer SJ. Eating behavior and stress: A pathway to obesity. Front Psychol 2014;5:434.
82.	Chistiakov DA, Grechko AV, Myasoedova VA, Melnichenko AA, Orekhov AN. Impact of the cardiovascular system-associated adipose tissue on atherosclerotic pathology. Atherosclerosis 2017;263:361-8.
83.	Icli B, Feinberg MW. MicroRNAs in dysfunctional adipose tissue: Cardiovascular implications. Cardiovasc Res 2017;113:1024-34.
84.	Franssens BT, Westerink J, van der Graaf Y, Nathoe HM, Visseren FL; SMART Study Group. et al. Metabolic consequences of adipose tissue dysfunction and not adiposity perse increase the risk of cardiovascular events and mortality in patients with type 2 diabetes. Int J Cardiol 2016;222:72-7.
85.	Antoniades C. 'Dysfunctional' adipose tissue in cardiovascular disease: A reprogrammable target or an innocent bystander? Cardiovasc Res 2017;113:997-8.
86.	Aldiss P, Davies G, Woods R, Budge H, Sacks HS, Symonds ME, et al. 'Browning' the cardiac and peri-vascular adipose tissues to modulate cardiovascular risk. Int J Cardiol 2017;228:265-74.
87.	Guzik TJ, Skiba DS, Touyz RM, Harrison DG. The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res 2017;113:1009-23.
88.	Antonopoulos AS, Tousoulis D. The molecular mechanisms of obesity paradox. Cardiovasc Res 2017;113:1074-86.
89.	Akoumianakis I, Antoniades C. The interplay between adipose tissue and the cardiovascular system: Is fat always bad? Cardiovasc Res 2017;113:999-1008.
90.	Guglielmi V, Sbraccia P. Obesity phenotypes: Depot-differences in adipose tissue and their clinical implications. Eat Weight Disord 2018;23:3-14.
91.	Paz-Filho G, Wong ML, Licinio J. Ten years of leptin replacement therapy. Obes Rev 2011;12:e315-23.
92.	Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: A review. Obes Rev 2007;8:21-34.
93.	de Candia P, Matarese G. Leptin and ghrelin: Sewing metabolism onto neurodegeneration. Neuropharmacology 2018;136:307-16.
94.	Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903-8.
95.	Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: Facts and expectations. Metabolism 2015;64:146-56.
96.	Paz-Filho G, Mastronardi C, Franco CB, Wang KB, Wong ML, Licinio J, et al. Leptin: Molecular mechanisms, systemic pro-inflammatory effects, and clinical implications. Arq Bras Endocrinol Metabol 2012;56:597-607.
97.	Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, et al. Leptin mediates the increase in blood pressure associated with obesity. Cell 2014;159:1404-16.
98.	Paz-Filho G, Mastronardi C, Wong ML, Licinio J. Leptin therapy, insulin sensitivity, and glucose homeostasis. Indian J Endocrinol Metab 2012;16:S549-55.
99.	Bassi M, Furuya WI, Zoccal DB, Menani JV, Colombari E, Hall JE, et al. Control of respiratory and cardiovascular functions by leptin. Life Sci 2015;125:25-31.
100.	Belin de Chantemèle EJ. Sex differences in leptin control of cardiovascular function in health and metabolic diseases. Adv Exp Med Biol 2017;1043:87-111.
101.	Beltowski J. Leptin and the cardiovascular system – A target for therapeutic interventions. Curr Pharm Des 2014;20:601-2.
102.	Feijóo-Bandín S, Portolés M, Roselló-Lletí E, Rivera M, González-Juanatey JR, Lago F, et al. 20 years of leptin: Role of leptin in cardiomyocyte physiology and physiopathology. Life Sci 2015;140:10-8.
103.	Dong M, Ren J. What fans the fire: Insights into mechanisms of leptin in metabolic syndrome-associated heart diseases. Curr Pharm Des 2014;20:652-8.
104.	Bell BB, Rahmouni K. Leptin as a mediator of obesity-induced hypertension. Curr Obes Rep 2016;5:397-404.
105.	Lu XY. The leptin hypothesis of depression: A potential link between mood disorders and obesity? Curr Opin Pharmacol 2007;7:648-52.
106.	Garza JC, Guo M, Zhang W, Lu XY. Leptin increases adult hippocampal neurogenesisin vivo and in vitro. J Biol Chem 2008;283:18238-47.
107.	Guo M, Huang TY, Garza JC, Chua SC, Lu XY. Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours. Int J Neuropsychopharmacol 2013;16:857-67.
108.	Guo M, Lu XY. Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates. Transl Psychiatry 2014;4:e486.
109.	Guo M, Lu Y, Garza JC, Li Y, Chua SC, Zhang W, et al. Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression. Transl Psychiatry 2012;2:e83.
110.	Liu J, Perez SM, Zhang W, Lodge DJ, Lu XY. Selective deletion of the leptin receptor in dopamine neurons produces anxiogenic-like behavior and increases dopaminergic activity in amygdala. Mol Psychiatry 2011;16:1024-38.
111.	Milaneschi Y, Lamers F, Bot M, Drent ML, Penninx BW. Leptin dysregulation is specifically associated with major depression with atypical features: Evidence for a mechanism connecting obesity and depression. Biol Psychiatry 2017;81:807-14.
112.	Kucerova J, Babinska Z, Horska K, Kotolova H. The common pathophysiology underlying the metabolic syndrome, schizophrenia and depression. A review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2015;159:208-14.
113.	Nousen EK, Franco JG, Sullivan EL. Unraveling the mechanisms responsible for the comorbidity between metabolic syndrome and mental health disorders. Neuroendocrinology 2013;98:254-66.
114.	Marazziti D, Rutigliano G, Baroni S, Landi P, Dell' Osso L. Metabolic Msyndrome and major depression. CNS Spectr 2014;19:293-304.
115.	Lee J, Lee S, Zhang H, Hill MA, Zhang C, Park Y, et al. Interaction of IL-6 and TNF-α contributes to endothelial dysfunction in type 2 diabetic mouse hearts. PLoS One 2017;12:e0187189.
116.	Nilsson J. Cytokines and smooth muscle cells in atherosclerosis. Cardiovasc Res 1993;27:1184-90.
117.	Rahvar AH, Haas CS, Danneberg S, Harbeck B. Increased cardiovascular risk in patients with adrenal insufficiency: A short review. Biomed Res Int 2017;2017:3691913.
118.	Wędrychowicz A, Zając A, Pilecki M, Kościelniak B, Tomasik PJ. Peptides from adipose tissue in mental disorders. World J Psychiatry 2014;4:103-11.
119.	Doolin K, Farrell C, Tozzi L, Harkin A, Frodl T, O'Keane V, et al. Diurnal hypothalamic-pituitary-adrenal axis measures and inflammatory marker correlates in major depressive disorder. Int J Mol Sci 2017;18. pii: E2226.
120.	Chesnokova V, Pechnick RN, Wawrowsky K. Chronic peripheral inflammation, hippocampal neurogenesis, and behavior. Brain Behav Immun 2016;58:1-8.
121.	Shelton RC, Miller AH. Eating ourselves to death (and despair): The contribution of adiposity and inflammation to depression. Prog Neurobiol 2010;91:275-99.
122.	Choi AJ, Ryter SW. Inflammasomes: Molecular regulation and implications for metabolic and cognitive diseases. Mol Cells 2014;37:441-8.
123.	McElroy SL, Keck PE Jr. Metabolic syndrome in bipolar disorder: A review with a focus on bipolar depression. J Clin Psychiatry 2014;75:46-61.
124.	Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT. Inflammasomes in neuroinflammation and changes in brain function: A focused review. Front Neurosci 2014;8:315.
125.	Agustí A, García-Pardo MP, López-Almela I, Campillo I, Maes M, Romaní-Pérez M, et al. Interplay between the gut-brain axis, obesity and cognitive function. Front Neurosci 2018;12:155.
126.	Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 2015;28:203-9.
127.	Bonaz B, Bazin T, Pellissier S. The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci 2018;12:49.
128.	Bonaz B, Sinniger V, Pellissier S. The vagus nerve in the neuro-immune axis: Implications in the pathology of the gastrointestinal tract. Front Immunol 2017;8:1452.
129.	Sherwin E, Sandhu KV, Dinan TG, Cryan JF. May the force be with you: The light and dark sides of the microbiota-gut-brain axis in neuropsychiatry. CNS Drugs 2016;30:1019-41.
130.	Graessler J, Qin Y, Zhong H, Zhang J, Licinio J, Wong ML, et al. Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: Correlation with inflammatory and metabolic parameters. Pharmacogenomics J 2013;13:514-22.
131.	Jie Z, Xia H, Zhong SL, Feng Q, Li S, Liang S, et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat Commun 2017;8:845.
132.	Ahmadmehrabi S, Tang WH. Gut microbiome and its role in cardiovascular diseases. Curr Opin Cardiol 2017;32:761-6.
133.	Tang WH, Hazen SL. The gut microbiome and its role in cardiovascular diseases. Circulation 2017;135:1008-10.
134.	Peng J, Xiao X, Hu M, Zhang X. Interaction between gut microbiome and cardiovascular disease. Life Sci 2018;214:153-7.
135.	Singh V, Yeoh BS, Vijay-Kumar M. Gut microbiome as a novel cardiovascular therapeutic target. Curr Opin Pharmacol 2016;27:8-12.
136.	Tang WH, Kitai T, Hazen SL. Gut microbiota in cardiovascular health and disease. Circ Res 2017;120:1183-96.
137.	Pevsner-Fischer M, Blacher E, Tatirovsky E, Ben-Dov IZ, Elinav E. The gut microbiome and hypertension. Curr Opin Nephrol Hypertens 2017;26:1-8.
138.	Griffin JL, Wang X, Stanley E. Does our gut microbiome predict cardiovascular risk? A review of the evidence from metabolomics. Circ Cardiovasc Genet 2015;8:187-91.
139.	Ettinger G, MacDonald K, Reid G, Burton JP. The influence of the human microbiome and probiotics on cardiovascular health. Gut Microbes 2014;5:719-28.
140.	Ferguson JF, Allayee H, Gerszten RE, Ideraabdullah F, Kris-Etherton PM, Ordovás JM, et al. Nutrigenomics, the microbiome, and gene-environment interactions: New directions in cardiovascular disease research, prevention, and treatment: A scientific statement from the American Heart Association. Circ Cardiovasc Genet 2016;9:291-313.
141.	Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S, et al. From gut dysbiosis to altered brain function and mental illness: Mechanisms and pathways. Mol Psychiatry 2016;21:738-48.
142.	Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R, et al. Current understanding of the human microbiome. Nat Med 2018;24:392-400.
143.	Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease. Curr Opin Gastroenterol 2015;31:69-75.
144.	Wiley NC, Dinan TG, Ross RP, Stanton C, Clarke G, Cryan JF, et al. The microbiota-gut-brain axis as a key regulator of neural function and the stress response: Implications for human and animal health. J Anim Sci 2017;95:3225-46.
145.	Grenham S, Clarke G, Cryan JF, Dinan TG. Brain-gut-microbe communication in health and disease. Front Physiol 2011;2:94.
146.	Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Mol Psychiatry 2016;21:786-96.
147.	Wong ML, Inserra A, Lewis MD, Mastronardi CA, Leong L, Choo J, et al. Inflammasome signaling affects anxiety – And depressive-like behavior and gut microbiome composition. Mol Psychiatry 2016;21:797-805.
148.	Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 2011;108:16050-5.
149.	Chirinos DA, Gurubhagavatula I, Broderick P, Chirinos JA, Teff K, Wadden T, et al. Depressive symptoms in patients with obstructive sleep apnea: Biological mechanistic pathways. J Behav Med 2017;40:955-63.
150.	Kerner NA, Roose SP. Obstructive sleep apnea is linked to depression and cognitive impairment: Evidence and potential mechanisms. Am J Geriatr Psychiatry 2016;24:496-508.
151.	Wu BG, Sulaiman I, Wang J, Shen N, Clemente JC, Li Y, et al. Severe obstructive sleep apnea is associated with alterations in the nasal microbiome and an increase in inflammation. Am J Respir Crit Care Med 2019;199:99-109.
152.	Montiel-Castro AJ, González-Cervantes RM, Bravo-Ruiseco G, Pacheco-López G. The microbiota-gut-brain axis: Neurobehavioral correlates, health and sociality. Front Integr Neurosci 2013;7:70.
153.	de Melo LG, Nunes SO, Anderson G, Vargas HO, Barbosa DS, Galecki P, et al. Shared metabolic and immune-inflammatory, oxidative and nitrosative stress pathways in the metabolic syndrome and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry 2017;78:34-50.
154.	Penninx BW, Lange SM. Metabolic syndrome in psychiatric patients: Overview, mechanisms, and implications. Dialogues Clin Neurosci 2018;20:63-73.
155.	Martinac M, Pehar D, Karlović D, Babić D, Marcinko D, Jakovljević M, et al. Metabolic syndrome, activity of the hypothalamic-pituitary-adrenal axis and inflammatory mediators in depressive disorder. Acta Clin Croat 2014;53:55-71.
156.	Vancampfort D, Correll CU, Wampers M, Sienaert P, Mitchell AJ, De Herdt A, et al. Metabolic syndrome and metabolic abnormalities in patients with major depressive disorder: A meta-analysis of prevalences and moderating variables. Psychol Med 2014;44:2017-28.
157.	Leonard BE. Inflammation as the cause of the metabolic syndrome in depression. Mod Trends Pharmacopsychiatry 2013;28:117-26.
158.	Penninx BW. Depression and cardiovascular disease: Epidemiological evidence on their linking mechanisms. Neurosci Biobehav Rev 2017;74:277-86.
159.	Pan A, Keum N, Okereke OI, Sun Q, Kivimaki M, Rubin RR, et al. Bidirectional association between depression and metabolic syndrome: A systematic review and meta-analysis of epidemiological studies. Diabetes Care 2012;35:1171-80.
160.	Zanoveli JM, Morais Hd, Dias IC, Schreiber AK, Souza CP, Cunha JM, et al. Depression associated with diabetes: From pathophysiology to treatment. Curr Diabetes Rev 2016;12:165-78.
161.	Chan KL, Cathomas F, Russo SJ. Central and peripheral inflammation link metabolic syndrome and major depressive disorder. Physiology (Bethesda) 2019;34:123-33.
162.	Burrage E, Marshall KL, Santanam N, Chantler PD. Cerebrovascular dysfunction with stress and depression. Brain Circ 2018;4:43-53. [PUBMED] [Full text]
163.	Han KM, Kim MS, Kim A, Paik JW, Lee J, Ham BJ, et al. Chronic medical conditions and metabolic syndrome as risk factors for incidence of major depressive disorder: A longitudinal study based on 4.7 million adults in south korea. J Affect Disord 2019;257:486-94.
164.	Barton BB, Zagler A, Engl K, Rihs L, Musil R. Prevalence of obesity, metabolic syndrome, diabetes and risk of cardiovascular disease in a psychiatric inpatient sample: Results of the metabolism in psychiatry (MiP) study. Eur Arch Psychiatry Clin Neurosci 2019. https://doi.org/10.1007/s00406-019-01043-8. [Last accessed on 2019 Oct 30].
165.	Aureli M, Grassi S, Prioni S, Sonnino S, Prinetti A. Lipid membrane domains in the brain. Biochim Biophys Acta 2015;1851:1006-16.
166.	Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell 2015;6:254-64.
167.	Borroni MV, Vallés AS, Barrantes FJ. The lipid habitats of neurotransmitter receptors in brain. Biochim Biophys Acta 2016;1858:2662-70.
168.	Davletov B, Montecucco C. Lipid function at synapses. Curr Opin Neurobiol 2010;20:543-9.
169.	Ueda Y. The role of phosphoinositides in synapse function. Mol Neurobiol 2014;50:821-38.
170.	Sebastião AM, Colino-Oliveira M, Assaife-Lopes N, Dias RB, Ribeiro JA. Lipid rafts, synaptic transmission and plasticity: Impact in age-related neurodegenerative diseases. Neuropharmacology 2013;64:97-107.
171.	Grela A, Rachel W, Cole M, Zyss T, Zięba A, Piekoszewski W, et al. Application of fatty acid and lipid measurements in neuropsychiatry. Clin Chem Lab Med 2016;54:197-206.
172.	De Berardis D, Marini S, Piersanti M, Cavuto M, Perna G, Valchera A, et al. The relationships between cholesterol and suicide: An update. ISRN Psychiatry 2012;2012:387901.
173.	Demirkan A, Isaacs A, Ugocsai P, Liebisch G, Struchalin M, Rudan I, et al. Plasma phosphatidylcholine and sphingomyelin concentrations are associated with depression and anxiety symptoms in a Dutch family-based lipidomics study. J Psychiatr Res 2013;47:357-62.
174.	Schneider M, Levant B, Reichel M, Gulbins E, Kornhuber J, Müller CP, et al. Lipids in psychiatric disorders and preventive medicine. Neurosci Biobehav Rev 2017;76:336-62.
175.	Müller CP, Reichel M, Mühle C, Rhein C, Gulbins E, Kornhuber J, et al. Brain membrane lipids in major depression and anxiety disorders. Biochim Biophys Acta 2015;1851:1052-65.
176.	Persons JE, Fiedorowicz JG. Depression and serum low-density lipoprotein: A systematic review and meta-analysis. J Affect Disord 2016;206:55-67.
177.	Maes M, Smith R, Christophe A, Vandoolaeghe E, Van Gastel A, Neels H, et al. Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: Relationship with immune-inflammatory markers. Acta Psychiatr Scand 1997;95:212-21.
178.	Jokinen J, Nordström AL, Nordström P. Cholesterol, CSF 5-HIAA, violence and intent in suicidal men. Psychiatry Res 2010;178:217-9.
179.	Jose PA, Raj D. Gut microbiota in hypertension. Curr Opin Nephrol Hypertens 2015;24:403-9.
180.	Yang T, Santisteban MM, Rodriguez V, Li E, Ahmari N, Carvajal JM, et al. Gut dysbiosis is linked to hypertension. Hypertension 2015;65:1331-40.
181.	DeMarco VG, Aroor AR, Sowers JR. The pathophysiology of hypertension in patients with obesity. Nat Rev Endocrinol 2014;10:364-76.
182.	Schlaich MP, Lambert E, Kaye DM, Krozowski Z, Campbell DJ, Lambert G, et al. Sympathetic augmentation in hypertension: Role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. Hypertension 2004;43:169-75.
183.	Barton DA, Dawood T, Lambert EA, Esler MD, Haikerwal D, Brenchley C, et al. Sympathetic activity in major depressive disorder: Identifying those at increased cardiac risk? J Hypertens 2007;25:2117-24.
184.	Dawood T, Schlaich M, Brown A, Lambert G. Depression and blood pressure control: All antidepressants are not the same. Hypertension 2009;54:e1.
185.	Esler M. Mental stress and human cardiovascular disease. Neurosci Biobehav Rev 2017;74:269-76.
186.	Nguyen SB, Cevik C, Otahbachi M, Kumar A, Jenkins LA, Nugent K, et al. Do comorbid psychiatric disorders contribute to the pathogenesis of tako-tsubo syndrome? A review of pathogenesis. Congest Heart Fail 2009;15:31-4.
187.	Gans RO. The metabolic syndrome, depression, and cardiovascular disease: Interrelated conditions that share pathophysiologic mechanisms. Med Clin North Am 2006;90:573-91.
188.	Teply RM, Packard KA, White ND, Hilleman DE, DiNicolantonio JJ. Treatment of depression in patients with concomitant cardiac disease. Prog Cardiovasc Dis 2016;58:514-28.
189.	Deuschle M. Effects of antidepressants on glucose metabolism and diabetes mellitus type 2 in adults. Curr Opin Psychiatry 2013;26:60-5.
190.	Roopan S, Larsen ER. Use of antidepressants in patients with depression and comorbid diabetes mellitus: A systematic review. Acta Neuropsychiatr 2017;29:127-39.
191.	Low Y, Setia S, Lima G. Drug-drug interactions involving antidepressants: Focus on desvenlafaxine. Neuropsychiatr Dis Treat 2018;14:567-80.
192.	Derijks HJ, Heerdink ER, De Koning FH, Janknegt R, Klungel OH, Egberts AC, et al. The association between antidepressant use and hypoglycaemia in diabetic patients: A nested case-control study. Pharmacoepidemiol Drug Saf 2008;17:336-44.
193.	Shi Z, Atlantis E, Taylor AW, Gill TK, Price K, Appleton S, et al. SSRI antidepressant use potentiates weight gain in the context of unhealthy lifestyles: Results from a 4-year Australian follow-up study. BMJ Open 2017;7:e016224.
194.	Shukla AP, Kumar RB, Aronne LJ. Lorcaserin hcl for the treatment of obesity. Expert Opin Pharmacother 2015;16:2531-8.
195.	Christou GA, Kiortsis DN. The efficacy and safety of the naltrexone/bupropion combination for the treatment of obesity: An update. Hormones (Athens) 2015;14:370-5.
196.	Dias S, Paredes S, Ribeiro L. Drugs involved in dyslipidemia and obesity treatment: Focus on adipose tissue. Int J Endocrinol 2018;2018:2637418.
197.	Subbaiah MA. Triple reuptake inhibitors as potential therapeutics for depression and other disorders: Design paradigm and developmental challenges. J Med Chem 2018;61:2133-65.
198.	Imprialos KP, Stavropoulos K, Doumas M, Tziomalos K, Karagiannis A, Athyros VG, et al. Sexual dysfunction, cardiovascular risk and effects of pharmacotherapy. Curr Vasc Pharmacol 2018;16:130-42.
199.	Abdelkader NF, Saad MA, Abdelsalam RM. Neuroprotective effect of nebivolol against cisplatin-associated depressive-like behavior in rats. J Neurochem 2017;141:449-60.
200.	Joca SR, Sartim AG, Roncalho AL, Diniz CF, Wegener G. Nitric oxide signalling and antidepressant action revisited. Cell Tissue Res 2019;377:45-58.
201.	Aftab A, Kemp DE, Ganocy SJ, Schinagle M, Conroy C, Brownrigg B, et al. Double-blind, placebo-controlled trial of pioglitazone for bipolar depression. J Affect Disord 2019;245:957-64.
202.	Erensoy H, Niafar M, Ghafarzadeh S, Aghamohammadzadeh N, Nader ND. A pilot trial of metformin for insulin resistance and mood disturbances in adolescent and adult women with polycystic ovary syndrome. Gynecol Endocrinol 2019;35:72-5.
203.	Cuomo A, Bolognesi S, Goracci A, Ciuoli C, Beccarini Crescenzi B, Maina G, et al. Feasibility, adherence and efficacy of liraglutide treatment in a sample of individuals with mood disorders and obesity. Front Psychiatry 2018;9:784.

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