ADOLESCENCE AND DEPRESSION: REDUCING CARDIOVASCULAR DISEASE THROUGH PREVENTIVE HEALTH CHECKS by Ashley Elizabeth Gueret BSN, Malaspina University-College, 2007 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN NURSING: FAMILY NURSE PRACTITIONER UNIVERSITY OF NORTHERN BRITISH COLUMBIA JULY 2017 © Ashley Gueret, 2017 ii ABSTRACT Adolescent depression is a prevalent, serious health condition seen in primary care that is associated with many adverse physiologic changes, including cardiovascular disease. The aim of this integrative review was to examine those cardiovascular changes and determine whether preventive health checklists can help screen, identify, and ultimately prevent these changes. The eight studies selected for this review do not provide enough evidence to support the use of preventive health checklists as a way to prevent the cardiovascular effects of depression in adolescents. However, they form the basis for recommendations to be implemented in the primary care setting for ways to mitigate the risk of cardiovascular disease in adolescents with depression including using a multidisciplinary approach and guidelines for monitoring vital signs, weight, and bloodwork of these adolescents. Areas for future research are suggested and limitations of the evidence are also acknowledged. Keywords: adolescent, depression, cardiovascular disease, preventive health checklists, primary care, nurse practitioner iii TABLE OF CONTENTS Abstract……………………………………………………………………………………...…. ii Table of Contents……………………………………………………………………………... iii List of Tables and Figures……………………………………………………………………... v Acknowledgements…………………………………………………………………………….vi Introduction…………………………………………………………………………………….. 1 Chapter One Background ……………………………………………………………. 5 Depression in Adolescence ……………………………………………. 5 Prevalence ……………………………………………………… 6 Physiology ……………………………………………………... 7 Screening for depression ………………………………………. 9 Treatment of Depression in Adolescents ……………………………. 10 Talking therapies …………………………………….............. 11 SSRIs………………………………………………………….. 12 Risks of SSRI use ……………………………………………...14 Cardiovascular Health Risk in Depression ……………………………14 Contribution of depression to cardiovascular disease …….…. 15 Behavioural factors …………………………………….16 Biological factors ………………………………………17 Pharmacological factors ……………………………….18 Screening of cardiovascular risk factors ………………………18 Cardiovascular risk predictors in adolescence ………………. 19 Lack of Preventive Health Checks for Patients With Mental Illness…21 Relevance to Scope of Practice and Role of NP ……………………...25 Primary health care and depression …………………………...27 Chapter Two Methods ………………………………………………………………. 32 Stage One: Identification of Issue and Search Strategy …………….. 32 Stage Two: Focused Search ………………………………………….. 34 Stage Three: Study Quality Analysis …………………………………35 Stage Four: Identification of Key Themes …………………………... 37 Chapter Three Findings ………………………………………………………………. 39 Gender Differences in the Expression of Cardiovascular Risk ……... 39 Diagnosis of Clinical or Self-Reported Depression …………………. 43 Pathophysiological Changes of Depression …………………………. 50 Arterial stiffness ……………………………………………….51 Endothelial dysfunction ……………………………………….53 Microcirculation changes …………………………………….. 55 Measures of Traditional Clinical Cardiovascular Risk Predictors……57 Physical measurements and family history ………………….. 57 iv Blood analysis ………………………………………………... 58 Review Limitations ……………………………………………………61 Chapter Four Discussion and Recommendations …………………………………....62 Gender, Diagnosis, and Clinical Measures …………………………...62 Preventive Health Checklists ………………………………………… 64 Treatment and Management Recommendations …………………….. 68 Chapter Five Conclusion …………………………………………………………..... 76 Glossary ……………………………………………………………………………………….77 References ………………………………………………………………………………….....79 Appendix A ……………………………………………………………………………………89 Appendix B ……………………………………………………………………………………97 v LIST OF TABLES AND FIGURES Table 1: Inclusion and Exclusion………………………....…..………………………………. 34 Table 2: Stage Two Focused Search Results Criteria ……………………………………… 35 Table 3: Evidence Rating for Research…..………………………………………….……… 37 Table 4: Summary of Recommendations……………………………………………………....75 Figure 1: Flowchart of articles………………………………………………………………...88 vi ACKNOWLEDGEMENTS The author thanks Lela Zimmer and Celia Evanson for their contributions to this project. The author would also like to acknowledge the generous contribution of the Canadian Nurses Foundation, whose support has enabled me to focus more time and energy on this project. Special thanks to my fellow UNBC Family Nurse Practitioner students whose friendship and honesty has been a constant source of strength and guidance, without which I would not be where I am today. Finally, I would like to extend an enormous thank you to all those that have joined me in celebrating successes and helped to lift me through the hard times, including my family for their unfailing support, the friends who have been by my side through thick and thin with their words of encouragement, comfort food, and wisdom, and all those lost too soon that never got to see me through to the end - I could not have done it without all of you. vii ABSTRACT Adolescent depression is a prevalent, serious health condition seen in primary care that is associated with many adverse physiologic changes, including cardiovascular disease. The aim of this integrative review was to examine those cardiovascular changes and ultimately treat depression in adolescents to prevent cardiovascular changes from occuring. The eight studies selected for this review do not provide enough evidence to support the use of preventive health checklists as a way to prevent the cardiovascular effects of depression in adolescents. However, they form the basis for an approach for comprehensive primary care that could help to mitigate the risk of cardiovascular disease in adolescents with depression , including using a multidisciplinary approach and guidelines for monitoring vital signs, weight, and bloodwork of these adolescents. Areas for future research are suggested and limitations of the evidence are also acknowledged. Keywords: adolescent, depression, cardiovascular disease, preventive health checklists, primary care, nurse practitioner 1 INTRODUCTION Adolescent depression is a serious health issue that has a high prevalence rate and a heavy burden of current and future morbidity (Thapar, Collishaw, Pine, & Thapar, 2012). In Canada, one in 20 young men and one in ten young women have experienced a major depressive episode while 40% of adolescents are sad for more than five days per year and 22% are hopeless and stressed (Acharya & Phillips, 2014; Black, Hamilton, Platzer, & Seal, 2014; Canadian Mental Health Association [CMHA], 2016). Additionally, 62% of 12-yearold children have so much stress and despair that they feel like their life is not worth living (Black et al., 2014). Almost half of all mental health disorders in adults have been present since adolescence and nearly 75% by the age of 21 (Van Cleve, Hawkins-Walsh, & Shafer, 2013). While the association between mental illness and physical health conditions such as cancer, heart disease, diabetes, arthritis, and asthma are well established and researched in adults (Miller, Constance, & Brennan, 2007) the future morbidities and negative health consequences of depression in adolescents are not as well known, although it has been suggested that future morbidities such as asthma, cardiovascular disease, and chronic headaches are associated with adolescent depression (Miller et al., 2007). This integrative literature review will examine what can be done by primary care practitioners who work with adolescents that have depression to mitigate their risk of future cardiovascular comorbidities. This topic arises from my experience working with adolescents suffering from depression. I work in acute care pediatrics and over the past several years I have noticed an influx of adolescents being admitted to hospital for depression. Many of these teenagers are admitted for stabilization after months of being depressed and on antidepressants. Most have 2 had multiple appointments with their primary care providers (PCP), yet while in hospital these adolescents have abnormal findings with their bloodwork and vital signs that show early hepatic, cardiac, or metabolic changes. The pediatricians and PCPs report that they do not know for how long the dysfunctions have been present and are unable to ascertain whether permanent changes have already begun to result in chronic illnesses or comorbidities for the adolescents. The role of the family nurse practitioner (FNP) is to work to promote, restore, and maintain health as well as prevent and treat illnesses for all patients, including adolescents with depression (College of Registered Nurses of British Columbia [CRNBC], 2016). It is well understood that patients who suffer from depression are at an increased risk of chronic illness due to poverty, social isolation, and unemployment, all of which are factors that are difficult, though not impossible, for NPs to influence or change (CMHA, Ontario, 2008). However, there may be other factors that NPs could influence or affect to decrease the likelihood of an adolescent with depression later manifesting a chronic illness. CMHA Ontario (2008) reported that people with serious mental illness who have access to primary care are not as likely to receive preventive health checks as their peers. The current national recommendation for preventive health checks for all adolescents is every one to two years (Greig et al., 2016), while the provincial recommendation is to have regularly scheduled checkups monitoring blood pressure, hearing, vision, weight, height, body mass index, and school and behavioural problems including severe mood swings, lack of pleasure or withdrawal from daily activities (Healthwise Staff, 2016). It is within this gap of higher morbidity and mortality rates for patients with mental health and whether preventive health checks would improve those outcomes, that this project will focus. 3 Adolescents with depression were selected for study because a review of the current literature suggests that much is known about the effects of depression on the physical health of adults but few studies have investigated the prevalence and association of mental health disorders and physiological health problems in adolescents (Aarons et al., 2008). In Canada, 70% of patients with mental illness state that their symptoms began in childhood or adolescence, thus the identification and treatment of depression, as well as the prevention of associated chronic illnesses are best suited to be addressed in adolescence (Acharya & Phillips, 2014). CMHA Ontario (2008) identified several barriers to health care for people with mental illness, including difficulty finding a PCP because providers are reluctant to take patients with mental health diagnoses, stigma that leads to ‘diagnostic overshadowing’ of physical health conditions as psychologically manifested conditions, decreased access to specialist care and surgical treatment, the need for longer appointment times, and decreased preventive health checks within the primary care setting. It is opportune to focus on preventive health checks because their usefulness for illness prevention and health promotion. Preventive health checks are key tools in primary care praction components and are endorsed and recommended for use in adults by the College of Family Physicians of Canada for the provision of comprehensive, evidence-based care (CRNBC, 2016; Dubey & Glazier, 2006). The Canadian Task Force on Preventive Health Care (CTFPHC, 2016) provides many preventive health checklists for PCP to use in practice, one of those checklists screens for depression in adults over 18 who present to primary care but they are no preventive health checklists available for depression screening in adolescents, or to detect changes to the cardiovascular health of adolescents with depression. Thus, there exists a gap 4 in the knowledge, preventive health checklists are recommended for use in primary care in Canada, and yet there is no clinically useful preventive health checklist for use in predicting the cardiovascular health of adolescents with depression. My research question is, would having preventive health checks during primary care visits improve later cardiovascular co-morbidities in adolescents living with depression? The purpose of my research question is to determine whether a preventive care checklist can enable NPs to provide comprehensive, evidence-based care to patients during periodic health examinations for the purposes of evaluating and mitigating the risk of future cardiovascular morbidities in adolescents with depression. This review begins with an in-depth discussion of the pathophysiology, clinical manifestations, and prevalence of adolescent depression; screening methods used for identifying both depression and cardiovascular disease; current treatment recommendations and risk of side effects for depression; cardiovascular risks related to depression; risk predictors currently used to identify cardiovascular risk in adolescents; the lack of preventive health checks in practice despite their support; and the relevance of treating adolescent depression in primary care. The methods section will detail how the literature search was conducted as well as how the articles for use in the review were graded. The findings will provide an analysis of the selected papers highlighting themes for further examination. Finally, the discussion section will provide a synthesis of the current evidence followed by recommendations for practice. 5 CHAPTER ONE Background Depression is a common primary care concern affecting many Canadian youth. Major depressive disorder is a complex condition, affecting mental, social, and physical well-being. It causes not only well-known psychological symptoms, but many physical manifestations, including cardiometabolic changes. Lesser known is whether the physical signs and symptoms of depression signal cardiometabolic changes and whether they can be identified and addressed in the adolescent period during primary care visits. Thus, the objective of this integrative review is to determine whether preventive health checks can be used in adolescents with depression to avert future cardiovascular co-morbidities. This section will provide the reader with necessary background information on depression, cardiovascular risk predictors, and preventive health checks. Depression in Adolescence Depression is a serious mood disorder that affects a person’s mental and physical health by causing persistent low mood; feelings of hopelessness, self-guilt, worthlessness, or despair; fatigue and decreased energy; changes in weight and appetite; difficulty concentrating or with memory; and loss of interest or pleasure in daily activities (Public Health Agency of Canada [PHAC], 2014). Criteria for the diagnosis of major depressive disorder (MDD) includes a change from baseline, either depressed mood or anhedonia, and the daily presence over the past two weeks of at least five out of nine symptoms: 1) feeling sad, tearful, or irritable; 2) decreased interest in daily activities; 3) weight change of at least five percent; 4) difficulty sleeping or sleeping too much; 5) agitation or somnolence; 6) fatigue and loss of energy; 7) feelings of worthlessness or guilt; 8) impaired social or 6 intellectual functioning; and 9) frequent suicidal ideation or thoughts (American Psychiatric Association, 2000). In order to make the diagnosis of depression the symptoms should cause significant distress to the daily functioning of the patient, be in the absence of other conditions that may mimic major depressive disorder, and not be in the presence of mania or hypomania (American Psychiatric Association, 2000). Adolescence represents a period of rapid physical growth and maturation as well as the social, intellectual, and emotional development of youth aged 13 to 18 (PHAC, 2012). Due to the changing nature of the adolescent mind and psyche, this is also a time when mental health disorders such as depression may emerge (PHAC, 2012; Waloszek et al., 2015a). Depression often develops at the median age of 15 and is diagnosed based on similar clinical symptoms and criteria as depression in adults (Thapar, Collishaw, Pine, & Thapar, 2012; Van Voorhees, Paunesku, Gollan, Kuwabara, Reinecke, & Basu, 2008). Depression is often a lifelong mood disorder that typically emerges at age 15 due to life-altering social and emotional changes and is marked by significant and pervasive physical and psychological symptoms. Prevalence. Adolescent depressive disorder is a serious health issue that has a prevalence rate of four percent worldwide and a heavy burden of current and future morbidity (Thapar et al., 2012). In Canada, five percent of young men and 12% of young women have experienced a major depressive episode while another 3 million adolescents are at risk of developing depression, potentially creating high economic and societal costs for Canadians (Acharya & Phillips, 2014; Canadian Mental Health Association [CMHA], 2016). Throughout the world, depression causes more disabling conditions and mortality in adolescents than any other medical condition (American Heart Association [AHA], 2015; 7 Waloszek et al., 2015a). Depression, with onset in adolescence, often perseveres into adulthood, meaning it has the potential to cause severe future chronic health disorders and comorbidities (de Ferranti & Newburger, 2016a; Suglia, 2015). The association between mental illness and future chronic physical health conditions such as cancer, heart disease, diabetes, arthritis, and asthma are well established and researched in adults (Miller, Constance, & Brennan, 2007). While the future morbidities and negative health consequences of depression in adolescents are not as well established, what is well known are the physical symptoms and psychological effects depression causes to all. Physiology. Depression is a “heterogenous disorder, involving a range of cognitive, somatic, and affective symptoms” (Bosch, Riese, Dietrich, Ormel, Verhulst, & Oldehinkel, 2009, p.944). There are several proposed theories about the pathophysiology of MDD and how it affects the brain as well as the cardiovascular, metabolic and endocrine systems within the body. Many twin and sibling studies have shown that depression is 30 to 40% familial and that family history remains the strongest genetic predictor of depression (Hasler, 2010). However, this means that 60 to 70% of depression is variable and susceptible to individual risk factors, including psychosocial stress, such as trauma, low income, low social support, and dysfunctional interpersonal relationships (Hasler, 2010). Some of the individual physiological variations that may contribute to MDD are: altered transportation of the neurotransmitter system (monoamines, dopamine, serotonin), changes to the hypothalamicpituitary-adrenal axis (HPA), altered gamma-aminobutyric acid (GABA) concentrations in the prefrontal and cortex areas of the brain, hippocampal volume loss, and circadian abnormalities (Hasler, 2010). 8 The importance of the physiological variations of depression is that many of them are also implicated in other co-morbidities, including cardiovascular disease (CVD). Those depressive physiological variations that share both familial and genetic pathways with CVD, and will therefore be examined in more detail, are the HPA axis dysfunction and changes to the neurotransmitter system. The hypothalamus is responsible for corticotropin-releasing hormone (CRH), which is discharged in response to stress and has been found to be exaggerated in individuals with depression (Hasler, 2010). Increased levels of CRH have been found to mimic many of the symptoms of MDD including alterations of appetite, sleep, and motor disturbances (Hasler, 2010). Additionally, CRH stimulates the adrenal gland to release cortisol, a corticosteroid that plays a part in increasing blood pressure, heart rate, lipid metabolism, and insulin levels (Hasler, 2010). Cortisol has been found in youth with somatic symptoms of depression and has been associated with low heart rate variability (HRV), a marker of cardiovascular dysfunction (Bosch et al., 2009). Low variation in the interval between heart beats or low HRV is a dysfunctional regulatory process of the HPA axis as well as the sympathetic nervous system, a section of the autonomic nervous system that is responsible for constricting the blood vessels and increasing the force of cardiac contractions (Mulle & Vaccarino, 2013). The neurotransmitters dopamine, serotonin, and noradrenaline are responsible for regulation of mood, concentration, and cognition; depression is thought to arise from either a depletion in or a decreased metabolism of these neurotransmitters (Hasler, 2010). Depression and its somatic and psychosocial symptoms may activate inflammatory mediators including cytokines, interleukin-6, and tumor necrosis factor, which has been shown to play an integral part in the dysregulation of the brain’s neurotransmitters and of the HPA axis (Hasler, 2010). 9 Depression is a complex pathophysiological process which contributes to the dysregulation of many different hormones and neurotransmitters and thus has multiple effects on the brain, metabolic, and cardiovascular systems. Depression contributes to cardiovascular risk through several pathophysiological functions including: increased rates of CRH from the hypothalamus, which stimulates the release of cortisol and contributes to alterations in blood pressure, lowered heart rate variability, lipid metabolism, and insulin levels; and decreased metabolism of the neurotransmitters serotonin, dopamine, and noradrenaline, which increase the production of the body’s stress and inflammatory mediators. Depression causes the body to react to stress, thus changing the pathophysiological functions of the body. If these changes are left unchecked, it can lead to a chronic state of stress and increase the risk of cardiovascular morbidity. Screening for depression. Depression in adolescence often goes unrecognized and is therefore undertreated as compared to adults due to the fact that adolescents’ symptoms often fluctuate between irritability and sadness, which can be mistaken for normal teenage mood reactivity as opposed to depression (Thapar et al., 2012). This is important because even youth who receive treatment for MDD may progress to recurring or treatment-resistant depression in adulthood putting them at higher risk of morbidity and disabling conditions in the future (Van Voorhees et al., 2008). MDD is often cyclical, with periods of exacerbations and remissions happening frequently throughout the course of a lifetime. During periods of exacerbation, the levels of cortisol and other inflammatory mediators increase causing sympathetic nervous system dysfunction that over time can cause dysfunction and eventually permanent damage. 10 The significant negative health, disability, and societal costs of depression have prompted many experts including the American Academy of Pediatrics and the US Preventive Services Task Force to recommend depression screening annually for all adolescents (Kelly, 2016). The Guidelines and Protocols Advisory Committee (2010) recommend periodically screening children and youth for early depression in British Columbia while Greig et al. (2016) in a position statement for the Canadian Pediatric Society recommend following the US Preventive Services Task Force guideline of annual screening, provided there are systems for the treatment of depression in place. These differences of expert opinions results in a controversy of care for healthcare providers about how often routine screening for depression in adolescents should be done. Depression screening is important not only to identify those at highest risk of suicide, one of the leading causes of death for adolescents (Kelly, 2016), but also to identify those adolescents with depression that require further screening for CVD risk. Routine preventive health screening represents an important component of the adolescent periodic health encounter, not only for identifying depression, but for identifying it early enough to both effectively treat MDD, prevent suicide, and to significantly mitigate the risk of other long-term physical health sequelae, including cardiovascular disease. Treatment of Depression in Adolescents Treatment of depression in adolescents is important to not only mitigate the physical and psychological effects of depression, but also to decrease the pathophysiological changes that occur during depression to also decrease the CVD and other morbidity risks. The symptoms of depression (see page 5) can cause many physical, social, and occupational impairments for adolescents, thus both the screening and the treatment of depression are 11 cost-effective ways of decreasing risk for CVD as well as decreasing expenses due to future comorbid health conditions (Miller et al., 2007; Vitiello et al., 2006). Adolescents are treated for depression most often because of impaired functioning; decreased quality of life; somatic symptoms; disruptive, antisocial, or aggressive behaviours; suicidal behaviours; hallucinations, delusions or abnormal perception; and hyperactivity, inattention, or concentration problems (Vitiello et al., 2006). Several longitudinal studies suggest that 6090% of MDD episodes in adolescence will go into remission within one year, however within five years 50-70% of patients will develop depressive symptoms again (Thapar et al., 2012). Treating adolescent depression in the most effective manner is essential for decreasing the detrimental and persistent effects of depression as only one third of adolescents are able to return to their pre-depression level of functioning after three months of optimal treatment (Vitiello et al., 2006). This failure to return to the adolescents’ previous level of functioning perpetuates somatic symptoms and decreased quality of life that eventually leads to chronic medical conditions. Talking therapies. Basic interventions for any youth with MDD include having regular routines for sleep, eating, and exercise; having consistent parenting that maintains boundaries, limits, and consequences; and encouragement to avoid any substances or alcohol (Guidelines and Protocols Advisory Committee [GPAC], 2010). Options for moderate to severe persistent symptoms of MDD include cognitive behavioural therapy (CBT), interpersonal psychotherapy (IPT), and antidepressants including selective serotonin reuptake inhibitors (SSRIs) (GPAC, 2010; Thapar et al., 2012). Generally, CBT and IPT are first line treatment options and accepted as moderately effective for mild depression in adolescents (Thapar et al., 2012). Both first line treatment options can also be used as 12 adjuncts to antidepressant medication for more treatment-resistant depression (Thapar et al., 2012). The biggest issue with CBT and IPT may not be their effectiveness or safety profile for the treatment of depression but rather the lack of qualified professionals to perform these specialized treatments and accessibility to these services in certain communities. Research has found that combining treatments used for depression has greater effectiveness for improving physical symptoms, quality of life, and overall functioning. These combined treatments include using both talk therapy and SSRIs, such as fluoxetine, as well as using physical activity interventions with a CBT approach (Parker et al., 2016; Vitiello et al., 2006). Physical activity is a low-cost, effective adjunct treatment for depression that not only improves the somatic symptoms of MDD but may mitigate the risk of cardiometabolic risk as well. SSRIs. SSRIs are the primary medication recommended for the treatment of adolescent mood disorders (Korczak, Canadian Pediatric Society Mental Health, & Developmental Disabilities Committee, 2013). SSRIs act to inhibit the transportation, impede the reuptake and increase the amount of serotonin in the brain (Korczak et al., 2013). They have been found to be moderately effective and more beneficial than harmful in children and youth (Korczak et al., 2013). However, while SSRIs have been approved for use in adolescents with depression by the Federal Drug Administration in the United States, they have not been approved by Health Canada (Garland, Kutcher, Virani & Elbe, 2016; Korczak et al., 2013). Yet, the Canadian Pediatric Society (CPS) supports the use of SSRIs for the treatment of MDD in adolescents and children (Korczak et al., 2013). Particularly, the CPS supports fluoxetine for treatment of MDD in adolescents as the majority of robust evidence has found fluoxetine to be generally well tolerated by both children and adolescents 13 (Korczak et al., 2013). Fluoxetine has been found to have some dose-dependent short-term side effects such as gastrointestinal upset, changes to sleep, headaches, restlessness, and appetite changes, all of which tend to disappear over time (Korczak et al., 2013). While fluoxetine has shown a 30-60% response rate in adolescence, the remission rates remain quite low, and there has yet to be consistently documented efficacy in trials (Garland et al., 2016). Further, the number of adolescents that need to be treated (NNT) for one extra patient to achieve symptom control is four compared with a number needed to harm (NNH) of 50112 for a suicide related event, or NNH of four to ten for any side effects (Garland et al., 2016; Korczak et al., 2013). Thus, there appears to be a favourable risk-benefit profile for fluoxetine, but insufficient or conflicting evidence in order to achieve Health Canada’s full support in the treatment of adolescent MDD. When initiating treatment for adolescent depression close initial monitoring of symptoms, adverse effects, and cardiometabolic changes should be noted by PCPs. This monitoring should occur weekly for four weeks after the adolescent starts medication, followed by every two weeks for four weeks, once at 12 weeks, and then as needed but no less than yearly (Korczak et al., 2013). Treatment of MDD with SSRIs should begin with a goal of achieving full remission and reaching the lowest effective dosage over one to two weeks (Korczak et al., 2013). It is detrimental to have an adolescent remain on a starting dose of medication for a long period of time if he or she continues to display symptoms, therefore adolescents should have their SSRI increased until complete response is achieved (doses are often similar to that of adults) and then continue for six to 12 months to decrease relapse (Korczak et al., 2013). Optimizing medication and monitoring of treatment in 14 adolescent MDD is important for both minimizing adverse effects associated with SSRIs and also for decreasing the likelihood of developing chronic and persistent health conditions. Risks of SSRI use. Fluoxetine is the most commonly used medication in the treatment of adolescent depression; however, citalopram has also been approved for use by the FDA (Korczak et al., 2013). In addition to cardiovascular risks induced by stress and depression, some SSRIs, as well as second generation antipsychotics used to treat depression, can cause adverse cardiometabolic changes. Both the FDA and Health Canada have issued warnings about the potential QT-interval prolongation and risk of arrhythmia that can occur with doses of citalopram greater than 40mg per day (Korczak et al., 2013). Therefore, adolescents with congenital prolonged QT syndrome, heart disease, or liver impairment should not be treated with citalopram or should be treated with caution and monitored closely (Korczak et al., 2013). In addition to the cardiac side effects there has been much concern over the increased risk of suicidal ideation and activity with SSRIs. This risk can be mitigated both by reaching the minimum effective treatment dosages within one to two weeks and by close clinical monitoring of the adolescents over the first 12 weeks of treatment (Korczak et al., 2013). However, given that the NNH of suicide is between five to ten times more than the side effects of SSRIs, the risk of suicidality is higher in untreated depression than with SSRI treatment. Cardiovascular Health Risk in Depression In addition to the cardiometabolic risk associated with some medications, depression has long been associated with adverse physical health outcomes and increased morbidity and mortality. In adolescents with depression these health outcomes include chronic conditions such as asthma and headaches as well as increased infectious diseases and problems with 15 weight (Aarons, Monn, Leslie, Garland, Lugo, Hough, & Brown, 2008; Miller et al., 2007). While many studies have outlined the relationship between cardiovascular disease (CVD) and depression in adults, only recently have researchers begun to question and identify whether depression in adolescence contributes to early markers of CVD as well. The bidirectional relationship between depression and CVD in adults results in higher rates of myocardial infarction (MI), increased mortality, and poor cardiovascular health due to cardiomyopathy and coronary artery disease (Elderon & Whooley, 2013; Miller et al., 2007; O’Neil et al., 2016b; Smolderen et al., 2015). As a result, there is an increased burden of CVD in healthcare, making it prudent to understand not only the traditional and nontraditional contributory risk factors but also the physiologic changes these factors cause and when in the course of illness these changes occur. In the past, CVD was considered a disease of middle-aged and older men that smoked, had high blood pressure and high cholesterol, were overweight or obese, and physically inactive. Today, CVD is not only the second leading cause of all deaths in Canada for men but for women as well (Statistics Canada, 2012). Additionally, statistics show that nine out of 10 Canadians have at least one risk factor for CVD while four out of 10 have at least three or more risk factors (Government of Canada, 2016). While the traditional risk factors of age, gender, family history, ethnicity, smoking, high blood pressure, diabetes, increased cholesterol levels, obesity, and physical inactivity remain important causes of CVD, there is increasing evidence that psychosocial factors, such as depression and stress contribute heavily to the occurrence of CVD and MI (Elderon & Whooley, 2013; O’Neil et al., 2016b). 16 Contribution of depression to cardiovascular disease. There are multiple biological, behavioural and pharmocological factors that have been implicated in the bidirectional relationship between CVD and depression. Some of the behavioural factors include increased rates of smoking, poor diet, and physical inactivity which are more predominant amongst those with depression (Elderon & Whooley, 2013). The pharmacological factors include medication nonadherence and adverse effects from antidepressant medications (Elderon & Whooley, 2013). Finally, the biological links between depression and CVD include lower HRV, increased catecholamine levels, platelet activation, endothelial dysfunction, microvascular changes and overproduction of inflammatory mediators (Dhar & Barton, 2016; Elderon & Whooley, 2013; O’Neil et al., 2016a). Although the clinical manifestations of CVD are not usually apparent until middle age, the atherosclerosis process begins in childhood and adolescence, first as fatty streaks, the precursor of plaque, in the aorta during childhood and then in the coronary arteries by adolescence (Rodrigues, Lima, Carvalho, Vera, Frota, Lopes, & Oliveria, 2015). Systemic arterial hypertension has been identified as a independent risk factor of CVD in adolescents, but is a more powerful risk factor when combined with a high BMI (Rodrigues et al., 2015). Other important adolescent CVD risk factors include family history, sedentary activity, and poor nutritional status (low fruit and vegetable consumption with high intake of fats and carbohydrates) (Rodrigues et al., 2015). Behavioural factors. Depression can change a person’s cognitive functioning by decreasing their insight, judgement, and concentration, as well as affecting their sleep habits which may impair their energy (CMHA Ontario, 2008b). These changes to cognition and energy may negatively impact the person’s ability, initiative, and motivation to adopt healthy 17 behaviours such as not smoking, physical activity, and a healthy diet (CMHA Ontario, 2008b). MDD can feel all-consuming, making accomplishing the smallest things difficult so people feel like they have little ability to make important health changes. Moreover, people may self-medicate with drugs and alcohol as a consequence or response to their depressive symptoms, which can also increase risk for CVD (CMHA Ontario, 2008b). Biological factors. Inflammation, HPA axis activation, and sympathetic nervous system deregulation interact in a significant way to form a strong correlation between MDD and CVD. The effects of stress and depression on CVD include the development of endothelial dysfunction, platelet activation, glucose intolerance, increased visceral fat mass, and increased catecholamine, cytokine, and cholesterol production (Dhar & Barton, 2016; Elderon & Whooley, 2013). These biologic adaptations cause physiologic changes to the heart such as cardiac dysrhythmia, decreased blood flow, increased blood viscosity, atherosclerosis, hypertension, left ventricular hypertrophy, and decreased HRV, all risk factors contributing to cardiac mortality and MI (Dhar & Barton, 2016; Elderon & Whooley, 2013). A healthy heart should have beat-to-beat variations in response to autonomic nervous system changes (Dekker, Crow, Folsom, Hannan, Liao, Swenne & Schouten, 2000). The input from the nervous system may include activation of the fight-or-flight system, communicating to the heart to either beat faster to pump more blood to the body or for the heart to slow down to conserve energy. In a person with depression, there is low HRV, meaning that the autonomic nervous system and the heart are less able to react to changes in the environment, increasing cardiovascular risk and mortality (Dekker et al., 2000). While biologic and physiologic signs of inflammation have been linked to both CVD and MDD, 18 there are many different factors at work causing much overlap in the bidirectional relationship between the two illnesses. Pharmacological factors. Antidepressants are the mainstay of treatment for depression, however, they do have several negative effects to the cardiovascular system including bradycardia (low heart rate), tachycardia (fast heart rate), low blood pressure, orthostatic hypotension, electrocardiogram changes, electrolyte abnormalities, decreased cardiac conduction and output, arrhythmias, and sudden cardiac death (Yekehtaz, Farokhnia, & Akhondzadeh, 2013). SSRIs are used as first-line treatment for depression because of their favorable side effect profile, as such adverse cardiovascular events are mild and less likely to occur at therapeutic levels (Yekehtaz et al., 2013). The most common cardiovascular side effects of SSRIs are mild bradycardia, orthostatic hypotension, and QT interval prolongation (Yekehtaz et al., 2013). Screening of cardiovascular risk factors. Recently, CVD has been found to be more prevalent amongst young women, aged 25-55 with a prior or concurrent history of depression (O’Neil et al., 2016b; Smolderen et al., 2015). Among women the more severe the prior or current depressive symptoms were, the greater the risk of CVD (O’Neil et al., 2016b). Yet, the risk of CVD was still present even if the women did not have a diagnosis of MDD but rather simply symptoms of depression (Elderon & Whooley, 2013). In fact, women with MDD or depressive symptoms have an increased risk of acute MI that is independent of other comorbid conditions, traditional cardiovascular risk factors, and previous health status (Elderon & Whooley, 2013; Smolderen et al., 2015). Given that most CVD-related deaths are preventable, assessment of both traditional and non-traditional, as well as modifiable and non-modifiable risk factors remains a priority. 19 Younger women are more likely to experience depressive symptoms over their lifetime and are more likely to die from CVD than ever before (O’Neil et al., 2016a). In Canada, females with depression are 80 percent more likely to have CVD than their non depressed counterparts (CMHA Ontario, 2008b). The American Health Association understands the significant role depression plays in cardiac mortality and nonfatal cardiac events, which made them add depression as a moderate risk factor for CVD (O’Neil et al., 2016a; O’Neil et al., 2016b). Assessments for 10-year risk of CVD, such as the Framingham Risk Equation (FRE), are completed in primary care on both male and female patients aged 30-74 by healthcare practitioners (D'Agostino, Vasan, Pencina, Wolf, Cobain, Massaro, & Kannel, 2008). Many primary care providers use risk prediction screening to help patients make informed decisions about the harms versus benefits of treatment for a certain condition , in the case of the FRE, the tool predicts absolute CVD risk of developing either a MI, angina, coronary insufficiency, heart failure, stroke, or intermittent claudication. Currently the FRE does not take into account the increased risk depression infers for CVD, despite many adult studies showing that depression is linked to CVD. Additionally, there is a growing amount of evidence that CVD begins in adolescence and shares many of the same pathophysiological changes as those seen in adults, including increased blood pressure and dyslipidemia, yet there is currently no tool for use by primary care providers to screen or predict cardiovascular risk in the adolescent population. This lack of cardiovasular risk screening appears to be largely due to the fact that there have been no long term studies done to identify which risk factors in youth are most predictive of future cardiovascular morbidity and a lack of consistency about which clinical manifestations confer the most risk from adolescence to adulthood (Bloetzer, Bovet, Suris, Simeoni, Paradis, & Chiolero, 2015). 20 Cardiovascular risk predictors in adolescence. The FRE predicts cardiovascular risk in adults based on an algorithm that accounts for age, total cholesterol, HDL, nontreated or treated systolic blood pressure (SBP), smoking, and diabetes (D’Agostino et al., 2008). While the same physiologic and biologic pathways and changes exist in the bidirectional relationship between depression and CVD in adolescents, cardiovascular risk predictors differ slightly in children and adolescents from that of adults. Early identification of CVD is becoming more imperative as the occurrence of cardiovascular mortality and non-fatal MIs in young men and women increases, and yet there are no validated CVD risk predictor tools for use in adolescence, further underlining the need for accurate prevention and intervention (Bauer, Marcus, El ghormli, Ogden, & Foster, 2014). The strongest predictor of cardio-metabolic risk in adolescents is increased body mass index (BMI), which is positively associated with elevated insulin levels, increased triglycerides, and decreased HDL levels, risk factors common with CVD in adults (Bauer et al., 2014). Studies have shown that having a BMI greater than the 95th percentile has a better predictive ability for cardiovascular risk than either waist circumference or waist-to-height ratio alone or in combination (Bauer et al., 2014). Additionally, elevated BMI is superior to distinguishing adolescents with a clustering of three or more cardiovascular risk factors, making it something that can be easily identified and monitored throughout adolescence and into adulthood (Bauer et al., 2014). Thus, adolescents with a BMI in the 95th or higher percentile are predicted to have at least three cardiovascular risk factors, which without intervention will carry on into adulthood inferring considerable risk of future CVD, including atherosclerosis. 21 Many studies have shown that risk factors measured in adolescents and early adulthood predict atherosclerosis in adults aged 30 to 45 years (Gidding et al., 20 16). The physiological risk factors for atherosclerosis in middle age were measured using pathobiological determinants of atherosclerosis in youth (PDAY) scores, which measures age, gender, non-HDL cholesterol, HDL cholesterol, smoking, blood pressure, obesity and hyperglycemia (Gidding et al., 2016). As each risk factor is added, a one-point increase in the score is also added. An increase in the total score is associated with the odds ratio for an increase in atherosclerosis that would occur with one year of aging (Gidding et al., 2016). There is a strong association between the PDAY risk score measured in young adulthood and the presence and severity of coronary atherosclerosis in middle age (Gidding et al., 2016). Further, an increase in the PDAY risk score of young adults has a strong prediction for coronary artery calcium (CAC), a non-invasive measure of atherosclerosis (Gidding et al., 2016). In fact, measuring risk for CAC between the ages of 18 and 30 better predicts CAC in middle age (Gidding et al., 2016). This suggests that atherosclerosis risk should be screened, assessed, and lowered in adolescence and early adulthood when progression of vascular lesions can be slowed or even stopped. Lack of Preventive Health Checks for Patients with Mental Illness Due to the chronic nature of mental illness and the relationship between mental illness and chronic health conditions, there is a need for both chronic disease management but also prevention. While most mental illnesses are not preventable, the chronic diseases associated with mental illness can be mitigated, reduced, and perhaps even prevented, through a means of health promotion, disease prevention, access to primary care and continuity in care but only if those risks are targeted early enough in the course of the disease. Identifying which 22 specific morbidities an individual is most at risk for allows the healthcare professional to tailor which health promotion strategies the patient should focus on. Despite the fact that individuals with serious mental illness, including depression, have poorer health outcomes and higher mortality rates, people often lack access to preventive health screenings (CMHA Ontario, 2008a; CMHA Ontario, 2008b). Even patients with depression that have access to primary care are less likely to receive preventive health checks than those patients without mental illness (CMHA Ontario, 2008b). Preventive care, or identifying those at risk of a disease but who have not yet been formally diagnosed with the disease, has been stressed as important for the health o f all patients and touted as a foundation of primary health care (Lord, Malone, & Mitchell, 2010; Kelly, 2016). Preventive health checks are imperative for not only reducing mortality but also for increasing quality of life and reducing barriers to care (CMHA Ontario, 2008b; Lord et al., 2010). Preventive screening is well supported within Canadian healthcare for a variety of populations and diseases. The College of Family Physicians of Canada (2015) and the Canadian Task Force of on Preventive Health Care (CTFPHC, 2016) support preventive health checklists as a way to provide comprehensive, evidence-based care to patients. The principles of screening are to identify individuals who are at a higher risk of disease or to identify a disease that has a high prevalence in a seemingly healthy population (Kelly, 2016). Also, preventive screening helps recognize individuals at risk of substantial morbidity and mortality if a disease goes untreated as well as the preclinical detection of a disease that may be detectable and improved, avoided, or treated more easily before the full course of the disease sets in (Kelly, 2016). 23 Historically, primary care providers have provided low to moderate rates of preventive health to patients due to decreased awareness of guidelines, lack of familiarity with implementing guidelines, lack of belief that health outcomes can be changed, and lack of visit time (Dubey, Mathew, Iglar, Moinnedin, & Glazier, 2006). This has changed in recent decades as evidenced by easily accessed standards and practice guidelines on CPC and specialist college and government websites (e.g. http://www2.gov.bc.ca/gov/content/health /practitioner-professional-resources/bc-guidelines). As an adjunct to guidelines, the use of preventive health checklists has been found to improve the delivery of preventive health care to a clinically significant degree and has therefore been endorsed as an important approach for the health maintenance and prevention of disease by the College of Family Physicians of Canada and the CTFPHC (Dubey et al., 2006). Preventive health checks should be done yearly as part of a patients’ physical health exam. However, preventive health checks can be used any time as a quick and efficient way of addressing the relevant and pertinent risk assessments of each patient. Both depression and CVD are important diseases with high morbidity and mortality rates, warranting preventive screening. Screening for depression is recommended in children and adolescents between the ages of 10 and 18 every one to two years by the American Academy of Pediatrics and the Canadian Pediatric Society (CPS) (Greig et al., 2016; Kelly, 2016). The CPS (2016) and the Ontario Centre for Excellence for Child and Youth Mental Health (2016) recommend the following validated and reliable screening tools for use in diagnosing adolescents with depression: Patient Health Questionnaire (PHQ-9), Child Depression Inventory 2 (CDI-2), Beck Depression Inventory (BDI), Quick Inventory of Depressive Symptoms (QIDS), Mood and Feelings Questionnaire (MFQ), Reynolds Adolescent Depression Scale (RADS), and the 24 Kutcher Adolescent Depression Scale 6 (KADS-6). However, there is currently not enough evidence to provide clear guidelines around screening recommendations for pediatric and adolescent prevention of adult CVD including hypertension or dyslipidemia (de Ferranti & Newburger, 2016b). We do know that atherosclerosis can begin in childhood and adolescence and that certain youth are at increased risk for CVD based on their comorbidities, warranting screening for CVD in at least some of this population. While CVD screening and prevention in youth may not be well studied, CVD risk assessment in adults is, and includes the FRE. The FRE is an individual risk assessment tool widely used in current practice for the prevention of CVD as well as to help guide practice about when to appropriately treat patients to prevent future cardiovascular events (de Ferranti & Newburger, 2016b). The FRE is recommended by the College of Family Physicians of Canada and used as part of the preventive health checks for adults. Currently, the Canadian Pediatric Society (CPS) uses the Greig Record as a guide for preventive care visits in adolescents, however it does not include any recommendations around the screening of CVD in youth. Thus, a gap has been identified between the recommendations from the AHA to screen for cardiovascular risk in adolescents with depression and how this information is being translated into practice for use to screen and identify those adolescents most at risk. Additionally, international guidelines recommend that all patients prescribed medications for mental illness should have regular reviews of cardiovascular risk factors, including fasting glucose, lipid panel, and BMI (Osborn, Baio, Walters, Petersen, Limburg, Raine, & Nazareth, 2011). Osborn et al. (2011) found that patients with mental illness have decreased rates of BMI measurement, BP recording, cholesterol testing, and glucose levels. In fact, people with mental illness such as depression are half as likely to be screened for 25 CVD risk factors, as people without mental illness (Osborn et al., 2011). A comparative analysis of 26 different studies with 61 comparisons found that patients with mental illness were more likely to have inferior preventive health care in almost half of all compariso ns, most apparent in osteoporosis screening, BP monitoring, vaccinations, mammography, and cholesterol testing (Lord et al., 2010). In adults with depression there was inferior preventive care for BP monitoring and cholesterol, important risk factors to monitor CVD risk (Lord et al., 2010). Annual preventive health screening, cardiovascular risk assessment, and health promotion are recommended for all patients with mental illness by the National Institute for Health and Clinical Excellence in Great Britain (Osborn et al., 2011). Preventive health checks, when based on the best available evidence, are important for reducing barriers to care, improving quality of life for patients with mental illness, and identifying risk factors for CVD, making them useful and pertinent tool of practice for primary care. Relevance to Scope of Practice and Role of NP Recognizing, diagnosing, intervening, and treating adolescent depression are very relevant to the NP role and scope of practice. The NP role in Canada blends nursing theory and experience with advanced education, autonomy, integrity, and responsibility to emphasize an evidence-based, holistic healthcare approach that focuses on health promotion, disease prevention, and partnership development (Canadian Nurse Practitioner Initiative [CNPI], 2006; College of Registered Nurses of British Columbia [CRNBC], 2016). NPs develop therapeutic relationships, provide quality healthcare, and integrate the diagnosis and treatment of illnesses for people of all ages, including children and youth, as well as all different types of populations, such as First Nations people, people with mental illness, people with substance abuse problems, and other marginalized peoples. 26 While the NP role is distinct and separate from other professionals, it serves to supplement and complement other roles, increasing access to primary care (CNPI, 2006). Increasing access to primary care NPs is integral to the healthcare system; it allows NPs to engage patients in their own care and involve them in the decision-making process, it creates valuable and trusting therapeutic relationships between the practitioner and patients all while reducing pressures on other areas of the healthcare system (Canadian Nurses Association [CNA], 2011). Many studies show the high value NPs contribute to primary care including providing care that is safe, effective, timely, equitable, patient-centred and efficient (Naylor & Kurtzman, 2010). Patient outcomes such as mortality, satisfaction, and physical and mental functioning is comparable to that of physicians (Naylor & Kurtzman, 2010). In fact, Naylor and Kurtzman (2010) found that patients who seek care from NPs had higher satisfaction, more time for consultations, and more investigations with no differences to processes of care or cost of resources. Primary care also provides an excellent opportunity to diagnose, treat, and manage chronic illnesses such as CVD and mental illness. NPs can assess and mitigate risk, provide advice about lifestyle modification, recommend treatment, prescribe medications, and intervene for many common diseases. Both CVD and depression are more prevalent in marginalized people, and because NPs are often employed in contexts that serve vulnerable and marginalized populations, the NP role and scope of practice help to decrease barriers and stigmas and provide high quality care, health promotion, and partnership development, NPs are in a position to provide excellent healthcare for patients with both mental illness and CVD. A study found that almost 80% of FNPs treat and manage mental illness in their primary care practices while less than ten percent of NPs are considered to have specialized 27 knowledge or practice in mental illness (Munro, 2015). Having NPs either provide primary care within a community mental health setting or alongside mental health providers results in a modest increase of the self-perceived health status and functioning of patients with mental illness (Rogers, Maru, Kash-MacDonald, Archer-Williams, Hashemi, & Boardman, 2016). In addition, NPs improved coordination of formal and informal information and communication about patients’ needs, as well as provision of health promotion, prevention, and wellness services critical to many mental health patients (Rogers et al., 2016). Furthermore, NPs are particularly helpful in providing primary care to mental health patients because of their knowledge about medical comorbidities as well as the mental and physical adverse effects that can arise from psychopharmacological treatments (Rogers et al., 2016). Primary health care and depression. Primary care and primary health care are two similar but distinct concepts often used interchangeably. Primary health care refers to universally accessible health care for individuals and families in the community that they live in, by means that are acceptable to them, and at a cost that the community and country can afford (Muldoon, Hogg, Levitt, 2006). Primary health care is often the point of first contact through public health initiatives such as public health clinics by individuals, families, and communities with the national health care system. The primary health care focus is on disease prevention and health promotion while bringing both medical and curative care, support and rehabilitation where it is needed (CNA, 2005; Muldoon et al., 2006). Primary health care attempts to incorporate not only the necessities of health but also the social, economic, and physical environments that affect health, while keeping the individual an active participant in shared decision-making with healthcare professionals (CNA, 2005). Primary care is the ‘first-line’ clinical services that provide entry into the healthcare system 28 and is typically person-focused, provider-driven care based in clinical diagnosis and treatment sustained over time (CNA, 2005; Muldoon et al., 2006). Thus, NPs are members of multi-disciplinary primary care teams, who aim to provide primary care to patients and families, including the adolescent population, while integrating a primary health care focus into their practice. The World Health Organization (WHO) and the World Organization of Family Doctors (WONCA) (2008) identified seven reasons why mental health is best treated within primary care: 1) the burden of mental illness is prevalent; 2) there is a bidirectional relationship between mental and physical health and illness; 3) there is a large treatment gap for mental illness; 4) using primary care for mental illness increases access; 5) primary care for mental health promotes respect of human rights and dignity by minimizing stigma and discrimination; 6) utilizing primary care for mental illness is affordable and cost effective; and 7) including mental health in primary care improves health outcomes. Essential components of primary care services for mental health include early identification of mental illness, effective treatment of common mental disorders, management of patients with stable mental health disorders, referral to higher levels of mental health care, and mental health promotion and prevention. Therefore, the healthcare needs of adolescents with depression can be appropriately addressed by family nurse practitioners within their practice (WHO & WONCA, 2008). In Canada, 70% of patients with mental illness state that their symptoms began in childhood or adolescence, thus the intervention and treatment of depression, as well as the prevention of associated chronic illnesses is best suited to be addressed in adolescence (Acharya & Phillips, 2014). Unmet mental health needs, including adolescent depression, are 29 a serious concern within primary care in both Canada and the United States. Integrated mental health care for adolescents with depression is supported by both the chronic nature and the high prevalence of mental illness in children and youth, barriers to access appropriate care, and that care cannot and should not be dichotomized into either mental health or physical health (Van Cleve et al., 2013). This is significant because both a system and healthcare providers are needed to address, diagnose, treat, and manage adolescents with depression and cardiovascular risk. Arguments for pediatric mental health to be supported and delivered both within primary care and by primary care providers, such as nurse practitioners include: the present and future lack of access to mental health specialists; the availability of screening tools and decision algorithms to diagnose and treat common pediatric mental illnesses; the avoidance of stigma and barriers to care; and the increasing availability of holistic, multimodal, and effective treatment options (Van Cleve et al., 2013). To this end, family nurse practitioners with education and practice in pediatric development, behaviour, and mental health conditions can provide much needed healthcare and access to mental health services for children and youth with mild to moderate mental illness (Van Cleve et al., 2013). Mental healthcare is best taken up in primary care because this model of care “addresses the needs of all patients upon first point of contact” (Van Cleve et al., 2013, p.244). Primary care provides the perfect framework for addressing the mental health needs of adolescents because of the development of a long-term relationship between the provider and family/patient which may allow the provider to recognize subtle signs, symptoms, and variations of behaviour, development, and mental illness sooner. The majority of parental concerns during the adolescent period are related to behaviour and psychosocial changes 30 (Van Cleve et al., 2013). Moreover, because only one in five children with mental health issues actually receive mental health care, often due to the stigma and inability to access primary care, it is important for the early identification of mental illness to improve outcomes for children and adolescents (Van Cleve et al., 2013). The frequency of childhood and adolescent primary care visits allow NPs to recognize adolescents at risk of depression, learn about parental concerns, provide health promotion, assist with consistent parenting, and offer simple behavioural changes for youth (Van Cleve et al., 2013). Primary care allows NPs to use preventive approaches to reduce the risk of both depression and thus comorbid conditions in adolescents through early intervention of depression pathogenesis and modification of risk factors (Van Voorhees et al., 2007). Thus, already knowing and having a partnership with a provider may encourage earlier diagnosis, fosters trust, and provides the best position for adolescents with depression to receive care. Several factors influenced the development of this integrative review including: increased severity and prevalence of adolescent depression, the need to treat depression appropriately despite the risk of side effects, recent advancement of depression to a moderate risk factor for CVD by the American Heart Association, crossover of physiological effects between CVD and MDD, limited research of easy and efficient tools to screen for CVD in adolescents with MDD in primary care, and a lack of clinical guidelines about how to prevent, mitigate, and treat the risk predictors of CVD in adolescents with depression. While there may be many PCPs comfortable diagnosing, managing, and treating adolescents with depression in primary care practices, there remains aspects of these adolescents’ care that are not being properly addressed. This neglect of care adds to the detriment of not only the future health of these adolescents but also contributes to rising societal costs of both their 31 healthcare and their future function within society. The healthcare system provides many supports to aid PCPs in caring for adolescents with depression including: validated tools to screen for and diagnose depression in adolescents displaying signs and symptoms; clinical practice guidelines and protocols addressing the basic care, non-pharmacological management, and pharmacological treatment of adolescents with depression; evidence supporting the risks, benefits, and side effects of using fluoxetine, other SSRIs, and antipsychotic medication to treat adolescent depression and why treatment adolescent depression is more beneficial and safer than not treating it; and emerging research that depression in adolescents leads to long-term cardiovascular changes that put the individual at a higher relative risk of atherosclerotic changes, increased BMI, non-fatal MIs, and cardiac mortality. Additionally, there is validation that preventive health checklists provide both an efficient and reliable way to integrate important disease prevention and health promotion aspects of care into the primary care encounter, yet there are no tools available to monitor the cardiovascular risk to adolescents with MDD. The objective of this paper is to determine if preventive health checks for cardiovascular risks will help decrease future cardiovascular disease in adolescents with depression. 32 CHAPTER TWO Methods A literature review was carried out to determine if preventive health checks are effective tools for determining cardiovascular risk in adolescents with depression. The methodological process for reviewing the literature was completed in four stages. Stage One: Identification of Issue and Search Strategy Stage one began with identification of key terms related to the subjects of “adolescents”, “depression”, “preventive health check”, “cardiovascular risk predictors” and “improved health outcomes”. To ensure the search was conducted with all related terms, a concept map, thesaurus, and eMedicine Health from WebMD was used to identify synonyms and similar terms. Related medical terms for ‘depression’ include: clinical depression, major depressive disorder, dysthymia, major depression, and depressive disorder (WebMD, 2016). Some synonyms for adolescents include: teenagers, youth, young adults, teens, juveniles, and minors. Other related terms for ‘preventive health check’ include preventive screening, annual screening, or health screening. Associated terms for ‘cardiovascular risk predictors’ include: clinical risk predictors of cardiovascular mortality and cardiovascular morbidities. Lastly, related terms for ‘improved health outcomes’ are: improved quality of life; greater life expectancy; increased well-being; and decreased morbidity. The terms were further examined in a health-related database to determine the medical subject headings (MeSH) when applicable. MeSH terms for “depression”, include “depressive disorder, major” and “depression, physiological long term”. The MeSH terms for “preventive health check” are “preventive health service”, “health promotion”, “preventive health medicine”, “primary prevention” and “risk predictors”. 33 The databases used to conduct the literature search are those with relevance to health sciences, nursing, and medicine. To supply the best evidence for this integrative review, this literature search began at the top of the ‘6S pyramid’ with the highest quality evidence and searched systems, summaries, synopses of syntheses, syntheses (systematic reviews), synopses of studies and finally studies (Wilczynski & McKibbon, 2013). This led to searches of UpToDate, First Consult, ACP Journal Club, the National Guideline Clearinghouse, PubMed by MEDLINE, Science Direct, and Medline by OVID. An online search was conducted using professional and government websites such as Health Canada, Government of Canada, World Health Organization, and American Heart Association. The initial literature search was conducted in PubMed by MEDLINE, because it has natural language algorithms that find related keywords and subject headings, making it the best place to start using the following search terms: (adolescents OR youth) AND (depression OR major depression OR *depressive disorder) AND (improved physical health outcome* OR quality of life OR greater life expectancy) AND (mass screening) AND (cardiovascular risk predictors OR cardiovascular risk assessment OR cardiovascular risk management). The search implemented in Science Direct and Medline by OVID used different search terms to avoid duplication of articles and increase the robustness of search strategy. Science Direct included the terms (adolescents AND depression AND cardiovascular risk predictors AND preventive health checks) while the search in Medline by OVID included Adolescents OR youth + cardiovascular risk OR cardiovascular disease OR atherosclerosis + depression or major depressive disorder. The searches of UpToDate, First Consult, ACP Journal Club, National Guideline Clearinghouse, Health Canada, Government of Canada, World Health Organization, and American Heart Association were all conducted 34 using the key search terms ‘adolescents’, ‘depression’, ‘preventive health checks’, ‘cardiovascular risk factors’, and ‘improved health outcomes’. This strategy resulted in a total of 67,674 articles for further evaluation. Stage Two: Focused Search The search was narrowed by applying inclusion and exclusion criteria (Table 1) restricting articles to those from the last ten years, those with human subjects, English written articles, journal articles, those with abstracts available and those articles from North America, Canada, United States, Australia, New Zealand, Britain, and Europe. These countries were chosen because they are culturally and geographically more similar to Canada than Asia or Africa. Additionally, because this project focuses on depression and cardiovascular health specifically in adolescents, articles that do not have ‘depression’, ‘adolescents’, or ‘cardiovascular’ in the title or abstract were excluded. Finally, articles that did not include some focus on health promotion, health prevention or screening, or improved health outcomes were also excluded. This resulted in 53 total articles to be read in full. Table 2 details the systematic thinning of articles through the evaluation of their titles, abstracts, and text until eight original journal articles meeting all of the inclusion criteria and displaying none of the exclusion criteria were revealed for use in this integrative review. Table 1: Inclusion and Exclusion Criteria Inclusion Criteria Exclusion Criteria Publication dates less than 10 Any articles that do not focus on health promotion, years old (2006-2016) prevention, or improved outcomes Use of human subjects only Any article without ‘adolescents’ in title or abstract Written in English Any articles not based in North America, Australia, New Zealand, Britain, and Europe Journal articles only Full text available Title and abstract available Any articles without ‘cardiovascular’ in title or abstract Any articles withut ‘depression’ in title or abstract 35 Table 2: Stage Two Focused Search Results Database Search Exclusion Selection based on Abstract/Title n = 23 Read article PubMed by Medline n = 66494 Science Direct n = 912 Within 10 y n = 47992 Human subjects n = 42661 English n = 40155 Adolescents n = 3246 Abstract n = 3180 Journal articles n = 3171 Location n = 1049 n = 74 n=8 n=2 Medline by OVID UpToDate First Consult ACP Journal Club National Guideline Clearinghouse Health Canada Government of Canada WHO American Heart Association Total n = 11 n = 37 n = 39 n = 42 n = 19 n=9 n/a n/a n/a n/a n=8 n=3 n=4 n=0 n=0 n=1 n=0 n=0 n=0 n=0 n=5 n = 18 n/a n/a n=0 n=4 n=0 n=0 n = 54 n = 18 n/a n/a n=0 n=3 n=0 n=0 67,674 1132 53 8 n=5 Stage Three: Study Quality Analysis Stage three involved a detailed analysis of the chosen articles for quality of evidence . The Johns Hopkins Nursing Evidence-Based Practice (JHNEBP) Model was used to determine the quality of the eight articles. This model rates the strength of the evidence based on: 1) the type of study; 2) the strength of the study design including sample size, 36 whether participants are randomized, if there is a control group, whether the groups are treated equally, if the data collection methods are clearly described; 3) the study results including whether the results are clearly presented and analyzed properly; and 4) the study conclusions were based on clearly presented results and that the limitations are identified and discussed (The Johns Hopkins Hospital & The Johns Hopkins University, n.d.). In the JHNEBP Model evidence is rated as level I for experimental studies such as randomized controlled trials; level II for quasi-experimental studies; and level III for nonexperimental studies and qualitative reviews (The Johns Hopkins Hospital & The Johns Hopkins University, n.d.). Quality of the research is rated as follows: high or ‘A’ for research with consistent, generalizable results that have sufficient sample sizes, adequate internal and external control, and clear recommendations based on scientific results; good or ‘B’ for reasonably consistent results, sufficient sample size, some internal and external control, and fairly definitive conclusions based on fairly comprehensive literature review; and finally low/major flaws or ‘C’ for little evidence with inconsistent results, insufficient sample size, and unable to draw any conclusions (The Johns Hopkins Hospital & The Johns Hopkins University, n.d.). The articles chosen for this integrative review included one meta-analysis, one quasiexperimental, and six non-experimental studies, consisting of three longitudinal follow-up studies and three cohort studies. The level and quality of the evidence for the research articles used in this review are: ‘high’ for the meta-analysis and ‘good’ for the other seven study articles as seen in Table 3. 37 Table 3: Evidence Rating for Research Author/Date Title of Article Type of Article Level of Evidence Dietz & Matthews (2010) Cohort study Nonexperimental III Grade of Article B – good III B – good II A – high III B – good III B – good III B – good III B – good II B - good Flores et al. (2015) Depressive symptoms and subclinical markers of cardiovascular disease in adolescents Perceived health status and cardiometabolic risk among a sample of youth in Mexico Exploratory cohort study Nonexperimental Goldstein et Major depressive disorder and Systematic al. (2015) bipolar disorder predispose review with youth to accelerated meta-analysis of atherosclerosis and early quasicardiovascular disease experimental studies Louise et al. Associations between Longitudinal (2012) anxious-depressed symptoms Nonand cardiovascular risk experimental factors in a childhood study Meier et al. Associations between Longitudinal (2015) depression and anxiety Nonsymptoms with retinal vessel experimental caliber in adolescents and young adults Rottenberg et The association between Cohort study al. (2014) major depressive disorder in Nonchildhood and risk factors for experimental cardiovascular disease in adolescence Shah et al. Depression and history of Longitudinal (2011) attempted suicide as risk study factors for heart disease Nonmortality in young individuals experimental Waloszek et Early physiological markers Cohort study al. (2015a) of cardiovascular risk in Quasicommunity based adolescents experimental with a depressive disorder Stage Four: Identification of Key Themes Stage four involved a detailed thematic evaluation of these eight studies to identify key themes in relation to the research question. Themes identified in the literature included: gender differences in the expression of cardiovascular risk and depression; comparison of 38 clinical or self-reported diagnosis of depression in relation to cardiovascular risk; pathophysiological changes of depression; and measures of traditional clinical cardiovascular risk predictors in adolescents with depression. The findings section will provide a critical analysis of the quality of evidence presented in each research paper. 39 CHAPTER THREE Findings The following section will provide a critical analysis of the research findings, organized by key themes, with consideration of what is missing from the current findings, and indication of the relevant limitations and/or biases of each study. The themes identified include: gender differences in the expression of cardiovascular risk and depression; comparison of clinical or self-reported diagnosis of depression in relation to cardiovascular risk; pathophysiological changes of depression; and measures of traditional clinical cardiovascular risk predictors in adolescents with depression. The quality of the articles was evaluated based on the JHNEBP Research Evidence Appraisal tool. Of the eight studies included for use in this integrative review, one is of high quality or rated ‘A’, while the other seven are of good quality or rated ‘B’. Thus, the methodological quality of the research studies is acknowledged to have flaws, which will be addressed, discussed, and analyzed further throughout this integrative review. Gender Differences in the Expression of Cardiovascular Risk and Depression When determining whether the use of preventive health checks would improve cardiovascular co-morbidities in adolescents living with depression, it is important to identify whether gender is consistently identified as a risk factor. Many risk prediction algorithms and equations, including those for cardiovascular events such as the FRE as well as those predicting episodes of major depression, account for gender when estimating the probability of onset or risk of a specific disease or illness (D’Agostino et al., 2008; King et al., 2008). Gender as an independent patient characteristic is often used to distinguish the difference in risk of not only current health status but the future health of males and females. Traditionally, atherosclerosis developed later in life for females than males, likely due to the 40 protective nature of estrogen, making it imperative to determine if gender disproportionately affects both the risk of depression or CVD differently (Elovainio et al., 2005), in order to provide necessary screening at the appropriate time in life. Older studies have shown that a high level of depressive symptoms is associated with increased cardiovascular risk in young men only (Elovainio et al., 2005); however, more current literature was evaluated and found that gender differences still exist in the expression of depression and cardiovascular risk, though the higher risk is now inferred in females. Thus, gender is an integral component of health and must be a key focus of preventive health checks as it assists PCPs to easily and efficiently identify which patient is most at risk for certain health conditions and who would benefit the most from screening or assessments within primary care. Three of the eight studies showed differences of gender in the expression of depression and cardiovascular risk. Two studies showed gender differences in the clinical measurement of vital signs. Adolescent males had both higher brachial and continuous beatto-beat finger systolic blood pressures and heart rates as well as a lower rate of change for systolic blood pressure than adolescent females (Louise et al., 2012; Waloszek et al., 2015a). Blood pressure measurement in depressed boys compared to girls who are depressed was 113.8 mmHg versus 108.9 mmHg respectively (Louise et al., 2012). Gender accounts for many differences of health between men and women including: physical alterations with the amount of muscle mass, distribution of fat, and measurements of height, weight, hips, and waist; variances in the sex hormones of estrogen, testosterone, and progesterone, and how these hormones affect the metabolism and use of other substances including lipids, fatty acids, leptin, catecholamine, insulin, glucose, epinephrine, and nitric oxide; and physiologic modifications to the circulating blood volume, amount of free fluid, and amount of 41 hemoglobin (Wu & O’Sullivan, 2011). While blood pressure and heart rate are both easily obtainable and measurable signs of health, their elevation or lowered rate of change is not sufficient to solely predict future cardiovascular co-morbidity in adolescents with depression because many factors including infections, stress, dehydration, and anemia can elevate heart rate or blood pressure. However, subtle changes of heart rate and blood pressure measured over a period of time coupled with the well-known gender differences in weight, hormones, and metabolism can provide better, clearer information about the overall function, stress, and severity of damage or inflammation to the cardiovascular system. These specific vital signs along with gender are used to predict adult CVD in the FRE and thus may predict significant CVD when used in adolescents with depression. Thus, blood pressure and heart rate are important measurements of cardiovascular function, but not in absence of other factors. In addition, Louise et al. (2012) found that depressive symptoms in girls were associated with a higher BMI (0.6 kg/m2) and a higher insulin resistance (0.3 units) than in girls without depressive symptoms. While BMI is another easily obtainable and measurable sign of general health, its elevation is not a clinically useful determinant of altered cardiovascular health. However, elevated BMI and insulin resistance are two risk factors in the diagnosis of metabolic syndrome, the most predictive risk factor of CVD. Metabolic syndrome is defined as a cluster of interconnected factors including elevated blood pressure, dyslipidemia, dysregulated glucose homeostasis, increased adiposity, and insulin resistance, moreover the prevalence of metabolic syndrome increases dramatically as BMI increases (Kassi, Pervanidou, Kaltsas, & Chrousos, 2011). In fact, Kassi et al. (2011) found that an elevated BMI considered overweight increased the risk of metabolic syndrome five and a half times in adult females and six times in adult males compared to normal or underweight 42 patients, while an elevated BMI in the obese range increased the risk 32 times in adult males and 17 times in adult females. The third study showed that young women with both depression and previous attempts at suicide were at higher risk for both CVD and ischemic heart disease mortality but not for non-CVD mortality, whereas the opposite was true for young men (Shah, Veledar, Hong, Bremner, & Vaccarino, 2011). In fact, the hazard ratio for ischemic heart disease mortality in young women with depression and attempted suicide was 14.57 compared to t hat of young men which was 3.52, while the hazard ratio for CVD mortality in young women was 3.20 compared to 2.37 in young men (Shah et al., 2011). Furthermore, when adolescents who were taking antidepressants were excluded from data analysis, the hazard ratio of ischemic heart disease for depression was changed by less than 10%, indicating that the cardiovascular risk of depression remains even after it has been treated (Shah et al., 2011). There are some limitations in these studies that may affect the validity of their results. Two of the studies had relatively small sample sizes, one with very few male participants, which both limits the power of statistical analysis and causes wide confidence intervals (Shah et al., 2011; Waloszek et al., 2015a). This made it difficult to conclude what effects, if any, gender had on both depression and cardiovascular risk as many of the gender interaction results were not statistically significant (Shah et al., 2011; Waloszek et al., 2015 a). Waloszek et al. (2015a) determined that gender imbalances are expected in depression studies given the epidemiological differences of depression in women and that depression is more prevalent and presents earlier in women than in men, as well as the fact that women are more likely then men to seek care for depression, both of which may help explain some of the gender differences presented in the studies. 43 Thus, in determining whether gender affects cardiovascular risk in adolescents with depression, it appears that either gender contributes to physiological changes that may contribute eventually to CVD. For adolescent males, these changes include increased blood pressure and lower heart rate variability. Yet, for adolescent girls, more significant variances were found including increased BMI, increased insulin resistance leading to an increased risk of metabolic syndrome, as well as a marked risk of mortality from ischemic heart disease. Therefore, being female may be not only a contributing risk factor to cardiovascular morbidity, but also an equally important predictor in the determination of CVD. Therefore, it is advisable to include gender in a preventive health checklist when assessing for cardiovascular co-morbidity as being female not only significantly increases individual risk of CVD but its identification may help prevent future morbidity and mortality in adolescents with depression. Diagnosis of Clinical or Self-Reported Depression in Relation to Cardiovascular Risk Half of the studies examined for this integrative review described how the diagnosis of depression was determined. Participants were identified as having depression in one of two ways. First, some individuals’ depression was determined based on self-reported questionnaires that were completed by the individual, while other studies used clinical experts to administer a clinical tool. These two ways of diagnosing depression have many different implications not only for the research studies and their outcomes, but for future integration into practice as well. When determining whether preventive health checks would improve later cardiovascular co-morbidities in adolescents with depression, it is important to define which adolescents with depression are most at risk, the ones that have been clinically diagnosed, or the ones that have self-reported depressive symptoms. It is only just recently 44 that major depressive disorder has been considered a moderate risk factor for CVD, which may imply that a clinical diagnosis of depression has to be present to infer cardiovascular risk (de Ferranti & Newburger, 2016a). Currently, MDD is not part of the FRE, however, there have been a few studies in adults suggesting its addition to the risk equation (O’Neill et al., 2016b). Conversely, it is important to understand whether having subclinical, selfreported, or perceived depression can affect adolescents’ cardiovascular risk and lead to future co-morbidities. This is important not only for NPs to understand in order to effectively care for and appropriately manage and prevent cardiovascular co-morbidities, but is also important when allocating difficult to access resources such as mental health professionals. If adolescents require a diagnosis of MDD from a clinical expert this further taxes an already burdened system and may take a significant amount of time before reaching a diagnosis, perhaps delaying management of cardiovascular risk. However, if having depression by selfreported questionnaire infers a similar level of risk for CVD, primary care providers can assess risk for any adolescents based solely on depressive symptoms and use an appropriate preventive health checklist to stratify risk and determine who warrants management, treatment, and care of CVD sooner, in order to more effectively and efficiently reduce the risk of future co-morbidities. Three studies used self-reported questionnaires to identify depressive symptoms in adolescents. In each of the studies a different type of questionnaire tool was used to screen for depression, including the Children’s Depression Inventory: Short Version (CDI-S) (Flores et al., 2015); the Center for Epidemiologic Studies Depression Scale (CES-D) (Dietz & Matthews, 2011); and the Somatic and Psychological Health Report (SPHERE) (Meier et al., 2015). The only tool that has been identified as a recommended screening tool for 45 assessing depression by the CPS (2016) is the Child Depression Inventory 2 (CDI-2), a tool very similar to the CDI-S. Flores et al. (2015) report that the CDI is widely used in many countries and has been shown to be both valid and reliable for measuring depression in youth. In their study, Flores et al. (2015) dichotomized the adolescents into two groups based on their depressive scores, either less than average or average depressive symptoms, and greater than average depressive symptoms. The researchers then compared these levels of depressive symptoms to cardiometabolic measures by BMI status. Statistical significance was reported between the relationship of increased BMI and increased depressive symptoms, worse physical functioning, and lower quality of life scores (Flores et al., 2015). Another statistically significant trend was recognized between participants who were either ‘overweight’ or ‘obese’ and had both higher glucose and triglyceride blood levels as well as higher systolic and diastolic blood pressure readings (Flores et al., 2015). Moreover, what these findings suggest is that there is a correlation between self-reported depressive symptoms using a validated and reliable tool and the presence of cardiovascular risk factors such as increased BMI, increased glucose and triglyceride levels, and increased systolic and diastolic blood pressure. Meanwhile, the CES-D “has been used in a variety of settings and has shown construct validity in its ability to screen for the presence of depressive disorders” (Dietz & Matthews, 2011, p.580). In their study, Dietz and Matthews (2011) also divided the participants into three separate groups reflecting depressive severity based on the range of scores. These scores were: 0-7 or low, 8-14 or moderate, and 15-47 or high, which correlated closely with the clinical use of the CES-D, whereby scores greater than 16 generally “indicate the presence of clinically significant depressive symptoms” (Dietz & Matthews, 46 2011, p.580). So, while Dietz and Matthews make no mention of the reliability of this tool to produce consistent scores of depressive symptoms, they do conclude that their scores of high depressive symptoms and clinically significant depressive symptoms closely correspond to each other. Adolescents with the highest score of depressive symptoms were found to have statistically significant relationships with higher pulse wave velocity (PWV) or more arterial stiffness, even after adjusting for age, race, gender, BMI, smoking status, socioeconomic status, physical activity, blood pressure, and heart rate (Dietz & Matthews, 2011). Limitations of this study may include the fact that the authors do not mention whether this tool is appropriate for assessing depression in adolescents, and that the depressive symptoms and PWV were measured at a single point in time only, making it difficult to infer a relationship over a period of time. Finally, the study by Meier et al. (2015) used the SPHERE self-report questionnaire, which assesses symptoms of depression, anxiety, and somatic distress and yields a total score for not only overall mental health and well-being but also for affective symptoms of depression, somatization, and fatigue. The authors reported that SPHERE has adequate reliability, validity, and internal consistency, as well as accurate identification of over 90 percent of individuals with current diagnosable depression, anxiety, or somatoform disorders (Meier et al., 2015). Further, the study found that there is a correlation between higher selfreported rates of symptoms from depression/anxiety, somatization, and fatigue, with poorer overall mental health and well-being (Meier et al., 2015). In fact, the study found that adolescents with higher reports of depressive symptoms had statistically significant associations with wider retinal arteriolar caliber, a sign of impaired autoregulation and microvascular abnormality that predicts future risk of CVD, even after the authors controlled 47 for smoking and BMI (Meier et al., 2015). Moreover, while the symptoms for somatization, fatigue, and overall mental health also showed a trend toward widening of arteriolar caliber, the effects did not reach statistical significance (Meier et al., 2015). However, this study also has several limitations, including that the authors did not mention if the SPHERE questionnaire is validated or reliable for use in adolescents, nor does it specifically distinguish between depression and anxiety symptoms, making it unclear as to whether wider retinal arteriolar caliber is differentially associated with depression or anxiety. Another limitation is that the self-reported questionnaire and the retinal arteriolar caliber were not measured concurrently, in fact for most participants there was a mean time lapse of two and a half years between assessments which may have weakened the significance of the association. The authors make note of this limitation in their discussion and consequently performed a sub-analysis of those participants that had both depression/anxiety data and their retinal arteriolar caliber assessed within one year of each other for which the results remained statistically significant (Meier et al., 2015). A third limitation is that both retinal vessel caliber and the self-reported questionnaire were each only taken at a single point in time, making the direction of the association between these two items unclear, perhaps limiting their significance to practice. Thus, while this study shows a statistically significant association between depression/anxiety and wider retinal arteriolar caliber, a marker of endothelial dysfunction and a known risk factor for future CVD, the limitations of using a tool that is not specific to adolescents nor depression make it difficult to conclude whether these self-reported symptoms of depression do, in fact, correspond to an elevated expression of cardiovascular risk. 48 One study examined the association between CVD and depression using a clinical diagnosis of unipolar depression measured by the Diagnostic Interview Schedule (DIS), a standardized, structured interview tool based on the DSM-III criteria (Shah et al., 2011). The DSM is an authoritative guide to the accurate, consistent, and standardized diagnosis or classification of mental health disorders used by health care professionals around the world (American Psychiatric Association, 2013). Further, the DIS is a fully structured questionnaire administered by trained interviewers, not necessarily clinicians, to ascertain the existence or absence of mental health disorders based on the DSM (University of Florida Health, 2017). This tool mimics a clinical interview to determine whether psychiatric symptoms are clinically significant and whether or not they can be attributed to a medical condition or substance use (University of Florida Health, 2017). As the DIS is a fully specified tool, it remains valid and reliable even when non-clinicians administer it (University of Florida Health, 2017). This study by Shah et al. (2011), in which the DIS was implemented for diagnosis of depression, was conducted with a large sample of 7968 young adults aged 17-39. The results showed that depression is related to all-cause CVD mortality; 51 participants died from cardiovascular-related deaths, including six people with depression and four that had attempted suicide. This can be stated in terms of a hazard ratio of 2.38 for CVD mortality in people with depression after adjusting for age, gender, and ethnicity, and a hazard ratio of 2.21 after adjusting for traditional risk factors (Shah et al., 2011). Additionally, ischemic heart disease (IHD) mortality also had significant associations with depression. Over the fifteen years of follow-up, there were 251 total deaths, 15 from suicide and 51 from CVD (Shah et al., 2011). Of the 28 people who died from IHD, five had depression, making the 49 hazard ratio almost four times higher for people with depression, even after adjusting for gender, race, and traditional risk factors (Shah et al., 2011). More importantly, when the authors controlled for subjects taking antidepressant therapy, the hazard ratio of IHD was changed by less than ten percent. This study suggests that to mitigate the cardiovascular risk associated with depression, PCPs need to do more than simply treat adolescents’ underlying depression. Once can infer that to prevent future CVD mortality in young patients with depression, their risk must be predicted and managed early using a preventive approach to reduce stress, eat a healthy diet, and be more physically active. Important limitations to note with this study are the limited power of analysis (10% instead of the usual 5%) and wide confidence intervals related to the low number of cardiac events in younger participants, perhaps contributing to bias (Shah et al., 2011). However, the authors acknowledge that while the limited power of analysis made it difficult to draw definite conclusions about CV risk related to gender differences, reducing the ratio of outcomes to risk factors increased the accuracy of the relative risk estimation (Shah et al., 2011). Shah et al. (2011) reduced the ratio of risk factors to outcomes by combining all of the risk factors and using the FRE to convey overall CVD risk rather than individual CVD risk factors. Additionally, the authors performed a series of sensitivity analyses between the risk factors and outcomes, under which the results remained robust, lending to the validity of the entire study (Shah et al., 2011). In conclusion, three studies used self-reported, subclinical, or perceived symptoms of depression while one study used a clinical diagnosis of depression to evaluate the associations with cardiovascular risk. All four of the studies found statistically significant associations between the symptoms of depression and various physiological changes that 50 could infer future cardiovascular risk, including wider retinal arteriolar caliber, increased PWV, and increased traditional risk factors. The study using a clinical diagnosis of depression by Shah et al. (2011) also found an increased mortality from cardiovascular causes in depressed individuals than in individuals without depression. While these associations were all significant, none of the studies, with the exception of the study by Shah et al. (2011), examined cardiovascular changes over time, making it difficult to know whether these physiological changes represent an incidental variation or whether they represent a gradual or permanent physiological dysfunction that may eventually contribute to end cardiovascular damage. However, when determining whether self-report or a clinical diagnosis of depression makes a difference to predicting the risk of CVD, it appears as though both confer risk. Therefore, preventive health checklists should include assessment of depressive symptoms as a stimulus to screen for CVD risk factors. Pathophysiological Changes of Depression Half of the studies examined for this integrative review described pathophysiological changes of CVD in adolescent depression. This section will examine the four studies that found both autonomic and endothelial dysfunction, including changes such as heart rate variability, shorter pulse transit time, wider retinal arteriolar caliber, and brachial artery dilation (Dietz & Matthews, 2010; Goldstein et al., 2015; Meier et al., 2015; Walsozek et al., 2015). Early identification and management of these pathophysiological and endothelium changes may potentially reverse damage and reinstate function. However, this early identification requires knowledge of the problem and a systematic way in which to screen for these potential problems in adolescents with depression. This may best be done using a preventive health check, which is able to accurately guide the PCP to those patients most at 51 risk of these pathophysiological changes and therefore those most at risk of developing cardiovascular disease. Arterial stiffness. Three studies chose to look at different measurements of arterial stiffness in adolescents as a pathophysiological sign of cardiovascular dysfunction. Arterial stiffness represents a decrease in the intrinsic elasticity of the vessel wall, usually caused by calcification of atherosclerotic plaques (Cecelja & Chowienczyk, 2012). This stiffness reduces the artery’s ability to respond to pressure changes, often causing hypertens ion and increasing the workload of the heart, which may over time lead to cardiac morbidity and mortality (Cecelja & Chowienczyk, 2012). Arterial stiffness can be measured by any of the following: increased carotid artery intima-media thickness (CIMT); faster pulse wave velocity time (PWV); or shorter pulse transit times (PTT) (Cecelja & Chowienczyk, 2012; Dietz & Matthews, 2011; Goldstein et al., 2015; Waloszek et al., 2015a). In fact, PWV that is measured over the aorta of the heart has been found to be an independent predictor of cardiovascular morbidity and mortality, while an increase in intima-media thickness represents atherosclerosis (Cecelja & Chowienczyk, 2012). One prospective cohort study and a meta-analysis reviewed CIMT as a risk predictor of CVD in adolescents with depression. Both found that there was no correlation between these variables (Dietz & Matthews, 2011; Goldstein et al., 2015). Dietz and Matthews (2011) report that adult studies have shown a correlation between increased CIMT and depression, suggesting that increased CIMT may be an advanced sign of cardiovascular dysfunction that is better correlated to age than disease process. There are a few important limitations in these studies by Dietz & Matthews (2011) and Goldstein et al. (2015) including: the relatively small sample size (157 participants) of one study (Dietz & Matthews, 2011), which may not 52 represent enough of the population to draw accurate conclusions; and the fact that another study is not considered current as it was published in 2005 and measured the CIMT of participants in 2001, perhaps using older technology that is not as accurate in measuring CIMT as ultrasound machines are today (Elovainio et al., 2005). Finally, both studies determined the relationship between arterial thickening and depression by self-reported depressive symptoms, which may not accurately depict adolescents who experience more chronic or severe depression that may contribute to poorer health behaviours such as increased time doing sedentary activities or greater disruption of circadian sleep cycles (Dietz & Matthews, 2011; Elovainio et al., 2005; Goldstein et al., 2015). However, an earlier and perhaps a more accurate predictor of cardiovascular dysfunction in adolescents is PWV, a sign of increased vascular stiffness that can be found even when there is a low prevalence of atherosclerosis (Cecelja & Chowienczyk, 2012). PWV measures arterial stiffness based on the principle that pressure waves travelling from the aorta to a predetermined end-point are faster if the arterial vessel walls are stiffer (Dietz & Matthews, 2011). Waloszek et al. (2015a) measured the pulse transit time (PTT) in their study, which measures arterial stiffness from the R-wave to the following diastolic pressure point, also noting that the transit time is shorter in stiffer vessels due to the decreased resistance of the vessel walls, thus allowing blood to travel faster from the heart to the periphery (Waloszek et al., 2015a). Both the studies by Dietz and Matthews (2011) as well as by Waloszek and colleagues (2015a) found significant associations between stiffer vessels and depressive symptoms in adolescents. Dietz and Matthews (2011) found a significant relationship between PWV and depressive symptoms in adolescents even after adjusting for age, race, gender, BMI, education level of parents, smoking status, physical activity, blood 53 pressure, and heart rate. In fact, the more severe the depression, the higher the PWV. In the study by Waloszek et al. (2015a) adolescents with depression also had significantly shorter PTT when compared with their non-depressed cohorts. Both of these studies suggest that there are early vascular changes of CVD associated with depression in adolescents; however, both studies had relatively small sample sizes that may have limited the validity of the findings. Endothelial dysfunction. Another early sign of CVD is impaired endothelial function, a loss of the integrity and then dysfunction of the blood vessel wall often due to the chronic exposure of noxious stimuli such as stress that eventually overwhelms the body’s defense mechanisms (Mudau, Genis, Lochner, & Strijdom, 2012). This process is thought to be the pathophysiological link between exposure to cardiovascular risk factors, including depression, and atherosclerosis (Mudau et al., 2012). Waloszek and colleagues (2015a) measured endothelial functioning in adolescents with depression using an EndoPAT machine, a non-invasive finger plethysmography, which captures the arterial vasodilation of a finger from each hand at rest and after shear stress (a five-minute cuff occlusion of the brachial artery in one arm to induce vasodilatory molecules). The EndoPAT has been found to be both reliable and valid in capturing nitric-oxide mediated vasodilation and finger endothelial function in both pediatric and adolescent populations (Tomfohr, Murphy, Miller, & Puterman, 2011; Waloszek et al., 2015a). Waloszek et al. (2015a) found that adolescents with depression had poorer endothelial functioning when compared with their healthy peers, indicative of increased cardiovascular risk and future atherosclerosis. Goldstein et al. (2015) reviewed five studies that measured endothelial function by either “ultrasound-determined brachial artery flow-mediated dilation or by digital pulse-wave 54 amplitude, in which higher values are considered better” (p. 968). Of the five studies from this meta-analysis, one showed no relationship between endothelial dysfunction and depression in adolescents, while the other four, similar to Waloszek et al. (2015a), showed some change in endothelial dysfunction in adolescents with depression. Of the studies that showed an association between endothelial dysfunction and depression in adolescents, one study found this not to be significantly present over time nor to predict future endothelial function; one showed attenuated endothelial function only in adolescent girls with higher levels of anger, depression and anxiety; one showed decreased nitrite concentrations in depressed adolescents suggesting decreased nitric oxide production, a sign of endothelial dysfunction; and the last study demonstrated a smaller brachial artery diameter in participants with depression, which is indicative of stiffer vessels (Goldstein et al., 2015; Osika et al., 2009; Tomfohr et al., 2011; Waloszek et al., 2015a). Both the meta-analysis by Goldstein et al. (2015) and the cross-sectional study by Waloszek et al. (2015a) admitted that it is difficult to conclusively form a relationship between depression in adolescents and future cardiovascular risk as most of the study sample sizes were small and had insufficient power to be statistically significant. However, five smaller studies have been presented equalling a total number of 563 participants, showing that there is likely some level of endothelial dysfunction in adolescents with depressive symptoms. What that association is specifically has yet to be determined. Some of the studies in the meta-analysis suggested the relationships between endothelial dysfunction and adolescent depression were significant only in females, while other studies concluded that depressive symptoms that were self-reported were less significant than when MDD was diagnosed from the use of semi-structured interviews (Goldstein et al., 2015). Whether or not 55 this association would be stronger in a study with a larger sample sizes, one thing is certain; more longitudinal research is needed to investigate endothelial dysfunction as it relates to adolescents with depression. Further, more information is needed on whether the EndoPAT would be a valuable and reliable non-invasive method of identifying adolescents with depression at risk of cardiovascular disease in primary care. Microcirculation changes. A well documented marker of premature subclinical CVD is deviation to either wider or narrower calibers of small blood vessels (Meier et al., 2015). This can be measured more specifically in the microcirculation of the retina, as it shares anatomical and physiological characteristics with other end organs such as the heart and kidneys that may indicated early microvascular abnormality (Meier et al., 2015). Moreover, changes to the retinal vessel caliber has been shown to predict future risk of CVD, and in adults this change to the vessel caliber has been associated with depression (Meier et al., 2015). The authors speculate that while the direct pathophysiological mechanism of changes to the microvasculature is not clear, it is thought that endothelial dysfunction is caused by damage to the nitric oxide-mediated vasodilation of the vessels, causing them to become wider, a sign of impaired autoregulation (Meier et al., 2015). In the study of adolescents by Meier et al. (2015) the six largest arterioles and venules closest to the optic disc were measured to assess the average diameter of both types of vessels. The researchers found that symptoms of anxiety, depression, and poorer overall mental health were positively associated with wider arteriolar caliber (Meier et al., 2015). Additionally, these findings were unchanged after controlling for blood pressure, smoking status, and BMI (Meier et al., 2015). This large population study had its limitations, including that it only measured retinal vessel caliber at a single point in time and thus cannot 56 distinguish whether depression and anxiety cause wider vessel caliber, or wider arteriolar caliber contributes to anxiety and depression (Meier et al., 2015). Furthermore, the study did not measure retinal vessels at the same time as the adolescents self-reported their depression and anxiety symptoms, perhaps weakening the association (Meier et al., 2015). As discussed earlier, a sub-analysis of 345 study participants who had their retinal vessel caliber measured within one year of self-reporting their depressive symptoms continued to reveal a statistically significant association between wider retinal arteriolar vessel caliber and depressive symptoms (Meier et al., 2015). When determining whether preventive health checks would improve later cardiovascular comorbidities in adolescents with depression, one needs to understand the physiological changes inherent in CVD and whether these changes can be found in adolescents. The relationship between cardiovascular health and depression has been established in adults, yet until recently, health care professionals were unsure of whether this link exists in adolescence as well. The studies presented have shown three different indicators of cardiovascular health found in adolescents with varying levels of depression, including arterial stiffness, endothelial dysfunction, and microcirculation changes. These physiological variations in adults have been found to be predictors of cardiovascular disease, and while the studies presented have their limitations mostly related to sample sizes, they have also suggested that early physiological changes may occur in adolescents with depression. Given this evidence, PCPs need to focus on how to best identify these variations within primary care, which risk factors contribute to the manifestation of these physiological changes, and how they can help the adolescent prevent CVD from ever taking place. Thus, using preventive health checks that support the identification of risk and need for 57 intervention may improve the health of adolescents with depression and potentially reduce their risk of future CVD. Measures of Traditional Clinical Cardiovascular Risk Predictors Physiologic changes within the body can be difficult for PCPs to either identify or measure easily, thus there is a need to understand if any traditional clinical cardiovascular changes can be more easily observed and measured, and whether their use can help predict and thus prevent future CVD. Six of the eight studies in this integrative review examined clinical measures of cardiovascular risk factors including BMI, waist circumference, blood pressure, family history, and bloodwork such as increased cholesterol, triglycerides, fasting blood glucose, and insulin levels. The clinical measures of cardiovascular risk factors will be divided into: 1) physical measurements and family history; and 2) blood analysis. Physical measurements and family history. Five of the six studies found an association between depressive symptoms or MDD in adolescents and increased BMI (indicating obesity), increased waist circumference, or increased abdominal fat (Flores et al., 2015; Goldstein et al., 2015; Louise et al., 2012; Rottenberg et al., 2014; Shah et al., 2011). Bauer et al. (2014) recognize cardio-metabolic risk as being positively correlated with an increased BMI and that using BMI as a physical measurement of cardio-metabolic risk is only predictive when identified alongside elevated insulin or those with three or more other cardiovascular risk factors (i.e. increased fasting glucose, increased blood pressure, increased total cholesterol or triglycerides). Thus, increased BMI measurement in an adolescent who is depressed as a lone predictive factor of CVD, may not be enough to determine risk. Additionally, only one study measured and found a correlation between depression in adolescents, increased CVD risk factors, and a family history of CVD (Rottenberg et al., 58 2014). Yet, the predictive value of family history of cardiovascular dysfunction has been widely used in screening measures including the FRE, which recognizes that a strong family history of premature CVD increases an individuals’ own risk of having early heart disease (D’Agostino et al., 2007). Two studies examined whether increased blood pressure, a common indicator of cardiac dysfunction, was related to adolescents with depression. Louise et al. (2012) found that males with depression had lower rate of variability in systolic blood pressure, while Waloszek et al. (2015a) found that in adolescents with depression both the mean systolic and diastolic blood pressures were higher than in the control group, however, the differences did not reach statistical significance. Overall the limitations for these studies include relatively small sample sizes, decreased strength of associations due to attrition of participants, and study designs that make it difficult to allow for the causal direction of relationships between variables to be made (Flores et al., 2015; Goldstein et al., 2015; Louise et al., 2012; Rottenberg et al., 2014; Shah et al., 2011; Waloszek et al., 2015a). However, given how many of the research studies found that obesity is associated with depression in adolescents, and the previous strong predictive value of family history as a risk factor for CVD in adults, screening for cardiovascular risk should focus on these two clinical markers in depressed adolescents until more evidence about the usefulness of blood pressure and heart rate can be found. Blood analysis. Four of the six studies demonstrated a relationship between adolescents with depression and either increased fasting blood glucose or insulin resistance (Flores et al., 2015; Goldstein et al., 2015; Louise et al., 2012; Waloszek et al., 2015a). Increased fasting blood glucose causes microvascular changes, thus making it a risk factor for cardiovascular disease (Canadian Diabetes Association [CDA], 2013). Moreover, two 59 studies found adolescents with depression had increased levels of triglycerides with no changes to HDL, LDL, or total cholesterol, and one of those studies found increased triglycerides to be statistically significant in males with depressive symptoms only (Louise et al., 2012; Waloszek et al., 2015a). The correlation between impaired fasting glucose levels, insulin resistance, and increased triglycerides is thought to be due to metabolic syndrome, a clustering of clinical and physiological variables that can lead to CVD (Goldstein et al., 2015). The CDA (2013) defines metabolic syndrome as a syndrome of at least three of the following abnormalities: increased waist circumference, blood pressure greater than 130/85, increased fasting blood glucose, elevated triglycerides, and reduced HDL, all of which carry significant risk of CVD. The International Diabetes Federation (2015) outlines the criteria for metabolic syndrome in adolescents aged 16 and older the same as for adults, while children aged 10-15 need to have obesity greater than the 90 th percentile as assessed by waist circumference and all of the four other abnormalities to be diagnosed. Goldstein et al. (2015) recognize that there is an increased prevalence among adults with MDD and metabolic syndrome. However, what is not as well understood is whether there is a correlation between adolescent depression and metabolic syndrome and if the same risk of cardiovascular morbidity and mortality is conferred from metabolic syndrome in adolescent depression, although Flores et al. (2015) found an association between depression and increased BMI, waist circumference, fasting glucose levels and lower levels of HDL cholesterol in adolescents. Traditional risk factors of CVD that are increased in adolescents with depression include BMI, waist circumference, and abdominal fat, thus using the measurements of BMI and waist circumference in a preventive health checklist would be important in helping to 60 determine risk of cardiovascular co-morbidity. As only one study examined family history of CVD, it is difficult to gauge whether a family history of CVD is a significant risk factor to include in a preventive health checklist for adolescents with depression. However, other studies have examined family history in adults and determined it to be predictive enough of CVD to include in risk equations such as the FRE for cardiovascular risk. Three other potentially important risk factors that should be considered for inclusion in a preventive health checklist examining cardiovascular co-morbidity in adolescents with depression are insulin resistance, impaired fasting glucose, and increased triglycerides as several studies found these to be significant in this particular population as well. After a thorough review of the current literature, two things are clear: 1) there is a gap in the knowledge about the use of preventive health checklists in adolescents with depression to mitigate the future risks of CVD; and 2) there appears to be an association between depression and CVD even in adolescence. However, what is needed now is to know how this information can be translated into care? The purpose of understanding an association between disorders is to determine whether a causal relationship exists. By knowing if one condition causes another, healthcare providers can assist the patient to intervene in the disease process by mitigating or even preventing the secondary condition from developing. To assess and intervene in a disease, healthcare providers need to understand the signs and symptoms indicative of the disease, to both recognize its onset and also to ensure that appropriate health promotion and disease prevention strategies aimed specifically at changing the course of the disease are undertaken. Without the understanding of the cause, signs, or symptoms of a disease, a preventive health checklist cannot be created. This integrative review has provided some of the signs and symptoms that may indicate 61 cardiovascular dysfunction that may present in the adolescent with depression, providing not only an specific course for disease prevention and health promotion, but also for the creation of a preventive health checklist for primary care providers to follow when providing care to this population. By adequately screening, identifying, and treating depression in adolescents, healthcare providers may be able to reduce cardiovascular risks and prevent future cardiovascular morbidities. Review Limitations There are limitations present in this integrative review. The evaluation and interpretation were completed by one person, potentially leading to errors in analysis. Also, it is acknowledged by the author that the specific question of whether preventive health checklists would improve later cardiovascular co-morbidities in adolescents living with depression has also not been directly addressed by the findings. Additionally, while preventive health checks are identified as being valuable when treating patients with mental health disorders and have evidence supporting their use within primary care, it was beyond the scope of this integrative review to determine whether PCPs are actually using preventive health checklists in practice or whether they find them useful for health screening in adolescents. It is recognized that these limitations are important in determining whether cardiovascular co-morbidities can be prevented in adolescents with depression. This review found several cardiovascular risk predictors that could be used as part of a preventive health checklist to assess for and potentially prevent CVD in adolescents with depression. The next section provides a discussion and synthesis of the findings derived from the eight studies examined in this review with recommendations for future practice and research. 62 CHAPTER FOUR Discussion and Recommendations This integrative literature review was undertaken to determine if having preventive health checklists during primary care visits improve later cardiovascular co-morbidities for adolescents with depression. The seven non-experimental studies and one meta-analysis utilized in this review do not provide enough data to support the use of preventive health checklists in primary care to improve cardiovascular co-morbidities in adolescents with depression. While the literature did not directly address using preventive health checklists in adolescents with depression, it did find several physiological changes that occur in adolescents with depression, which may increase their individual risk for cardiovascular comorbidity and mortality. PCPs are well positioned to provide necessary screening, discuss risks, prevent illness, and counsel adolescents on their health as 70 percent of them visit their healthcare provider at least once every four years (Ham & Allen, 2012). Moreover, NPs provide primary care, have longer appointment times, and focus on health promotion and disease prevention, making the use of preventive health checklists well-suited for NP practice. A synthesis of the evidence will provide the necessary foundation to support recommendations for future practice as well as those factors that could possibly be used in a preventive health checklist for measurement of both screening for depression and potential cardiovascular co-morbidities in adolescents with depression. Gender, Diagnosis, and Clinical Measures in the Expression of Cardiovascular Risk The American Health Association recently recognized MDD as a moderate risk factor for accelerated atherosclerosis before the age of 30 (de Ferranti & Newburger, 2016a; Goldstein et al., 2015). Although more and stronger evidence is needed, the studies reviewed showed that adolescents with depression may be at higher risk of cardiovascular co- 63 morbidities if they are female and they have: depressive symptoms by either clinical diagnosis or self-report; stiffer blood vessels as measured by faster PWV and shorter PTT; poorer endothelial functioning as evidenced by decreased nitric oxide production; widening or narrowing of vessel diameters; increased BMI; high fasting blood glucose levels; increased triglycerides; and insulin resistance. Currently, it is believed that these atherosclerotic vascular changes are minor and can be minimized or prevented if identified and reversed in time (de Ferranti & Newburger, 2016a). Having MDD places adolescents in a moderate risk category for CVD, however, this risk can be elevated to high risk with the addition of several risk factors, including: abnormal fasting lipids, hypertension, increased BMI, elevated fasting blood glucose, cigarette smoke exposure, sedentary lifestyle, and family history of early CVD (de Ferranti & Newburger, 2016a). While CVD does not generally manifest as overt mortality and morbidity until adulthood, it is clear that the atherosclerotic process begins during the years of childhood and adolescence (de Ferranti & Newburger, 2016a). However, what is not clear, is the direction of the association between the risk factors identified in adolescents with depression. Is the elevated risk of CVD a result of simply having depression, or is it related to having prior traditional risk factors of CVD that lead to MDD, or is it because depression and CVD share similar genetic components making it more likely to have both co-morbidities? This review of the literature was also not able to answer this question given that none of the articles studied investigated genetic components of MDD and CVD with the exception of whether any of the study participants parents had a family history of CVD, which is a well established risk factor for CVD in the adult population. 64 Unfortunately, much of the evidence used in this integrative review that helped identify these cardiovascular risk predictors were from small, non-experimental grade B studies that were sometimes unable to show statistical significance due to low incidence of events, low numbers of participants, and most were not longitudinal. Thus, it is recommended that high-quality, longitudinal research be conducted following adolescents with depression well into adulthood in order to investigate the association between depression and these cardiovascular risk predictors. This relationship is important for health care providers to understand as it will allow for the identification of those adolescents with depression at highest risk of CVD due to atherosclerotic changes, as well as the much-needed evidence to support how to best mitigate such increased risk. Having a better understanding of the causal relationship will provide information that can be included in evidence-based screening tools, such as preventive health checklists, as well as imperative information on how to manage and treat such cardiovascular risk predictors in order to prevent future cardiovascular mortality. This integrative review has suggested that further understanding of the relationship, future significance, morbidity, and mortality of cardiovascular risk predictors in adolescents with depression is needed before creating a preventive health checklist. Therefore, a recommendation from this review is the creation of high quality, longitudinal evidence evaluating the cardiovascular risk predictors in children, youth, and adults with depression that can potentially be used to create a preventive health checklist for use in adolescents with depression. Preventive Health Checklists Preventive health checklists and screening tools are used to identify patients at increased risk of disease even if they appear to look healthy. Preventive health care and 65 screening tools are both recommended and developed by the Canadian Task Force on Preventive Health Care (CTFPHC), which appraises and synthesizes the most current literature in order to disseminate evidence-based preventive health guidelines into primary care practice. There are certain characteristics that make a disease a good candidate for screening, this includes substantial morbidity and mortality if the disease goes untreated, high prevalence of the disease, the existence of the disease is detectable, a cost -effective treatment is available, and preclinical detection of the disease improves prognosis and management (Kelly, 2016). Cardiovascular disease has both a high rate of prevalence as well as significant morbidity and mortality if not detected early, given that depression is a moderate risk factor of CVD, it makes sense that there be a screening test to detect CVD in adolescents with depression. In order for the CTFPHC to publish preventive health guidelines they must first develop analytic frameworks, review scientific literature, synthesize scientific evidence, perform analyses of decisions and cost, obtain peer feedback from experts, write reports to summarize evidence, translate evidence-based knowledge into clinical practice, conduct systematic reviews, develop and implement evidence-based tools to improve clinical practice, identify gaps in the literature and ways to address these gaps, and publish results of the guidelines for public use (CTFPHC, 2016). Moreover, screening tests need to be easy to perform and interpret, measurable, have low risk, morbidity, and cost as well as be highly sensitive and specific (Kelly, 2016). Thus, with any preventive health screening conducted in primary care, there must be parameters to define who is screened, when they are screened, why they are screened, what they are being screened for (the disease or illness being prevented), and the method for screening (the tool to be used). Without the use of such 66 parameters the process of providing preventive health screening for every patient for every possible disease and illness would become overwhelming for healthcare providers and risk either over-estimating patients’ risk for disease or failing to complete any preventive health screening due to time limitations of screening so many patients. As well preventive health checklists need to be based on high grade evidence that clearly shows positive health benefits to cost ratio, as well as exactly which risk factors contribute the highest, most reliable, and most predictive risk of cardiovascular co-morbidity in order for those factors to be weighted and thus provide an accurate prediction of risk over time. Adherence to recommended preventive health screening by PCPs is lowest for the adolescent population, even though preventive health screenings are warranted as tools that significantly increase life expectancy at no increased cost to the healthcare system (De Hert, Dobbelaere, Sheridan, Cohen, and Correll, 2011; Ham & Allen, 2012; Rasmussen, Thomsen, Kilsmark, Hvenegaard, Engberg, Lauritzen & Sogaard, 2007). This lack of provider adherence is due to factors such as a deficiency of evidence supporting specific health screening and behaviour counselling; lack of time to deliver preventive health recommendations; lack of healthcare provider confidence in behaviour modification skills; lack of guidelines for how often recommended screening should occur; and the perceived lack of interest for disease prevention and behaviour change from adolescents (Ham & Allen, 2012). However, preventive health screening in adolescence is necessary to help prevent and decrease the rates of mortality and chronic conditions, some would even argue it is more important and also better done in the adolescent period before both permanent health and physiologic changes can develop. Yet most preventive health checklists and screening tools are developed for use during adulthood a period of time when significant behaviour and 67 health changes are harder to make and more chronic and genetic changes are likely to occur, perhaps making it more difficult to actually change the course of a disease. Thus, it is the recommendation of this review that more emphasis be put on prevention during the adolescent period by creating preventive health checklists to predict health risk and supporting providers to implement early behaviour modification counselling. This integrative review revealed several factors present in adolescents with depression that could be predictive of cardiovascular co-morbidities and thus could potentially be used as part of a preventive health checklist. Yet, while this review has added some much-needed evidence supporting the creation of a preventive health checklist in adolescents with depression to predict cardiovascular co-morbidity, more high-quality research on the outcomes of depression in adolescents is needed. By identifying these specific evidencebased risk predictors and how to best screen for these risks, preventive health screening recommendations can be prioritized and narrowed to include only the relevant parameters. This would allow PCPs to focus their valuable time on preventive health services and behavioural counselling that are going to result in positive health outcomes for these adolescents with depression. Additionally, by prioritizing and narrowing the scope of screening, PCPs are reassured that they can provide these preventive health services within the time constraints of busy office visits. Further, this review provides evidence for PCPs showing the importance of integrating preventive health screening into adolescent primary care visits as well as the need for a screening tool that includes all the important information in one convenient tool that can be used in daily, routine clinical practice. There remains a gap in the knowledge to answer the question of whether preventive health checklists help prevent cardiovascular co-morbidity in adolescents with depression, including not only a lack 68 of high quality evidence on which to base preventive health screening, but also an easy-touse tool with which to actually perform the screening. Thus, it is the recommendation of this integrative review that after collection of high-quality evidence, the CTFPHC develop guidelines as well as a quick, easy, and evidence-based preventive health checklist for the evaluation of cardiovascular health in adolescents with depression, as well as how often the recommended screening should occur and any specific health behaviour counselling that PCPs can use within office appointments. With such significant changes to screening and prevention guidelines appropriate education communicating those changes should be offered to those healthcare providers caring for youth, thus helping boost their confidence in screening and behaviour modification skills. Treatment and Management Recommendations for Adolescents with Depression Preventive health checklists will help identify adolescents with depression who are at risk of cardiovascular co-morbidity, but will not address how to treat or manage these cardiovascular co-morbidities in adolescents. There is little evidence regarding the outcomes of depression in adolescents, there is also very little evidence about the management of preventing cardiovascular co-morbidities. Thus, there is a need for not only further research on cardiovascular outcomes in adolescents with depression, but also prevention strategies, treatment, and management of the potential consequences as well. However, it stands to reason that adolescents with depression would benefit from the same prevention strategies that are recommended for either adults with cardiovascular risk factors or other adolescents with identified metabolic symptoms. One primary care strategy currently in use to assist PCPs with the screening, management, and treatment of adolescents is to establish a strong 69 therapeutic relationship and to actively seek collaboration with community programs that specifically address adolescent health issues (Ham & Allen, 2012). This collaborative strategy should be supported for use in primary care for adolescents with depression at risk of cardiovascular disease as medical interventions are lacking and until there is more evidence-based information, a team approach including behaviour, nutritional, and emotional therapy is likely most beneficial (Ham & Allen, 20 12). One such team approach program currently exists at BC Children’s Hospital Provincial Mental Health Metabolic Program (Provincial Health Services Authority [PHSA], 2017). This program is geared toward providing screening, education, medical management and assessment, as well as monitoring and follow up for youth with metabolic symptoms including central weight gain, high blood sugar, hypertension, increased lipids, insulin resistance, and elevated triglycerides (PHSA, 2017). Currently the clinic accepts referrals for youth who have any one of the following: risk of developing metabolic conditions but who need to be treated with an second-generation antipsychotic (SGA); already developed metabolic side effects during treatment with SGA; metabolic conditions and require mental health support (PHSA, 2017). A team consisting of a child psychiatrist, pediatric endocrinologist, dietician, lifestyle coach, nurse practitioner, physiotherapist, and pediatrician work with youth to manage their metabolic side effects through healthy eating, physical activity, stress management, and improving their sleep habits (PHSA, 2017). This program focuses primarily on assessing, treating, and managing metabolic syndrome caused by SGA in youth. However, as this integrative review has shown, adolescents with depression also suffer from many of the same symptoms of metabolic syndrome including insulin resistance, elevated fasting blood glucose, and elevated BMI. Thus, it is the 70 recommendation of this integrative review that this program be adapted or expanded to include the ever-increasing numbers of adolescents with depression. Such a program will provide the much-needed multidisciplinary team approach that focuses on healthy eating, physical activity, stress management, and healthy sleep habits to mitigate the cardiovascular co-morbidities that many adolescents with depression share with these adolescents taking SGA. Further, it may be worth noting that creating and disseminating high-quality evidence and guidelines takes time, time that some adolescents struggling with depression and physiologic cardiovascular changes may not have. Thus, PCPs may want to consider borrowing strategies from other similar groups of adolescents to provide evidence-based recommendations for monitoring, screening, and managing such patients until more research can be done. This writer suggests looking at the body of evidence, including not only what has been presented in this review, but also that related to adolescents taking SGA who experience cardiometabolic changes, in order to provide current information to PCPs about how to best provide care for those adolescents with depression. Correll (2008) suggests the following health strategies for adolescents with metabolic syndrome caused by SGA: 1) Primary prevention – education on healthy lifestyle and how to maximize adherence to healthy behaviours including limiting sugary beverages; regularly eating breakfast; endorsing frequent small meals; avoid meals with high levels of processing, sugar or fat ; increasing soluble fibre; limiting sedentary activity by reducing screen time to two hours or less a day; and promoting at least an hour of physical activity per day; 2) Secondary prevention – for those that have mild metabolic abnormalities or significant increase in BMI, it is suggested that the above lifestyle instructions be intensified and a non-pharmacological weight loss 71 treatment be started; 3) Tertiary prevention – for those that have hyperglycemia, dyslipidemia, or hypertension, it is recommended that weight reduction interventions be intensified and treatments be targeted to metabolic or endocrine abnormalities in conjunction with pediatric specialists. While increased BMI has been identified as the strongest predictor of cardiovascular risk in the literature and was found by this review to be strongly associated with cardiovascular disease particularly in adolescents with depression, it is only one part of the equation when assessing for risk. As is the case with any screening tool or risk prediction tool, multiple factors need to be taken into account in order to have a better understanding of what is going on. As it was noted earlier, elevated BMI is a better cardiovascular risk predictor when it is included with at least three other signs of dysfunction, and in the case of the adoescent with depression this would include hypertension, dyslipidemia, and insulin resistance or increased fasting glucose. However, simply having an increased BMI does not mean that cardiovascular risk is inferred, just as having a low or average BMI does not mean that risk is averted, these measurements in and of themselves are just that, measurements. To calculate risk the entire person needs to be taken into consideration and risk should be predicted based on the individual, just as their treatment and management is tailored and individualized to what is important and meaningful for that patient. Today there is increasing peer, media, and societal pressures for adolescents about weight, whereby being thin is emphasized and exemplified as the ideal while being overweight or obese is considered undesirable and unhealthy. It is not the intention of these recommendations to further perpetuate this psychosocial stigma but instead to acknowledge that an elevated BMI may be 72 a cardiovascular risk predictor in adolescents with depression and as such may need to be assessed, monitored, or managed as per the individual’s risk and personal health status. Therefore, it is a recommendation of this review that adolescents with depression at risk of CVD be educated on the above provided primary prevention strategies. Secondary prevention should be considered for adolescents with psychiatric illness in the following situations: BMI is greater than the 95th percentile or waist circumference is greater than the 90th percentile; there is a seven percent or higher weight gain over three months; or BMI is between 85-94.9 percentile and there is one adverse health consequence such as hyperglycemia, dyslipidemia, hyperinsulinemia, hypertension, sleep disorder, orthopedic problems or gall bladder disease (Correll, 2008). Adolescents that require secondary prevention should have more intensive medical treatment implemented by their PCPs including increased monitoring of screen time less than an hour each day, supervised physical activity of at least an hour each day, structured dietary intake, and goal setting (Correll, 2008) with the overall goal of creating healthy habits that prevents disease and promotes health. Additionally, management of the adolescent with depression should include assessing mood and depressive symptoms, asking about any suicidal intentions, monitoring vital signs for changes to BP and heart rate, and considering the need for bloodwork to assess for increased fasting blood glucose and dyslipidemia at a minimum of once a year. If after secondary prevention there continues to be a worsening of bloodwork or vital signs, a referral to a multidisciplinary team such as the Provincial Mental Health Metabolic Program should be strongly encouraged. Moreover, more current and relevant research is needed to determine whether these management strategies are clinically useful in adolescents with depression to prevent cardiovascular co-morbidities. 73 In addition to management strategies, it is a suggestion of this review that routine monitoring be done in order to detect emerging problems early. The need for monitoring to prevent CVD in children and adolescents has been acknowledged within European psychiatric literature, however, specific guidelines for this population have not yet been formulated (De Hert et al., 2011). Furthermore, Correll (2008) and De Hert et al. (2011) have made recommendations for the monitoring of weight gain and metabolic side effects in adolescents taking SGA that includes: personal and family medical history at baseline and then annually; review of lifestyle modifications at baseline and then every three months; height, weight, and calculation of BMI at baseline and then every three months; blood pressure, heart rate, fasting blood glucose, and lipids at baseline, three months and then every six months; all of these measurements should continue unless abnormalities are detected. Therefore, it is suggested that further research be done to evaluate and create evidence-based monitoring guidelines. However, until such research is complete, at least annual review of lifestyle modifications, vital signs, weight, height, fasting blood glucose and lipids should be considered in adolescents with depression to minimize and hopefully prevent future cardiometabolic consequences. Finally, more research is needed to understand the effect of standard nonpharmacological treatments (consistent parenting and normalizing routines of sleep, eating, and physical exercise) on preventing cardiovascular comorbidities in adolescents with depression. Such research on adolescents with depression should be extended to include both the effects of pharmacological treatment with fluoxetine and the psychotherapeutic interventions of cognitive behavioural therapy and interpersonal therapy on the prevention of future morbidity and mortality. A promising longitudinal, randomized controlled trial 74 investigating the effects of cognitive behaviour therapy and mindfulness-based sleep intervention on preventing depression and improving cardiac health is currently being conducted in Melbourne, Australia (Waloszek et al., 2015b). This Sleep and Education: Learning New Skills Early (SENSE) study is due to finish in later 2017, after a two-year follow-up with participants has been completed and will hopefully represent a significant piece of research supporting treatment of adolescent depression and cardiovascular health but also add important evidence to the already existing body of evidence outlining the relationship between depression, sleep, and cardiovascular health. More research is needed to add meaningful and significant discussion about adolescent depression and the devastating sequelae that can occur as a result. Until that time, it is the recommendation of this review that PCPs continue to help diminish the effects of depression by both counselling patients about the standard non-pharmacological treatments and, in accordance with the standards and scope of practice of the provider, treatment with medications such as fluoxetine as well. Thus, by properly treating and addressing adolescent depression, hopefully later cardiovascular co-morbidities can be prevented or minimized. Thus, while this integrative review was unable to provide the answer about whether preventive health checklists can decrease future cardiovascular co-morbidities in adolescents with depression, several other important recommendations can be made, as seen summarized in Table 4. 75 Table 4: Summary of Recommendations Research 1) High-quality, longitudinal research needs to be conducted on adolescents with depression as they transition into adulthood, investigating the causal relationship between depression and cardiovascular risk predictors, to understand how to screen, manage, and treat both co-morbidities Prevention 2) Creation of a quick, easy-to-use preventive health checklists based on high grade evidence that clearly show positive health benefits to cost ratio, as well as the parameters for who should be screened, when, why, and what they should be screened for; that is, exactly which risk factors contribute the highest, most reliable, and most predictive risk of cardiovascular co-morbidity in order for those factors to be weighted and thus provide an accurate prediction of risk over time Education 3) More education and training of PCPs on preventing CVD in adolescents with depression and supporting providers to implement early behaviour modification counselling to mitigate these risks Treatment and Management 4) A multidisciplinary approach should be used to promote disease prevention and health promotion in adolescents with depression which focuses on healthy eating, physical activity, stress management, and healthy sleep habits to mitigate their cardiovascular co-morbidities 5) Implementation of primary prevention strategies including education on healthy lifestyle and how to maximize adherence to healthy behaviours including limiting sugary beverages; regularly eating breakfast; endorsing frequent small meals; avoid meals with high levels of processing, sugar or fat; increasing soluble fibre; limiting sedentary activity by reducing screen time to two hours or less a day; and promoting at least an hour of physical activity per day for all adolescents with depression 6) Monitoring of weight gain and metabolic side effects in adolescents with depression should include: personal and family medical history at baseline and then annually; review of lifestyle modifications at baseline and then every three months; height, weight, and calculation of BMI at baseline and then every three months; blood pressure, heart rate, fasting blood glucose, and lipids at baseline, three months and then every six months; all of these measurements should continue unless abnormalities are detected 7) PCPs continue to help diminish the effects of depression by both counselling patients about standard non-pharmacological treatments such as sleep, exercise, CBT, counselling, and diet as well as the use of medications such as fluoxetine until more research can be done to support which treatments are most effective at mitigating cardiovascular risk 76 CHAPTER FIVE Conclusion Adolescent depression can have many devastating effects on the developing youth, including significant disability and cardiovascular morbidity. As future primary care providers, it is our responsibility to educate both ourselves and our adolescent patients about such risks and help them mitigate and prevent those risks from negatively impacting their young lives. Although the evidence was not robust, this review has suggested that adolescents with depression are at risk for stiffer blood vessels as measured by faster PWV and shorter PTT, poorer endothelial functioning as evidenced by decreased nitric oxide production, widening or narrowing of vessel diameters, increased BMI, high fasting blood glucose levels, increased triglycerides, and insulin resistance, all of which contribute to a higher risk of cardiovascular co-morbidity and mortality. The risk of adolescent depression has been identified by the American Heart Association as a moderate risk factor for cardiovascular disease and yet there have been no recommendations put forth to practitioners about how to address this risk. While this integrative review was not able to answer the question whether preventive health checklists decrease cardiovascular risk in adolescents with depression, several recommendations have been made to assist primary care providers in predicting, preventing, and mitigating the cardiovascular risks until more high -quality longitudinal epidemiological studies and research can be done investigating the causal relationship between depression and cardiovascular disease in adolescents. Until such time as evidence-based guidelines can be made, the recommendation coming from this review is that practitioners use a multidisciplinary approach for adolescents with depression that includes education on diet, exercise, and sleep, as well as regular monitoring of BMI and bloodwork. 77 Glossary All citations from Medical Dictionary (Merriam-Webster, 2015) unless otherwise indicated. adolescence: the period of life from puberty to maturity terminating legally at the age of majority anhedonia: psychological condition characterized by inability to experience pleasure in normally pleasurable acts atherosclerosis: a chronic disease characterized by fatty deposits and fibrosis causing abnormal thickening and hardening of the inner layer of the arterial walls body mass index: a measure of body fat that is the ratio of weight in kilograms to the square of the body’s height in meters bradycardia: relatively slow heart action caliber: the diameter of a round or cylindrical body cognitive behavioural therapy: psychotherapy that combines cognitive and behavioural therapy by identifying faulty or maladaptive patterns of thinking, behaviour, or emotional response and substituting them with desirable patterns of thinking, behaviour, or emotional response endothelium: a cellular tissue composed of a single layer of thin flattened cells that lines internal body cavities and blood vessels hazard ratio: a comparison between the probability of events in a treatment group, compared to the probability of events in a control group, used primarily to determine if treatment progress is faster or slower than those not receiving treatment (Statistics How To, 2017a) heterogenous: consisting of dissimilar or diverse ingredients or constituents interpersonal therapy: psychotherapy that focuses on a patient’s interpersonal relationships, it is particularly useful in treating patients with depression ischemic heart disease: disease caused by narrowed cardiac arteries, which restricts blood flow and oxygen to the cardiac muscle and includes acute myocardial infarction and atherosclerotic cardiovascular disease (American Heart Association, 2016) myocardial infarction: an acute episode of ischemic heart disease marked by the death or damage of heart muscle due to insufficient blood supply to the heart muscle usually as a result of a coronary artery becoming blocked by a blood clot formed in response to a ruptured or torn fatty arterial deposit nurse practitioner: a registered nurse who is qualified through advanced training to assume some of the duties and responsibilities formerly assumed only by a physician 78 plaque: an atherosclerotic lesion plethysmography: an instrument for determining and registering variations in the size of an organ or limb resulting from changes in the amount of blood present or passing through it power of analysis: determines the sample size required to detect an effect within a sample with a given degree of confidence (Kabacoff, 2017) retinal artery: a branch of the ophthalmic artery that passes to the retina in the middle of the optic nerve and branches to form the arterioles of the retina second generation antipsychotic: class of medication used to treat some mental health conditions such as pervasive developmental disorders, disruptive behaviour disorders, and obsessive-compulsive disorders that have a more favourable neuromotor side-effect profile with fewer extrapyramidal adverse effects than first generation antipsychotics (De Hert et al., 2011) sensitivity: proportion of people with the disease who will have a positive test result (Statistics How To, 2017b) specificity: proportion of people without the disease who will have a negative test result (Statistics How To, 2017b) somatic: of, relating to, or affecting the body statistical significance: a result from testing that is likely not to have occurred randomly or by chance, but is likely to be attributable to a specific cause, commonly expressed as the p value systolic blood pressure: the highest arterial blood pressure of a cardiac cycle occurring immediately after systole of the left ventricle of the heart triglycerides: any of a group of lipids which are widespread in adipose tissue and commonly circulate in the blood 79 References Aarons, G. 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Journal of Tehran University Heart Center, 8(4), 169-176. 88 Figure 1: Flowchart of articles Abstraction journals, electronic databases, grey literature n = 67,674 Number of articles excluded per exclusion criteria n = 67, 621 Number of articles after screening (relevant to topic) n = 53 Number of articles excluded due to inappropriate subject age, publication greater than 10 years old, not original research and duplication n =7 Number of total articles included in integrative review n=8 Read full articles and use inclusion and exclusion criteria n = 15 89 Appendix A: Literature Matrix Author/ Date Title/Focus/ Question Dietz & Matthews (2010) Depressive symptoms and subclinical markers of cardiovascular disease in adolescents To investigate associations between depressive symptoms and subclinical indexes of cardiovascular disease including arterial stiffness Authors hypothesize that youth with increased self-reported depressive symptoms will have greater arterial stiffness and greater carotid artery intima media thickening (IMT) Population/ Participants/ Sample 157 adolescents aged 15-21 years Sample was 213 youth recruited from local high schools between age 14-16 80 black youth and 77 white youth 75 youth were female and 82 were male Follow-up was done on average 3.3 years later to measure labbased cardiovascular function and subclinical markers Setting/ Country Pittsburgh, USA Setting not discussed Methods/ Methodology/ Analysis Measured depression using centre for epidemiologic studies depression scale (20-item inventory) Measured hostility using validated tool Used pulse wave velocity (PWV) to measure arterial stiffness based on faster time for pressure waves travelling from aorta to a standard destination in stiff vessels Used ultrasound to measure IMT in 4 different locations of right and left carotid Outcomes/ Findings/ Implications Higher rates of PWV associated with higher depressive symptoms Depression is associated with early changes in functioning of the cardiovascular system Hostility did not moderate the relationship between depression and PWV Depression was not associated with IMT in adolescents Limitations/ Future Research Assessment of depressive symptoms and PWV was done at only one point in time which limits inferences that can be made over time Time of day that PWV and IMT data was collected was not standard Dietary intake was not controlled for No blood tests to measure for confounding variables of CVD 90 Author/ Date Title/Focus/ Question Flores et al. (2015) Perceived health status and cardiometabolic risk among a sample of youth in Mexico Examine the difference between self-reported perceived mental and physical health status including self-rated health, depressive symptoms, quality of life, and cardiometabolic risk factors in normal, overweight, and obese youths Population/ Participants/ Sample 181 youths aged 11-18 recruited from primary care clinics Inclusion criteria for the study included: age, reading ability, no serious mental illness diagnoses Setting/ Country Mexico Setting not discussed Methods/ Methodology/ Analysis Used self-reported questionnaires Weight, height, and waist circumference were measured in a standardized fashion by medical personnel Used youth quality of life instrument and measured perceived general health, physical function, body shape, satisfaction, and symptoms of depression 164 youth received standardized lab testing for metabolic measures such as glucose and cholesterol levels Outcomes/ Findings/ Implications Presence of depression was positively correlated with HDL Symptoms of depression were significantly correlated with increased BMI, waist circumference, and glucose levels BMI moderates the association between perception of mental and physical health and actual measured cardiometabolic health Limitations/ Future Research Sample was not representative of all Mexicans which may have led to selection bias Depression was determined by self-report Can perceived health status be used to identify youth who are at greater risk of cardiovascular disease? 91 Author/ Date Goldstein et al. (2015) Title/Focus/ Question Major depressive disorder and bipolar disorder predispose youth to accelerated atherosclerosis and early cardiovascular disease: A scientific statement from the American Heart Association Population/ Participants/ Sample Any studies with youth or young adults less than 30 years were included Sample was searched using the following terms: major depressive To increase awareness disorder or of mood disorders bipolar disorder among youth as a (BD) crossmoderate risk factor for referenced with early cardiovascular cardiovascular disease by summarizing disease or heart evidence and disease or suggesting management atherosclerosis or strategies for health coronary disease care providers or coronary vessels or coronary or endothelium or endothelial or arterial stiffness or vascular stiffness or arterial pressure Setting/ Country North America (USA and Canada) Global literature search and use of evidence from many different countries Methods/ Methodology/ Analysis Literature review of MEDLINE Meta-analysis Outcomes/ Findings/ Implications Evidence of CVD mortality from clinical diagnosis of MDD Youth with MDD and BD have increased prevalence of traditional risk factors including obesity, dyslipidemia, and insulin resistance Autonomic dysfunction is common in youth with MDD After accounting for contributing factors, a significant association between MDD and CVD remains Limitations/ Future Research There remain many questions about whether SSRIs moderate the risk of CVD in youth with MDD or contribute to it Future research about effect of vitamin D, omega-3, and sleep therapy on MDD is needed Need more evidence about maltreatment, sedentary behaviours, and contribution of alcohol and drugs on increasing the risk of MDD and CVD 92 Author/ Date Title/Focus/ Question Louise et al. (2012) Associations between anxious-depressed symptoms and cardiovascular risk factors in a longitudinal childhood study To investigate the cross-sectional and longitudinal childhood associations between depression scores and range of cardiovascular and related metabolic risk factors Population/ Participants/ Sample 2900 pregnant women were recruited at 18 weeks of pregnancy Depression and cardiovascular risk factors were assessed in their offspring at ages 5, 8, 10, and 14 Children were excluded if they were part of a multiple birth, there was any congenital malformations, or any siblings already in the study Setting/ Country Australia Setting not discussed Methods/ Methodology/ Analysis Longitudinal cohort study 3 sets of analyses: 1) Cross sectional between depression scores and BMI/BP at ages 5, 8, 10, 14 2) Cross sectional between depressed scores and fasting lipids at age 14 3) Longitudinal analyses between depressed scores over time on BMI and BP Outcomes/ Findings/ Implications Males at 14 years old with depression had decreased systolic BP and increased triglycerides Females with increased depressive scores had higher BMI Males with increased depressive symptoms had lower rate of change for systolic BP Males with increased depressive scores had increased fasting blood glucose Limitations/ Future Research Some participants were lost to follow up There seems to be hormonal component that moderates the relationship between MDD and CVD Women typically present with MDD younger than males and yet this study shows increased CV risk for males 93 Author/ Date Title/Focus/ Question Meier et al. (2014) Associations between depression and anxiety symptoms with retinal vessel caliber in adolescents and young adults Investigated whether an association between depression/anxiety symptoms and retinal vessel caliber is apparent as early as adolescence and young adulthood Population/ Participants/ Sample 865 adolescent and young adult monozygotic and dizygotic twin pairs and their siblings Setting/ Country Queensland, Australia Setting not discussed Mean age for mental health assessment was 16.5 year Follow up eye exam done a mean of 2.5 years later Recruited from all primary and secondary schools in all regions of one area of a province Represent a variety of traits Author/ Date Title/ Focus/ Question Population/ Sample Setting/ Country Methods/ Methodology/ Analysis Longitudinal study Outcomes/ Findings/ Implications Adolescents and young adults Validated and with symptoms reliable self-report of depression and questionnaires to anxiety had determine depression wider retinal and anxiety arteriolar caliber Limitations/ Future Research Symptoms of depression were self-reported and may not accurately predict depression Retinal vessel caliber measured from digitalized photographs using computer-assisted software Study done using twins which may overestimate associations due to genetic factors Provides evidence that depression and anxiety in adolescence may cause pathophysiologic 2 masked and trained changes at the graders averaged the microscopic arteriole and venule level that could measurement from be indicative of photograph for both early eyes for all cardiovascular participants disease Correlation and reliability of graders found to be high Methods/ Methodology/ Findings Does bedside fundoscopy have the same ability to evaluate arteriole changes to predict CV risk in primary care? Limitations/ Future Research 94 Rottenberg The et al. association (2014) between major depressive disorder in childhood and risk factors for cardiovascular disease in adolescence Children with MDD, neverdepressed siblings of child with MDD, and healthy controls Hungary Patients with MDD recruited from mental health 7-14 years facility, healthy Inclusion criteria controls includes: Current recruited When in life DSM-IV from public MDD first definition of schools becomes MDD, no associated with medical traditional risk conditions, a factors for biological parent CVD after and sibling adjusting for willing to parental participate in history of study CVD Author/ Date Title/ Focus/ Question Population/ Sample Setting/ Country Analysis Cohort study Used semistructured interviews to determine diagnosis of MDD Used standardized scales for height, weight, and BMI Youth with MDD had higher levels of obesity Increased levels of parental CVD risk factors and patient CVD risk factors even after they have been statistically controlled for Parental history of CVD was done by self-report May have been some selection bias from sample There was no medical information on CVD risk factors for the parents such as BP or bloodwork which may have overestimated risk There was lots of missing information from parent questionnaires which may also have skewed data Used a multi-nomal logistic regression for statistical analysis Do traditional risk factors (i.e. family history) further compound CVD risk of MDD in youth? Methods/ Methodology/ Findings Limitations/ Future Research 95 Shah, Veledar, Hong, Bremner, Vaccarino (2011) Depression and history of attempted suicide as risk factors for heart disease mortality in young individuals Examined whether a clinical diagnosis of depression and history of suicidal attempt are associated with ischemic heart disease and total CVD mortality in young adults Author/ Date Title/ Focus/ Question Selected from a national study conducted from 1988-1994 on civilian, noninstitutionalized participants USA Minimized bias by testing for possible depression/race interaction and adjusted for race/ethnicity in analysis Original study was looking at diet and health indicators Participants were selected from a complex, multistage sampling design Depression and history of attempted suicide are related to CVD mortality and ischemic heart disease Risk factor history determined only by asking and may be affected by recall bias Females with depression were at higher risk for CVD and ischemic heart disease mortality but not for non-CVC mortality Low event rate of ischemic heart disease and mortality because of young age of the population making the power of analysis limited Used FRE as lone predictor of CVD Used FRE as the only predictor of CVD but has it been validated in young adults (less than 30)? Calculated population attributable risk for depression and attempted suicide and for traditional CV risk to test association between depression/suicide and study outcomes Used mortality data until 2006 for same participants Population/ Sample Analysis History of depression measured with DSM-III and structured interviews Setting/ Country Methods/ Methodology/ Findings Limitations/ Future Research 96 Waloszek et al. (2015a) Early physiological markers of cardiovascular risk in community based adolescents with a depressive disorder Hypothesized that depressed adolescents would have poorer CV functioning as measured by continuous beat-to-beat HR & BP, endothelial functioning, glucose, and cholesterol levels, and a higher level of CV risk factors Studied multiple indices of CV risk of physically healthy adolescents with a current depressive episode and closely matched healthy controls Melbourne, Australia Community sample Analysis Cohort study Measured psychological measures using Centre for Epidemiologic Studies Depression Scale (CES-D) 204 depressive students recruited from high Measured schools (12- cardiovascular 2 groups from 18 years old) measures of body general composition, community 25 students automatic brachial met criteria BP and HR, One group had for study continuous finger to meet DSMwith 25 BP and HR, pulse IV-TR matched transit time (PTT), diagnostic controls blood analysis, criteria endothelial functioning, and The other group Pathobiological was age-matched Determinants of controls with no Atherosclerosis in past or present Youth risk score Axis I pathology (PDAY) No significant differences between depressed group and control group in age, weight, height, BMI, percentage of fat, or waist-to-height ratio Depressed patients had significantly shorter mean PTT (stiffer vessels present little resistance so blood is able to travel faster from the heart to the periphery) Depressed patients also had significantly lower Framingham Reactive Hyperaemia Index (FRHI), a measure of endothelial dysfunction Depressed patients also had higher mean glucose, triglycerides, and higher CV risk scores Only 12 out of 50 participants were male Did not ask whether increased blood glucose and triglycerides were related to diet Cross-sectional design limits causal relationships Relatively small sample size PTT is not as accurate as pulse wave velocity at measuring stiffer coronary vessels 97 Appendix B: Johns Hopkins Nursing Evidence-Based Practice Research Evidence Appraisal Tool Example Article Title: Number: AUTHOR(S): PUBLICATION DATE: JOURNAL: SETTING: SAMPLE Yes Does this evidence address my EBP question? (COMPOSITION & SIZE): No Do not proceed with appraisal of this evidence Level of Evidence (Study Design) A. Is this a report of a single research study? If No, go to B. 1. Was there manipulation of an independent variable? 2. Was there a control group? 3. Were study participants randomly assigned to the intervention and control groups? If Yes to all three, this is a Randomized Controlled Trial (RCT) or Experimenta l Study If Yes to #1 and #2 and No to #3, OR Yes to #1 and No to #2 and #3, this is Quasi Experimental (some degree of investigator control, some manipulation of an independent variable, lacks random assignment to groups, may have a control group) If No to #1, #2, and #3, this is Non-Experimental (no manipulation of independent variable, can be descriptive, comparative, or correlational, often uses secondary data) or Qualitative (exploratory in nature such as interviews or focus groups, a starting point for studies for which little research currently exists, has small sample sizes, may use results to design empirical studies) NEXT, COMPLETE THE BOTTOM SECTION ON THE FOLLOWING PAGE, “STUDY FINDINGS THAT HELP YOU ANSWER THE EBP QUESTION”  LEVEL I  LEVEL II  LEVEL III Yes No Yes No Yes No Yes No 98 B. Is this a summary of multiple research studies? If No, go to Non-Research Evidence Appraisal Form. 1. Does it employ a comprehensive search strategy and rigorous appraisal method (Systematic Review)? If No, use Non-Research Evidence Appraisal Tool; if Yes: a. Does it combine and analyze results from the studies to generate a new statistic (effect size)? (Systematic review with meta-analysis) b. Does it analyze and synthesize concepts from qualitative studies? (Systematic review with meta-synthesis) If Yes to either a or b, go to #2B below. 2. For Systematic Reviews and Systematic Reviews with meta-analysis or metasynthesis: a. Are all studies included RCTs?  LEVEL I b. Are the studies a combination of RCTs and quasi-experimental or quasi-experimental only?  LEVEL II c. Are the studies a combination of RCTs, quasi-experimental and non-experimental or non-experimental only?  LEVEL IIl d. Are any or all of the included studies qualitative? COMPLETE THE NEXT SECTION, “STUDY FINDINGS THAT HELP YOU ANSWER THE EBP QUESTION” STUDY FINDINGS THAT HELP YOU ANSWER THE EBP QUESTION:  LEVEL IIl Yes No Yes No Yes No Yes No