Angelos Halaris, MD

This activity offers CE credits for:
	1. Physicians (CME)
	2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

To goal of this activity is to understand the relationship between endothelial function and arterial stiffness.

At the end of this CE activity, participants should be able to:

• Identify tools to assess endothelial dysfunction

• Understand the sequelae of comorbid ischemic heart disease and depression

• Explain the concept of psychcardiology and its role in the diagnosis and management of heart disease/psychiatric illness

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

 This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and 

. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 

™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants:

 AANPCP and AAPA accept certificates of participation for educational activities certified for 

It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Angelos Halaris, MD, has no conflicts to report.

Ebrahim Haroon, MD (peer/content reviewer), reports that he receives funding from the NIH.

 staff and CME Outfitters staff have no disclosures to report.

Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

For content-related questions email us at editor@psychiatrictimes.com; for questions concerning CME credit

The epidemiological aspects of the high comorbidity between cardiovascular disease (CVD) and major depressive disorder (MDD) were reviewed in 

 of this CME article in the September issue. The focus was on mental stress as a likely common instigator underlying both CVD and MDD. The role of the autonomic nervous system not only in regulating heart function but also in modulating the body’s inflammatory response to physical and mental insults threatening the integrity and the homeostatic balance of body and mind was discussed.

In Part 2, the role of the endothelium in undergoing pathological changes that lead to atheromatosis and atherosclerosis with ensuing sequelae are discussed. Endothelial dysfunction can be assessed using blood tests and applanation tonometry, the latter being a non-invasive procedure that can be carried out in ambulatory settings. Finally, the concept of psychocardiology as an emerging integrated approach to diagnose and manage heart disease patients and psychiatric patients vulnerable to heart and/or cerebrovascular disease is examined. The suggested formation of multidisciplinary teams will go a long way toward improved outcomes and a reduction in morbidity and mortality.

Endothelial dysfunction and arterial stiffness

MDD, by virtue of its proinflammatory status, leads to endothelial dysfunction that ultimately can lead to arterial stiffness. Studies have related arterial stiffness to absolute 10- to 12-year risk of stroke, coronary heart disease, and death. In addition to markers of inflammation, markers of endothelial function can be assessed in peripheral blood. Circulating biomarkers of endothelial function, include e-selectin, p-selectin, soluble intercellular adhesion molecule-1 (s-ICAM1), endothelin-1, asymmetric dimethylarginine (ADMA), von Willebrand Factor (vWF), and vascular cell adhesion molecule-1 (VCAM-1). These markers have been measured in the blood of subjects with CVD as well as in psychiatric populations with mood and anxiety disorders.

 assessed hopelessness, depression, and select endothelial markers. They found high levels of hopelessness to be significantly associated with e-selectin, whereas high levels of hopelessness were significantly associated with s-ICAM1.

In a large population-based cohort study (N=852), depressive symptoms were assessed with the Patient Health Questionnaire-9 and (major and minor) depressive disorder with the Mini-International Neuropsychiatric Interview.

CRP, SAA, sICAM-1, IL-6, IL-8, TNF-Î±) and endothelial dysfunction (sVCAM-1, sICAM-1, sE-selectin, vWF) were measured with immunoassays and combined into two standardized sum scores. Biomarkers of inflammation (

CRP, TNF-Î±, SAA, sICAM-1) and endothelial dysfunction (sICAM-1, sE-selectin) were univariately associated with depressive symptoms and depressive disorder. The researchers concluded that both inflammation and endothelial dysfunction are associated with depressive disorder, independent of lifestyle factors.

 assessed psychological constructs in a cohort of post-acute coronary syndrome patients and measured markers of inflammation, endothelial function, and myocardial strain. They determined that depressive symptoms were associated with elevated inflammation, endothelial dysfunction, and myocardial strain. By contrast, positive psychological constructs, such as optimism and gratitude, were linked to better endothelial function.

The index of arterial stiffness with the greatest pathophysiological and clinical background is pulse wave velocity. The shape of the arterial pressure waveform provides a measure of systemic arterial stiffness and can be assessed noninvasively by using the technique of pulse wave analysis. As determined by pulse wave analysis, arterial stiffness has been shown to be an independent marker of cardiovascular risk.

 The approach has been successfully utilized to assess arterial stiffness in depression, aging, and coronary artery disease (CAD).

 Our unpublished data clearly indicate that arterial stiffness increases as a function of age in physically and mentally healthy men and women. However, in the presence of MDD, arterial stiffness is significantly increased with the highest values observed in postmenopausal women with MDD whether untreated or under treatment with an antidepressant medication.

The association between depression-and likely other psychiatric disorders-and CVD is bidirectional, with both entities sharing common pathophysiology. A 2013 study of 45 young individuals at increased risk for depression provided evidence of an altered cardiovascular risk profile in young adulthood even without overt depressive symptoms. Such vulnerability may precede or follow the onset of depression and may share common risk factors.

Following myocardial infarction (MI) the presence of depression has a cumulative effect on mortality. The Montreal Heart Study followed 222 post-MI hospitalized patients and found that the cumulative mortality rate for depressed patients post-MI was significantly higher than the rate for non-depressed patients, with the greatest effect occurring in the first 6 months.

 Premature ventricular contractions and elevated Beck Depression Inventory (BDI) scores were significantly related to mortality at 18 months.

The Montreal group also examined longer-term survival and measured BDI scores of 892 post-MI patients at admission and again at 1 year.

 They found a significant dose-response relationship between BDI scores and cardiac mortality, and these results remained significant even after controlling for multiple measures of cardiac disease severity. Patients with the highest initial BDI scores had the worst prognosis; an improvement in depressive symptoms lessened cardiac mortality only for patients with mild depression. The researchers concluded that the link between depression and cardiac mortality may be a relatively permanent marker for long-term survival.

Heart failure is a serious syndrome that, depending on severity, interferes with normal functioning, significantly impairs the capacity of an individual to lead a normal life, and may ultimately lead to death. Close to one million new cases of heart failure will occur in the US in 2018 and, as reported at the Annual Cardiovascular Conference in Snowmass, Colorado, most of them could have been prevented.

Before discussing preventive measures, what is our understanding of the pathophysiology of this syndrome? Several models have been proposed but inflammation remains at center stage. To quote from an earlier publication by Seta and colleagues,

 “heart failure progresses, at least in part, as a result of the toxic effects exerted by endogenous cytokine cascades on the heart and the peripheral circulation.” Animal and clinical data support the presence of an inflammatory cascade that is involved at least in the progression of heart failure.

The main risk factors for the development of heart failure are ischemic heart disease and hypertension followed by diabetes, dyslipidemia, metabolic syndrome, obesity, alcoholism, and smoking. Atherosclerotic cardiovascular disease must be diagnosed early in the process to prevent serious sequelae. Diagnostic biomarkers including assessment of arterial stiffness may eventually be introduced into psychiatric practice since stress-related illness can lead to endothelial dysfunction as a preamble to atheromatosis and atherosclerosis.

Effective management of hypertension and dyslipidemia, including education of the patient, dietary counseling, and diabetes control, especially with administration of inhibitors of the sodium-glucose transporter, are huge steps toward the prevention of heart failure. The Framingham Heart Study concluded that obese individuals had double the risk of new-onset heart failure, compared with those who were of normal weight.

 Obesity must be addressed in primary care, general medicine, cardiology, and psychiatric practices.

Psychological interventions can be effective, especially if combined with nutritional counseling and regular follow-ups. Smoking must be addressed in most all practices independent of specialty or subspecialty area. Pharmacological and psychological interventions, preferably in combination, can be quite effective in enabling permanent smoking cessation. The administration of psychotropic compounds that are known to cause weight gain and metabolic syndrome must be avoided especially since newer agents are available that do not have such an adverse effect on the organism.

Lifestyle modification with expert counseling as part of general and/or psychiatric practice can go a long way toward preventing ischemic heart disease and associated consequences. Key lifestyle factors include maintaining a normal body weight, regular exercise, smoking cessation, drinking in moderation, and a healthy diet made up primarily of vegetables and fruit.

Chest pain is a common presenting complaint in a cardiology clinic and can have numerous etiologies beyond heart disease. It is a common and potentially complex patient complaint, amounting to more than 6 million cases in the US annually. After extensive and costly evaluations, many patients receive a diagnosis of non-cardiac chest pain (NCCP). Approximately 30% of all coronary angiograms prove to be negative for significant coronary artery disease CAD, thus patients receive a diagnosis of NCCP.

Unexplained chest pain is often comorbid with anxiety, depression, and somatoform disorders. In a recent study, the comorbidity of psychiatric conditions and NCCP was examined prospectively in a cohort of 231 NCCP patients free of a current or lifetime cardiac diagnosis.

 The findings indicate that 44% of the NCCP patients suffered from a current Axis I psychiatric diagnosis; anxiety disorders (41%) and mood disorders (13%) were the most prevalent. Patients with NCCP may also have exaggerated or abnormal cardiac pain perceptions, visceral hyperalgesia, and/or abnormal cardiac sensitivity to a variety of stimuli.

Treatment of NCCP includes psychotherapy and psychotropic medications, such as antidepressant and antianxiety drugs. (For additional information, the interested reader is referred to a recently published review article on this topic.

The relationship between certain psychiatric disorders and CVD/cerebrovascular disease (CBVD) is complex. To address these issues, multidisciplinary teams of specialists in cardiology, psychiatry, and psychology as well as established researchers with diverse expertise in basic laboratory, clinical, and cardiodiagnostic methods are needed. Such integrated teams with the requisite expertise have recently begun to work collaboratively, but more needs to be done. Only through cohesive interactions of such multidisciplinary teams can we succeed in unraveling the complex relationships between mental stress, inflammation, immune responses, and psychiatric disorders and CVD/CBVD.

A number of collaborative care treatment programs have been formed that focus on the management of depression and anxiety disorders in patients with CVD as well as other conditions such as diabetes and cancer. The National Institutes of Health funded the Bypassing the Blues (BtB) study, the first trial to examine the impact of a collaborative care strategy for treating depression in patients with cardiac disease.

Another relevant multicenter clinical trial is the Comparison of Depression Interventions after Acute Coronary Syndrome (CODIACS) randomized controlled trial. Results from this ambitious study demonstrated that for patients with post-acute coronary syndrome depression, active treatment had a significant beneficial effect on depressive symptoms. The researchers concluded that this kind of depression care is feasible, effective, and is likely to be cost-neutral, therefore it should be tested in a large phase 3 pragmatic trial.

Last but certainly not least, TEAMcare is a highly successful model of practice-based interventions that address concomitant depression and chronic medical conditions in the primary care setting. These and others are notable examples of successful programs based on the psychocardiology concept.

The psychocardiology concept would promote recognition of the high comorbidity between psychiatric disorders and CVD/CBVD and lead to more effective treatment approaches. A close interaction between the two specialties will lead to improved diagnostic and prognostic assessments, and significantly reduce patient suffering and health care costs.

Such a concept could lead to the formation of teams of clinicians and researchers who would provide patient assessment and management and pursue multidisciplinary research. Designing and implementing training modules that focus on psychocardiology in psychiatric and internal medicine residency programs would be an excellent start. A formal subspecialty with fellowship training and board certification might follow after the successful implementation of pilot programs (

Adoption and implementation of the psychocardiology concept will be a process over many years. The short- and long-term goals that private and hospital-based cardiology and psychiatry practices might consider are outlined in 

 lend themselves to implementation as part of “Good Clinical Practice” regardless of whether a formal psychocardiology team has been assembled.

CVD and psychiatric disease (notably mood and anxiety disorders) comorbidity is highly prevalent and poses major and urgent challenges. Stress plays a critical role in the generation and progression of both disease entities. To address the complex factors that underlie the comorbidity, the concept of psychocardiology is proposed, which will lead to multidisciplinary teams who could be sponsored jointly by cardiology and psychiatry services/departments.

Many of the short-term recommendations can be implemented right away, while longer-term goals will have to wait for additional research and validation. To that end, federal and private funding for the establishment of pilot programs would be a highly desirable first step to prove the validity of the psychocardiology concept and the utility of the proposed tests and procedures for introduction into practice.

Post-tests, credit request forms, and activity evaluations must be completed online at 

 (requires free account activation), and participants can print their certificate or statement of credit immediately (80% pass rate required). This Web site supports all browsers except Internet Explorer for Mac. For complete technical requirements and privacy policy, visit 

PLEASE NOTE THAT THE POST-TEST IS AVAILABLE ONLINE ONLY ON THE 20TH OF THE MONTH OF ACTIVITY ISSUE AND FOR 18 MONTHS AFTER.

Dr Halaris is Professor of Psychiatry and Behavioral Neuroscience, Loyola University Stritch School of Medicine, Loyola University Medical Center, Maywood, IL.

 Do DP, Dowd JB, Ranjit N, et al. Hopelessness, depression, and early markers of endothelial dysfunction in US adults. 

 van Dooren FE, Schram MT, Schalkwijk CG, et al. Associations of low grade inflammation and endothelial dysfunction with depression: The Maastricht Study. 

 Celano CM, Beale EE, Beach SR, et al. Associations between psychological constructs and cardiac biomarkers after acute coronary syndrome. 

 Hayward CS, Kraidly M, Webb CM, et al. Assessment of endothelial function using peripheral waveform analysis: a clinical application. 

 I-Mei Lin, Hsueh-Chen Lu, Chih-Sheng Chu, et al. The relationship between brachial-ankle pulse wave velocity and depressive symptoms among patients with coronary artery disease. 

 Rybakowski JK, Wykretowicz A, Heymann-Szlachcinska A, et al. Impairment of endothelial function in unipolar and bipolar depression. 

 Mannie ZN, Williams C, Diesch J, et al. Cardiovascular and metabolic risk profile in young people at familial risk of depression. 

 Frasure-Smith N, Lesperance F, Gravel G, et al. Social support, depression, and mortality during the first year after myocardial infarction. 

 Lesperance F, Frasure-Smith N, Talajic M et al. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. 

 Seta Y, Shan K, Bozkurt B et al: Basic mechanisms in heart failure: the cytokine hypothesis. 

 Petersen JW, Felker M. Inflammatory biomarkers in heart failure. 

 Kenchaiah S, Evans JC, Levy D. Obesity and the risk of heart failure. 

 White KS, Raffa SD, Jakle KR, et al. Morbidity of DSM-IV Axis I disorders in patients with noncardiac chest pain: psychiatric morbidity linked with increased pain and health care utilization. 

 Meresh E, Piletz J, Halaris A. Noncardiac chest pain: systematic review of the literature on prognosis. 

 Rollman BL, Belnap BH, LeMenager MS, et al. The Bypassing the Blues treatment protocol: stepped collaborative care for treating post-CABG depression. 

 Rollman BL, Belnap BH. The Bypassing the Blues trial: collaborative care for post-CABG depression and implications for future research. 

 Meyer T, Belnap BH, Herrmann-Lingen C et al. Benefits of collaborative care for post-CABG depression are not related to adjustments in antidepressant pharmacotherapy. 

 Whang W, Burg MM, Carney RM, et al. Design and baseline data from the vanguard of the Comparison of Depression Interventions after Acute Coronary Syndrome (CODIACS) randomized controlled trial. 

 Davidson KW, Bigger JT, Burg MM et al. Centralized, stepped, patient preference-based treatment for patients with post-acute coronary syndrome depression: CODIACS vanguard randomized controlled trial. 

 McGregor M, Lin EHB, Katon WJ. Teamcare: an integrated multicondition collaborative care program for chronic illnesses and depression. 

 Katon W, Lin EH, Von Korff M, et al. Integrating depression and chronic disease care among patients with diabetes and/or coronary heart disease: the design of the TEAMcare study. 

 Lin EH, Von Korff M, Ciechanowski P, et al. Treatment adjustment and medication adherence for complex patients with diabetes, heart disease, and depression: a randomized controlled trial. 

 Rosenberg D, Lin E, Peterson D, et al. Integrated medical care management and behavioral risk factor reduction for multicondition patients: behavioral outcomes of the TEAMcare trial. 

Articles

The goal of this activity is to understand the relationship between endothelial function and arterial stiffness.

Psychocardiology, Part 2: Fixing the Broken Heart

To goal of this activity is to understand the bidirectional relationship between depression and cardiovascular disease.

• Explain the reasons for the high comorbidity between depression and cardiovascular disease

• Understand the role of the autonomic nervous system in regulating heart function

• Assess autonomic nervous system activity through measurement of heart rate variability

 This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 

 staff and CME Outfitters staff, have no disclosures to report.

For content-related questions, email us at editor@psychiatrictimes.com; for questions concerning CME credit

Every affection of the mind that is attended with either pain or pleasure, hope or fear, is the cause of an agitation whose influence extends to the heart.

Heart-brain interactions have been known to mankind since Hippocratic times and written about extensively in the medical and nonmedical literature over the centuries. The epigraph by the 17th century physician holds great validity and urgency in the present day. Heart-brain interactions are now recognized to be complex and multifaceted, and to engulf several functions and systems of the body. At least in certain conditions, as will be described below, they appear to be bidirectional. The consequences of heart-brain dysfunction can lead to pathological manifestations involving many organ systems, with dire consequences.

There is evidence that cardiovascular disease (CVD) and psychiatric disorders are far more closely interrelated than had been assumed. Moreover, findings indicate that CVD and psychiatric disorders, notably depressive and anxiety disorders, have a bidirectional relationship. A common pathophysiological link underlying this comorbidity is mental stress and stress susceptibility that is confounded by genetic and epigenetic factors, psychosocial and environmental influences, and lifestyle choices. In recognition of the multifactorial complexity underlying these high rates of comorbidity and associated patient needs for management and recovery, the term “psychocardiology” was coined.

In Part 1 of this 2-part CME article, the following topics are discussed: key epidemiological data to illustrate the high comorbidity between CVD and depression, mental stress as a common instigator behind the comorbidity, and the autonomic nervous system. In Part 2, the following will be discussed: the concept of endothelial dysfunction as a preamble to atheromatosis and atherosclerosis; depression in association with myocardial infarction; the role of inflammation in heart disease and heart failure as well as non-cardiac chest pain.

CVD and depression are two of the world’s leading health problems. CVD is the leading cause of mortality worldwide and accounts for approximately 16.7 million deaths every year.

 The most common types of CVD are coronary artery disease and cerebrovascular disease.

It has been estimated that CVD is responsible for close to 1 million deaths and more than six million hospital admissions with an annual cost to the US economy in excess of $350 billion.

 In the US, major depressive disorder (MDD) afflicts approximately 17 million people annually with a direct and indirect cost to the nation exceeding $50 billion in today’s dollar estimates.

The incidence of MDD has been steadily increasing over the past decades. Using the Disability Adjusted Life-Years measure, MDD was classed as the fourth leading burden of disease worldwide for both sexes in 1990. By 2004, it advanced to third place, and according to the World Health Organization’s estimate, will rank second to CVD by the year 2020 and will be the leading cause of disease burden by 2030.

Numerous studies published over the past two decades have confirmed the bidirectional association between CVD and depression. In a meta-analysis, clinical depression was identified as a significant risk factor for mortality in patients with coronary heart disease.

 The Multiple Risk Factor Intervention Trial (MRFIT) of middle-aged men established an association between depressive symptoms and all-cause mortality with a higher risk of CVD-related death and more specifically stroke mortality.

Mental stress can produce profound alterations in the physiology and chemistry of the CNS and the autonomic nervous system, peripheral organs, and the endocrine, vascular, and immune systems. The perception of mental stress is subject to high individual variability and vulnerability, which is based, in part, on genetically determined and epigenetically modified stress susceptibility and stress resilience. Chronic and inescapable stress ultimately lead to pervasive mental status changes and pathological alterations to the cardiovascular system that may lead to irreversible tissue and organ damage.

The autonomic nervous system and heart rate variability

In addition to activating the hypothalamic-pituitary-adrenal axis (HPA), stress activates the sympathetic branch of the autonomic nervous system. This activation leads to a reduction in vagal tone that can have consequences in the body’s immune responses. The imbalance in autonomic nervous system function, especially if prolonged, has profound effects on cardiovascular physiology and the immune system. These pathophysiological changes contribute significantly to the comorbidity between CVD and psychiatric disorders. Thus, the autonomic imbalance and decreased parasympathetic activity may be the final common pathway to numerous diseases and conditions associated with increased morbidity and mortality.

Psychophysiological consequences of stress include sympathoadrenal hyperactivity, with a concomitant decrease in vagal tone, increases in plasma catecholamines, vasoconstriction, elevated heart rate, and platelet activation. The Heart and Soul Study clearly established that in patients with coronary artery disease, depressive symptoms are associated with elevated levels of norepinephrine.

 These changes, singly and additively, exert adverse effects on the cardiovascular system. Elevated and sustained catecholaminergic action on the heart, blood vessels, and platelets leads to changes in hemodynamic factors with increased shear stress. The decrease in parasympathetic tone may predispose to ventricular arrhythmias and possibly explain the excessive cardiovascular mortality found in patients with CVD and comorbid depression.

Heart rate variability (HRV) is an index of a healthy heart and good cardiac function with the ability to adapt to external and internal stressful demands. Diminished high-frequency HRV reflects decreased parasympathetic tone and has been observed at least in some depressed patients. The results of a large cohort study demonstrated that depressed patients, when compared with healthy controls, have significantly both lower total HRV and lower HRV in the respiratory frequency range.

 These findings are compatible with theoretical models, notably the polyvagal theory coined by Porges.

 These models have linked the parasympathetic system to the etiopathology of depression based on the premise that low vagal tone is associated with reduced social engagement and an impaired response to environmental stimuli and challenges.

Heart rate variability can also be significantly decreased in severe coronary artery disease or heart failure. The risk of sudden death after acute myocardial infarction is significantly higher with decreased HRV. Indeed, HRV is a post-myocardial infarction prognostic factor (along with age, left-ventricular ejection fraction, frequency of arrhythmia). In patients with coronary artery disease, diminished HRV is far more common in depressed patients.

Our group has recently published studies in which we included HRV measurements along with inflammation biomarkers and relevant rating instruments before and after pharmacological treatment of unipolar or bipolar depressed patients.

 We also addressed methodological issues such as duration of ECG monitoring and recording and corrections for respiratory and muscular artifacts. We are encouraged by our findings, which confirm in large part and expand on previously published studies of HRV in psychiatric cohorts. Taken together, with further research and methodological refinements, HRV measurements could be introduced into the diagnostic and prognostic armamentarium for the evaluation and management of stress-related disorders, notably depression and comorbid heart disease.

It is now possible to obtain accurate readings after short ECG tracings obviating the need for time intensive Holter monitors. The raw data must be subjected to correction of tracing artifacts by means of commercially available software programs. For the rationale of conducting such measurements and detailed description of data processing, the reader is referred to our recently published work. It is also noteworthy and of potential clinical significance that administration of therapeutic compounds with anticholinergic activity as part of their pharmacologic profile may exert unwanted and possibly deleterious effects over prolonged exposure to such agents.

The autonomic nervous system is involved in exerting regulatory input to the immune system. Simultaneous and sustained reduction in parasympathetic tone due to illness chronicity, recurrence, and severity may lead to disinhibition of the body’s inflammatory response as the immune system becomes overactive. Vagal nerve efferent inputs that regulate inflammation via the cholinergic anti-inflammatory pathway are well documented and measurements of inflammatory biomarkers in mood disorders can differentiate at least some of these patients from healthy subjects.

Amongst the various pathophysiological processes that have been identified as playing major contributory roles to the comorbidity between CVD and depression is inflammation. The inflammatory response aims to restore homeostasis and health; however, inflammation can persist and expand, both centrally and peripherally, especially in instances of chronic physical or mental illnesses that perpetuate the stressful condition. The relationship between stressful events and the onset of inflammation-related diseases, notably cardiovascular, neurological, and immunological, has been documented in the literature. A growing body of evidence has also identified inflammatory events associated with affective, anxiety, and psychotic disorders.

Evidence for a connection between mood disturbances and the immune system dates back more than two decades, and the connection continues to be studied.

 Activation of inflammatory processes as a common link between depression and CVD has received increased attention. Proinflammatory cytokines have been implicated in the pathogenesis of atherosclerosis and CVD.

 Endothelial damage leads to the release of pro-inflammatory cytokines that induce a sequence of events leading ultimately to thrombus formation and vascular occlusion.

Inflammation is a major contributing causal factor to depression and has been thought to play a major role in endothelial damage of the cerebral vasculature. This has led to the designation of “vascular depression” that presents with many of the typical symptoms of depression. Interleukin-6 (IL-6), secreted in response to stress, is one of the most potent stimulators of the HPA axis and induces the release of other pro-inflammatory cytokines. It is postulated that depression is a disease of inflammation in response to chronic psychological stress.

Cardiovascular pathology and inflammation

Inflammation plays a major role in the development of atherosclerosis and atherothrombosis with the associated clinical sequelae that lead to high morbidity and mortality. Immune-competent cells are involved both in the early stages of atherosclerosis and the subsequent events leading to plaque formation and rupture and the ensuing acute coronary syndromes.

During the past two decades, circulating compounds have been identified as markers of inflammation and atherosclerosis. These compounds include acute phase proteins, C-reactive protein (CRP), fibrinogen, immunoglobulins, adhesion molecules, and cytokines. Most of these biomarkers have also been shown to be abnormally regulated in many, but not all, patients with depressive syndromes without any evidence of other inflammatory processes, cardiovascular, or immune system pathology. Fibrinogen, CRP, tumor necrosis factor alpha (TNF-Î±), interleukin-1 (IL-1), and IL-6 have been discussed extensively in the cardiovascular literature. Indeed, a case has been made that CRP and depression have prognostic value in predicting adverse cardiac events.21 The literature is replete with findings that indicate persisting CVD vulnerability after full recovery from a depressive episode, although there appears to be a time lag between mood improvement and immune marker normalization. However, the role of CRP in mediating inflammatory response and whether elevated blood levels in depression or CVD should always be considered a risk factor must be reexamined in view of findings that there is a pentameric and a monomeric CRP with the latter posing a toxic threat.

A growing field of research involves CRP levels posttreatment with antidepressants. Several studies have sought to answer whether CRP levels change with various MDD treatments. Pizzi and colleagues

 randomized patients with coronary heart disease and MDD to receive sertraline or placebo for 20 weeks. At 20 weeks, levels of CRP decreased significantly from baseline with sertraline treatment, whereas they did not significantly change in the placebo group. Moreover, patients treated with sertraline demonstrated a decrease in depressive symptoms with a lower Beck Depression Inventory score.

Similar results were obtained from a meta-analysis conducted by Hiles and colleagues.

 The researchers considered various antidepressant treatment studies in patients with MDD that measured CRP, IL-10, and IL-6 at baseline and posttreatment. The results showed that treatment with antidepressants resulted in a significant reduction in CRP levels with the most notable reductions obtained after treatment with TCAs. As CRP levels decreased there was an accompanying reduction in depressive symptoms. While these co-occurring reductions may be correlated, it is not clear whether a reduction in CRP is indicative of response to treatment.

 treated patients with 20-mg fluoxetine or 20-mg escitalopram daily for two months. The results showed a significant decrease in CRP levels from baseline with both fluoxetine and escitalopram. However, unlike the results of other studies, the decrease in CRP was independent of the medication effects on depression symptoms. As indicated by the Hamilton Depression Rating Scale for depression, there was no notable response.

Findings from the three studies suggest that antidepressants can exert an anti-inflammatory effect as evidenced by a reduction in CRP levels. Whether this reduction in CRP is related to a reduction in depressive symptoms remains unclear. (For further discussion of this issue, the reader is referred to Halaris.

CRP polymorphisms help explain variations in CRP levels at the gene level, but differences in CRP also exist in the structure of the protein itself. CRP is present in two different forms: the pentameric (pCRP) and the monomeric (mCRP) isomer. These isomers are structurally unique from one another. CRP is believed to circulate as a pentamer in plasma, while mCRP is known to have limited solubility. Recently, it has been recognized that mCRP and pCRP have different biological activities, which raises questions about the role of each isomer in the inflammatory process. The differing biological activities of mCRP and pCRP may help explain the discrepancies in reported findings. Clearly more research focused on elucidating these issues must be completed before routine measurements of CRP in psychiatric patients can be justified.

 Harvey W. The circulation of the blood is further confirmed by probably reasons. 

On the Motion of the Heart and Blood in Animals

https://ebooks.adelaide.edu.au/h/harvey/william/motion/chapter15.html

 Waldman SA, Terzic A. Cardiovascular health: the global challenge. 

 American Heart Association: Heart Disease and Stroke Statistics: 2004 Update. Dallas, TX: American Heart Association; 2004.

 Demyttenaere K, Bruffaerts R, Posada-Villa J, et al. Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health surveys. 

 Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. 

 Gump BB, Matthews KA, Eberly LE, Chang YF, for the MRFIT Research Group. Depressive symptoms and mortality in men: results from multiple risk factor intervention trial. 

 Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. 

 Otte C, Neylan TC, Pipkin SS, et al. Depressive symptoms and 24-hour urinary norepinephrine excretion levels in patients with coronary disease: findings from the Heart and Soul Study. 

 Licht CM, de Geus EJC, Zitman FG, et al. Association between major depressive disorder and heart rate variability in the Netherlands Study of Depression and Anxiety (NESDA). 

 Porges SW. Cardiac vagal tone; a physiological index of stress. 

 Kop WJ, Stein PK, Tracy RP, et al. Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with expression. 

 Hage B, Britton B, Daniels D, et al. Low cardiac vagal tone index by heart rate variability differentiates bipolar from major depression. 

 Hage B, Britton B, Daniels D, et al. Heart Rate Variability predicts treatment outcome in major depression. 

 Pavlov V, Tracey K. The cholinergic anti-inflammatory pathway. 

 Halaris A. Myint A-M, Savant V et al. 2015. Does escitalopram reduce neurotoxicity in major depression? 

 Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. 

 Koenig W. Inflammation and coronary heart disease: an overview. 

 Mulvihill NT, Foley JB. Inflammation in acute coronary syndromes. 

 Connor TJ, Leonard BE. Depression, stress and immunological activation: the role of cytokines in depressive disorders. 

 Lind L. Circulating markers of inflammation and atherosclerosis. 

 Frasure-Smith N, LespÃ©rance F, Irwin MR, et al. Depression, C-reactive protein and two-year major adverse cardiac events in men after acute coronary syndromes. 

 Pizzi C, Mancini S, Angeloni L, et al. Effects of selective serotonin reuptake inhibitor therapy on endothelial function and inflammatory markers in patients with coronary heart disease. 

 Hiles SA, Baker A, de Malmanche T, et al. Interleukin-6, C-reactive protein and interleukin-10 after antidepressant treatment in people with depression: a meta-analysis. 

 Chavda N, Kantharia ND, Jaykaran. Effects of fluoxetine and escitalopram on C-reactive protein in patients of depression. 

 Halaris A. Do antidepressants exert effects on the immune system? In: Mueller N, Myint A-M, Schwarz MJ, Eds. 

Immunology and Psychiatry, Current Topics in Neurotoxicity

Angelos Halaris, MD

Articles

Psychocardiology, Part 2: Fixing the Broken Heart

Psychocardiology: Understanding the Heart-Brain Connection: Part 1