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Inflamation and Depression

Permanent Link: http://ncf.sobek.ufl.edu/NCFE004513/00001

Material Information

Title: Inflamation and Depression
Physical Description: Book
Language: English
Creator: Jeliazkova, Elena
Publisher: New College of Florida
Place of Publication: Sarasota, Fla.
Creation Date: 2011
Publication Date: 2011

Subjects

Subjects / Keywords: Inflamation
Psychiatry
Depression
Psychology
Psychoneuroimmunology
Genre: bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Over a century ago, Professor Julius Wagner von Jauregg received the Nobel Prize for his work on the immunological implications of psychiatry. In the past twenty years, Psychoneuroimmunology has produced novel research on the immunological implications of psychiatric disorders, such as depression. Established by the American Psychiatric Association, the Diagnostic and Statistical Manual of Mental Disorders, defines the depression as a depressed mood and loss of interest, insomnia or hypersomnia, fatigue, inability to concentrate, suicidality, psychomotor retardation and weight change. While no clear etiological explanation has been discovered, the pathophysiology of depression involves neurotransmitter imbalance. This review investigates the bidirectional relationship of the nervous and immune systems in depression. The immune system, the body�s highly adaptable defense mechanism, is composed of an innate and adaptive response. If adaptive mechanisms cannot squelch an invader, the inflammatory immune response may become chronic. Cytokines, identified as immune messengers, proliferate during inflammation. Patients with depression exhibit elevated levels of inflammatory markers, such as cytokines. Patients undergoing cytokine therapy experience depressive symptoms. In addition, anti-inflammatory drugs successfully treat depressive symptoms. Although these links are purely associative, treatments that address depression as an immunological disorder may be safer and more effective. If depression is approached as a multi-systemic immunological disorder, a more physiologically comprehensive etiology may be uncovered.
Statement of Responsibility: by Elena Jeliazkova
Thesis: Thesis (B.A.) -- New College of Florida, 2011
Electronic Access: RESTRICTED TO NCF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE
Bibliography: Includes bibliographical references.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The New College of Florida, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Local: Faculty Sponsor: Beulig, Alfred

Record Information

Source Institution: New College of Florida
Holding Location: New College of Florida
Rights Management: Applicable rights reserved.
Classification: local - S.T. 2011 J4
System ID: NCFE004513:00001

Permanent Link: http://ncf.sobek.ufl.edu/NCFE004513/00001

Material Information

Title: Inflamation and Depression
Physical Description: Book
Language: English
Creator: Jeliazkova, Elena
Publisher: New College of Florida
Place of Publication: Sarasota, Fla.
Creation Date: 2011
Publication Date: 2011

Subjects

Subjects / Keywords: Inflamation
Psychiatry
Depression
Psychology
Psychoneuroimmunology
Genre: bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Over a century ago, Professor Julius Wagner von Jauregg received the Nobel Prize for his work on the immunological implications of psychiatry. In the past twenty years, Psychoneuroimmunology has produced novel research on the immunological implications of psychiatric disorders, such as depression. Established by the American Psychiatric Association, the Diagnostic and Statistical Manual of Mental Disorders, defines the depression as a depressed mood and loss of interest, insomnia or hypersomnia, fatigue, inability to concentrate, suicidality, psychomotor retardation and weight change. While no clear etiological explanation has been discovered, the pathophysiology of depression involves neurotransmitter imbalance. This review investigates the bidirectional relationship of the nervous and immune systems in depression. The immune system, the body�s highly adaptable defense mechanism, is composed of an innate and adaptive response. If adaptive mechanisms cannot squelch an invader, the inflammatory immune response may become chronic. Cytokines, identified as immune messengers, proliferate during inflammation. Patients with depression exhibit elevated levels of inflammatory markers, such as cytokines. Patients undergoing cytokine therapy experience depressive symptoms. In addition, anti-inflammatory drugs successfully treat depressive symptoms. Although these links are purely associative, treatments that address depression as an immunological disorder may be safer and more effective. If depression is approached as a multi-systemic immunological disorder, a more physiologically comprehensive etiology may be uncovered.
Statement of Responsibility: by Elena Jeliazkova
Thesis: Thesis (B.A.) -- New College of Florida, 2011
Electronic Access: RESTRICTED TO NCF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE
Bibliography: Includes bibliographical references.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The New College of Florida, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Local: Faculty Sponsor: Beulig, Alfred

Record Information

Source Institution: New College of Florida
Holding Location: New College of Florida
Rights Management: Applicable rights reserved.
Classification: local - S.T. 2011 J4
System ID: NCFE004513:00001


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INFLAMMATION AND DEPRESSION BY ELENA JELIAZKOVA A Thesis Submitted to the Division of Natural Sciences New College of Florida in partial fulfillment of the requirements for the degree Bachelor of Arts Under the sponsorship of Professor Be ulig Sarasota, Florida May, 2011

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ii For my family Acknowledgements Professor Alfred Beulig Thank you for being my academic stronghold and effortlessly guiding me through New College. Thank you for supporting my academic and personal endeavors! Thank you to my family, Professor McCord, Professor Bauer, & Professor Gilchrist. And, to the countless individuals who have helped me.

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iii Table of Contents Acknowledgements ................................ ................................ ................................ .... i i Table of Contents ................................ ................................ ................................ ....... i i i List of Figures ................................ ................................ ................................ ............ i v Abstract ................................ ................................ ................................ ...................... v I Introduction 1.1. Psychiatry and the Nobel Prize ................................ ................................ ......... 1 1.2 Psychoneuroimmunology ................................ ................................ ................. 3 1.3 Scope of Study ................................ ................................ ................................ .. 5 II Curr ent Understanding of Depression 2.1. Diagnostic Definitions ................................ ................................ ...................... 7 2.2. Established Biomarkers ................................ ................................ ................... 11 2.3. Prevalence of Depression ................................ ................................ ............. 1 1 2.3.1. Comorbidity of Depression with ................................ ... 13 2.4. Biological Etiological Hypothesis ................................ ............................... 14 2.5. Accepted Treatments ................................ ................................ ....................... 16 2.5.1. Treatment Efficacy ................................ ................................ ........................ 18 III. Major Advances & Systematic Errors in Treatment Methodology 3.1. Diagnostic and Statistic al Manual of Mental Disorders, DSM IV TR ............ 20 3.2 Practice Guidelines for the Treatment of Patients with Major Depression ..... 22 ................................ ................................ ...................... 24 ................................ ................................ ................ 24 ................................ ................................ ........................... 26 IV. Systemic Background 4.1. Stress ................................ ................................ ................................ ................ 28 4.2. N ervous System 4.2.1. Neurons and Neurotransmitters ................................ ............................. 30 4.2.2. Central & Peripheral Nervous Systems ................................ .................. .33 4.3 Immune System 4.3.1. Innate & Adaptive Responses ................................ ................................ ..34 4.3.2 Cytokines ................................ ................................ ................................ ..36 V Chronic Inflammation in Depression 5.1. Proinflammatory Cyto kine Imbalance in Depression ................................ 38 5.2. Comorbidity of Depression in Patients Doing Cytokine Therapy ............. 39 5.3. Use of Anti Inflammatory Drugs for Depressive Symptoms .................... 41 VI Conclusion ................................ ................................ ................................ 42 Bibliography ................................ ................................ ................................ ......... 45

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iv List of Figures Figure 1. Function of Mono ................ 16 ................................ ......... 16 ................................ ............. 17 Figure. 4. Typical ................................ ................................ ................. 30 Figure 5 ................................ ................................ ........................... 31 Figure 6. Serotonin Function in Central Nervo us System ................................ 32

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v INFLAMMATION AND DEPRESSION Elena Jeliazkova New College of Florida, 2011 ABSTRACT Over a century ago, Professor Julius Wagner von Jauregg received the Nobel Prize for his work on the immunological implications of psychiat ry. In the past twenty years, Psychoneuroimmunology has produced novel research on the immunological implications of psychiatric disorders, such as depression. Established by the American Psychiatric Association, the Diagnostic and Statistical Manual of Me ntal Disorders, defines the depression as a depressed mood and loss of interest, insomnia or hypersomnia, fatigue, inability to concentrate, suicidality, psychomotor retardation and weight change. While no clear etiological explanation has been discovered, the pathophysiology of depression involves neurotransmitter imbalance. This review investigates the bidirectional relationship of the nervous and immune systems in composed o f an innate and adaptive response. If adaptive mechanisms cannot squelch an invader, the inflammatory immune response may become chronic. Cytokines, identified as immune messen gers, pr oliferate during inflammation. Patients with depression exhibit elevated leve ls of inflammatory markers, such as cytokines. Patients undergoing cytokine

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vi therapy experience depressive symptoms. In addition, anti inflammatory drugs successfully treat depressive symptoms. Although these links are purely associative, treatments that address depress ion as an immunological disorder may be safer and more effective. If depression is approached as a multi systemic immunological disorder, a more physiologically comprehensive etiology may be uncovered. ________________________ Professor Alfred Beulig Div ision of Natural Sciences

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1 Chapter I I. Introduction 1.1 Psychiatry and the Nobel Prize The Austrian Julius Wagner von Jauregg was the first psychiatrist to earn the Nobel Prize in medicine and physiology in 1927. Von Jauregg successfully treated g eneral paralysis of the insane ( GPI ), a fatal form of neurosyphilis, using malaria fever therapy (Whitrow 1990) With ethical issues aside, the treatment was rendered obsolete with the introduction of penicillin in 1929 (Shorter 1997 ). Syphilis can now be recognized and treated earlier with antibiotics. Von academic career, founded on thorough research and excellent professorship, surpassed that of his contemporary, Sigmund Freud. Unfortunately, because his publications entered journals of narr ow circulation, his contributions are not as widely (Whitrow 1990). W ith the outbreak of W orld War II the psychiatric community migrated from Europe to the United States (Shorter 1997 ). Unfortunately, t he interest in the immunolo gical perspective of psychiatry was replaced with interest in lucrative profitability in pharmacological advances and psychotherapy A t the Asylum of Lower Austria in Vienna in 1883 v on Jauregg observed a woman who suffered from mental illness and a chronic skin infection, erysipelas. After an attack of the skin infe ction, caused by streptococcal bacteria, the woman recovered from her severe mental illness (Shorter 1997 ) In 1887, v on Jauregg published the first documented review of the multi ple effects of typhoid, cholera, fevers, exanthemata and erysipelas on psychoses. Typhoid epidemics were i ncredibly common in mental

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2 institutions A fter the typhoid attacks, many patients mental symptoms were cured, and others were substantial ly decreased The co occurrence of relief from symptoms of mental illness and disease outbreak has been observed t hroughout history. Hippocrates observed the improvement of epilepsy with concurrent malarial infection. The Greek physician Galen reported depression cured by malarial fever. Among many others, the French psychiatrist Esquirol stated that infectious di seases could ame liorate and even cure patients with mental illness Before v on Jauregg Professor Alexander S. Rosenblum (1826 1902) of Odessa was the first psychiatrist to induce infection in patients with mental illness with positive results The West knew nothing of his research (Whitrow 1990). Von Jauregg concluded that infectious diseases could cure patients with mental illness. Some patients recovered only while prese nting symptoms of the infect ion, while others improved for months. Von Jauregg re ported that the different effects on psychoses could either be attributed to bacterial toxins and/or bacterial proteins. In 1888, v on Jauregg began his research by inoculating several patients with strepto co cci with negative results. He followed that w ith staphylococci and malaria (Whitrow 1990). He controlled t h e accompanying fever with quinine, a potent anti inflammatory (Shorter 1997 ). Upon investigat ing physiological reasons for malaria treatment improvements, v on Jauregg reported that at high t emperatures syphilitic spiroc h etes disappeared. No spirochetes were found in the brain of paralytics who had undergone high fever before their death. He also maintained that the induced fever may not be the primary mechanism of action (Whitrow 1990).

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3 By 1925, v on Jauregg treated over 1,000 paralytics. Over 60% experienced remission to varying degrees. Thirty percent of those experienced full remission (Whitrow 1990) His e pochal achievement temporarily w elded the fissure between psychiatry and physiolo gy Neurosyphi lis which had filled asylums, was completely eradicated. Afterwards, the fever cure was tried on every conceivable mental illness, without marked results. When penicillin replaced the need for fever therapy, the antibiotic was tested on pat ients w ith mental illness (Shorter 1997 ). In 1944, a 34 year old female paretic experienced auditory hallucinations, disorientation, and tremors. S he was treated with penicillin from March 23 rd to May 13 th At the end of treatment, she regained orientatio n, hallucinations subsided, and her speech and writing returned to normal. H er tremors disappeared and she regained proper functioning. According to Shorter (1997) penicillin could not cure any other major psychiatric disorder because few others are caus e d by a virus or bacterium Current research has suggested otherwise. As of 2010, the American Psychiatric Association acknowledges the role of infectious diseas e in depressive disorders (APA 2010) 1.2 Psychoneuroimmunology Chronic diseases, such as d ep ression, present multi fac eted symptoms. Most often more than one biological system is affected Recently, the western biomedical community has begun researching the interconnectedness of biological systems in response to the growing complexity of dise as es. Psychoneuroimmunology ( PNI ) endeavors to expose the bidirectional synergy of the immune and neuroendocrine system s that lead to behavioral and personality changes (Irwin and Miller 2007)

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4 During the first ten years of psychoneuroimmunology, research ers concentrated on the effect s of depression on the immune system. Specifically, th ey studied the role of cytokine hormones in depression Cytokines have multiple inflammatory and anti inflammatory roles. During the first decade, researchers discovered th at stress and depression lead to increased inflammation in the body. More recently, researchers have reversed this connection Research is currently directed at studying the immune system role in the development of depression (Irwin and Miller 2007) Is it possible that increased inflammation in the body is a marker of major depression? Can depression fueled by increased inflammation, be a behavioral symptom of an underlying immunological condition? Inflammation is the immune system response to a fore ign invader. The immune syst em can also produce inflammation due to toxicity, autoimmunity, and other stressors. As t he body is filled with immune cells various biological systems may become inflamed Undetected c hronic inflammation may continue indefinitely if the correct symptoms are not addressed. Inflammation can also remain undetected by tr aditional medical measurements. Inflammation is characterized by edema and flu lik e symptoms; however, b ehavioral changes can be sympt omatic of inflammation as well Thus r edefining and understanding bi directional communication s between the neuroendocrine and the immune system is integral to understanding chronic depression (Irwin and Miller 2007) PNI is demystifying the social stigma of major depression as a mental illne ss. The public is well educated in the effects of neurotransmitter imbalance in depression However, can the initial reason for this chemical imbalanc e begin elsewhere in the body?

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5 And, does the initial event involve the interactions of more than one biolo gical system? I f depression was merely a ch emical imbalance and i f psychotropic medication and counseling worked as efficaciously as the public is led to believe, these methods would elicit greater and fuller recovery. 1.3 Scope of Study Doctors canno t address depression exclusively as a psychological and brain imbalance with maximum effect Because of overw helming evidence depression must be explor ed from a multi systemic perspective. The exploration of these themes is addressed as follows: Chapter II exp lores the current understanding of depression according to the American Psychiatric Association (APA) Diagnostic categories, prevalence, established etiological theories and accepted treatments are explained. Major Depressive Episode, Major Depressive Di sorder, and Depressive Personality D isorder are defined. To substantiate the need for physiological criteria, current statistics of depression and widespread comorbidity with chronic disease are examined. The advantages and shortcomings of the biological m odel of depression are evaluated. To illustrate the inefficiencies of current diagnostic criteria, treatment efficacy is explored Chapter II I ex amines major advances and systematic errors in diagnostic and treatment methodology To elucidate the complex characteristics of diagnostic criteria, t he responsibilities and shortcomings of the 2000 Diagnostic and Statistical Manual of Mental Disorders, DSM IV TR are explored To educate the public, the methodology of the 2 010 Practice Guidelines for the Treatment of

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6 Patients with Major Depressive Disorder is critically examined. Because etiological investigations are not required for diagnosis the APA promotes disinterest in the physiological origins of depression. Chapte r IV provides an introductory dis course on the concept of stress and the immune and nervous systems. Unfortunately, stress has become a gen eralized psychosocial concept. P otential sources of exogenous physical stressors, including diet, environmental chemi cals and infectious agents, are rarely considered. In 1936, Hans Selye developed the General Adaptation Syndrome to define biological stress response s (Viner 1999) Central to our discussion, anatomy and function of the nervous system is elucidated. In add ition, the immune s ystem, responsible for defense mechanisms, is defined by innate and adaptive r esponse s Cytokine mechanisms are explored, as they relate to chronic conditions and chronic inflammation. To validate an immunological model of depression Ch apter V establishes chronic cytokine inflammation in depression. Patients undergoing cytokine therapy experience depressive symptoms as well In addition, antidepressants and anti inflammatory medications improve immune functioning and reduce depressive symptoms respectively. Thus, current data effectively establishes bidirectional ne uroendocrine and immune system mechanisms in depression Although chronic inflammati on in depression is associative rather than causal, this relation provides novel approaches to tre atment methodology. Unfortunately, the narrow diagnostic and treatment methodology of the psychiatric industry leaves many biological avenues unexplored. M ulti systemic immunological implications c an substantiate more comprehensive effective and safe app roaches to the treatment of depression.

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7 Chapter II II Current Understanding of Depression 2.1 Diag n ostic Definitions Published by the American Psychiatric Association (APA) for clinicians, the Diagnostic and Statistical Manual of Mental Disorders, Text Revision, DSM IV TR, is used to diagnose mental illness. The manual is available to the public. Depression can occur as an episode of two week duration or longer. It can also develop into a depressive disorder if the patient experiences more than one depressive episode. According to the APA (2000) the symptoms of a major depress ive episode are as follows : A. Five (or more) of the following symptoms have been present during the same two week period and represent a change from previous functioning; a t least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly due to a general medical condition, or mood incongruent delusions or hallucinations. (1) Depressed mood most of the day nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood. (2) Markedly diminished interest or pleasure in all, or alm ost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others)

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8 (3) Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains. (4) Insomnia or hypersomnia nearly every day (5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feeling s of restlessness or being slowed down). (6) Fatigue or loss of energy nearly every day (7) Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self reproach or guilt about being sick) (8) Diminished abi lity to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) (9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a s pecific plan for committing suicide. B. The symptoms do not meet criteria for a Mixed Episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). E. The symptoms a re not better accounted for by b ereavement, i.e., after the loss of a loved one, the symptoms persist for longer than two months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation ( APA 200 0 ).

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9 Other than the physiological symptoms mention ed above (appetite loss, weight loss, psychomotor agitation, insomnia and fatigue), the DSM IV TR states that there are no laboratory findings to identify a Major Depressive Episode ( APA 200 0 ). However, it is difficult to distinguish depression from a gen eral medical illness because many symptoms, such as anorexia, insomnia, weight loss and fatigue, can occur in other medical illnesses. For example, p and r ecurrent suicidality is common in HIV patients (Stoner et al 1998). The manual warns that many general medical conditions, such as cancer and diabetes, can induce similar tion, the psychiatrist cannot diagnose the symptoms as a Major Depr essive Episode. The depressive e pisode cannot also be diagnosed if it is the direct result of drug abuse, side effect to medication or toxin exposure ( APA 200 0 ). The diagnosis of a Major D epressive Disorder requires the criteria of a Major Depressive Episode, with extended longitudinal specifiers. For example, Depressive Disorder : Recurrent, Moderate, With Atypical Features, With Seasonal Pattern, With Full Interepisode Recovery ( AP A 200 0 ). homogenous subgroups, assist in treatment selection, and improve the prediction of

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10 prognosis ( APA 2000 A n extensive classification system is useless given the genera lized treatment options available to patients The manual claims that Depressive Personality Disorder may exist on a spectrum, preceded by Major Depressive Disorder. The personality disorder is characterized by the following: A. A pervasive pattern of depre ssive cognitions and behaviors beginning by early adulthood and present in a variety of contexts, as indicated by five or more of the following: 1. Usual mood is dominated by dejection, gloominess, cheerlessness, joylessness, unhappiness 2. Self concept centers around beliefs of inadequacy, worthlessness, and low self esteem 3. Is critical, blaming and derogatory toward self 4. Is brooding and give n to worry 5. Is negat ivi stic, critical, and judgmental toward others 6. Is pessimistic 7. Is prone to feeling guilty or remorseful B. Does not occur exclusively during Major Depressive Episodes and is not better accounted for by Dysthymic Disorder ( APA 200 0 ). Most appallingly, the manual does not provide physiological biomarkers for the disorder. Recover y of a mental disorder is diagnose d by partial and full remi differentiation of full r emi ssion from recovery requires consideration of many factors, including the characteristic course of the disorder, the length of time since the last period

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11 of disturbance, the total duration o f the disturbance and the need for continued evaluation symptoms after a period of time (A PA 200 0 ). 2.2 Established Biomarkers Although there are no accepted biological markers for Major Depressive Disorder, patients with Major Depressive Episode, Bipolar I and II all have similar abnormal laboratory findings. Thus, even though these patients express varied behavioral symptoms, their bodies share similar biological activi ties. The pathophysiology of the episode may involve the dysregulation of the serotonin, norepinephrine, and dopamine neurotransmitter systems among others Neuropeptide, hormonal and cerebral blood flow changes have been noted. The ne of these changes are present in all individuals with Major Depressive Episode, however, nor is any particular disturbance specific to depression ( APA 200 0 ) categories share abnormal laboratory findings, depression is defined generally without reference to episode, disorder, or personality disorder. 2.3 Prevalence of Depression Depression influences communities irrespective of socioeconomic, ethnic, educational and racial divisions (Myint 2007) The worldwide he althcare cost of depression is in the top three most costly diseases (Petty et al. 2008). Because it has such a negative health impact, it is the leading cause of life years lived with disability worldwide (Evans et al 2005). The lifetime population prevalence fo r major depressive

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12 disorder is 5 12% in men a nd 10 25% in women, creating a 1 :2 ratio F emale prevalence in major depression is doubled during the years of reproductive potential. Before menarche, males have higher rates of depression than girls. Men hav e similar rates of depression to women after menopause. The highest prevalence for major depression have been seen in children and adolescents over the last 50 to 100 years. Three generations ago, the onset age for the first depressi ve episode was fifty. The current onset age is 20 to 30 (Petty et al. 2008). The chronicity, intensity and treatment resistance of depression remain obstacles to successful treatment (Myin t 2007). Even with treatment, the disorder is recurrent and episodic (Petty et al 2008). Thirty percent of patients relapse within the first year of treatment, and another 30% par tially respond to treatment. Eighty percent of patients suffering from major depression experience at least one more episode during their life (Myint 2007). After three episodes, recurrence is expected and chronic (APA 2010). In addition, 20% 35% of patients experience chronic residual symptoms, including anxiety, and social and oc cupational impairment (APA 2010). People suffering from the disorder also suffer from elevated rates of physical illness. They are more likely to develop substance abuse problems such as alcoholism. They also have a 15% lifelong risk of suicide. Major dep ression has a high prevalence in first degree family members of affected individuals. Psychological factors such as stressful life events, childhood abuse, neglect, early parental death and separation are considered risk factors (Petty et al 2008). It is important to note that only 10 % 30% of

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13 people who experience stressful life events develop major depression. Similarly, many people who lack significant life stressors develop major depression (APA 2010) 2.3.1 Comorb idity of Depression with Chronic Dis ease In DSM IV TR depression is considered to be a mood disorder because the most apparent symptom is an atypical emotional state (Petty et al. 2008). Depression can also occur in Bipolar I and II Disorder, Depressive Disorder Not Otherwise Specified (NO S), Depressive Personality Disorder, Substance Induced Disorder, Adjustment Disorder, Attention Deficit Hyperactivity Disorder and Mood Disorder NOS, among others. Diseases that occur simultaneously have higher prevalence rates and are termed comorbid Pan ic Disorder, Obsessive Compulsive Disorder, Anorexia Nervosa and Borderline Personality Disorder occur comorbidly with Major Depressive Disorder (APA 2000) Because depressive symptoms occur comorbid ly with many other mental illnesses these disorders shar e common phys iological traits. Comorbid mental illness is frequently undiagnosed in other medical conditions. For example, anxiety, depression and psychosis are common comorbid illness (Stoner et al 1998). M edical conditions are rarely explored as etiolog ically relevant to psychiatric illness. However, the human body works multi systemically; thus comorbid chronic disease is not a random psychological phenomenon Twenty five percent of medically ill patients suffer from concurrent mental illness. For exa mple, r and multiple sclerosis have high comorbid rates with mental illness. Endocrine disorders, and

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14 are all etiologically relevant to clinical depression. Treatment of the endocrine disorder resolves psychiatric symptoms (Stoner et al 1998). HIV and AIDS (acquired immunodeficiency syndrome) cancer, obesity, diabetes, and chronic pain exist com orbidly with m ental illness. For example, HIV and AIDS patients experience depression, psychosis, delirium and agitation from psychological str ess and neurological changes. Twenty five percent of hospitalized cancer patien ts experience depression (Stoner et al 1998). In addition, 20% of obese boys and 30% of obese girls develop major depression Fortunately, comorbid depression with medical illness can be treated (Evans et al 2005). Because of the high comorbidity of depression with other medical conditions, psychiatrist s should more actively investigate the origin of 2.4 Biological Etiological Hypothesis According to the National Institutes of Mental Health (2009) multiple genes, acting together with environmental or other nongenetic factors, increase susceptibility to depression. Although depression can have a familial pattern, it can occur in patients without prior familial history of the disease. Furthermore, later episodes of depression can occur with out an est ablished origin In the 1950s, the discovery of the first psychotropic medications fueled interest in the neurochemical etiology of depression. The observations of the imipramine mechanism in depression led to the monoamine hypothesis. Imipramine, a tricy clic antidepressant, blocked the synaptic reuptake of norepinephrine. In the past 60 years, th e research method has not changed. O ur current understanding of depression is based on antidepressant mechanisms of action. Thus, the hypothesis indirectly descri bes

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15 depression by substantiating the current pharmaceutical drugs (Garlow and Nemeroff 2004). Researchers attempt to explain depression by investigating psychotropic mechanisms. Thus, research was never focused on depression i t self, but rather on antidepre ssants. According to the monoamine hypothesis, depression is demonstrated by low levels or imbalances of the neurotransmitters, serotonin, norepinephrine and/or dopamine in the synaptic cleft (Pinna et al. 2009). Figure 1 explains neurotransmitters and sy napses Functional deficits of these neurotransmitters at key sites in the brain lead to behavioral changes, such as depress ion (Myint 2007). Petty et al. (2008) suggests that the evidence that supports the biogenic amine hypothesis is ind irect Because m onoamine changes occur within two days of antidepressant treatment, this hypothesis does not explain why patients wait several weeks before effects kick in. Secondly, the hypothesis does not explain why drugs like cocaine and amphetamine, which also alter neurotransmitter availability, cannot treat depression. Thirdly, it cannot explain why antidepressants improve other psychiatric conditions, such as social phobia. Fourthly, it does not account for the physiological effects of electroconvulsive therapy. Ma ny other observations in major depression have not been replicated by the monoamine hypothesis, and others have yielded contradicting results Despite fifty years of advanced scientific research, no clear etiology of depression has been established (Gar low and Nemeroff 2004). Despite controversy new antidepressants are continually developed (Myint 2007). By only concentrating research on antidepressant mechanisms we are inadequately assessing the physiological characteristics of depression.

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16 2.5 Accepte d Treatments Patients with Major Depressive D isorder are typically treated with pharmacological, as well as psychological interventions. Patients with mild to moderate symptom severity usually respond to cognitive and behavioral techniques. Other patient s choose to treat their depression with antidepressants. The APA (2010) recommends electroconvulsive therapy for treatment resistant depression Figure 1. Function of Monoamine Oxidase in Presynaptic Neuron. Please refer to the Nervous System Chapter (M cCance 1998). Antidepressants aim to selectively block the reuptake of specific neurotransmitters in the synapse. Reuptake is inhibited within minutes of administration. By blocking reuptake, neurotransmitter levels increase in the synaptic cleft. The ful l effects of an antidepressant are felt within four to eight weeks. Within this time, the patient may experience amelioration or worsening of symptoms (Petty et al 2008). Figure 2. Monoamine oxidase inhibitor s (MAIOs) prevent the degradation of neuro transmitters by monoamine oxidase (McCance 1998)

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17 Until 1980, tricyclic antidepressants (TCAs) aimed to raise the level of serotonin and norepinephrine in the synaptic cleft. D octors introduced the monoamine oxidase inhibitors (MAOIs ) because of uncomfort able TCA side effects (Myint 2007). Figure 2 demonstrates how MAOIs either block transporters or inhibit re uptake by blocking degradation of the neurotransmitter in the presynaptic neuron. However, unwarranted side effects from this medication led to the development of the selective serotonin reuptake inhibitors (SSRIs) as illustrated in Figure 3 The SSRIs, the selective noradrenaline and serotonin reuptake inhibitors and the dual action antidepressants are the most current and widely used antidepressant s (Myint 2007). Figure 3 S elective serotonin reuptake inhibitors (SSRIs) are hypothesized to block serotonin re uptake (McCance 1998)

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18 2.5.1 Treatment Efficacy Many individuals have experienced an improvement in quality of life with acute antidepres sant treatment. Unfortunately, antidepressants demonstrate limited efficacy (Myint 2007). A pproximately 50% 60% of patients respond to treatment. A response is defined as 50% or greater reduction of symptoms. Symptom reduction excludes uncomfortable side effects and contraindications from other medication. Physical side multiple roles throughout the body (Berger 2009) Unfortunately, if depression is only a neurotransmitter imbalance, and if antidepressants accompl ished their intended goal, sensibly, depressive symptoms would decrease witho ut unintended side effects. According to Healy (1997) psychiatric treatments garner large placebo response s because treatment is heavily influenced by nonspecific factors such a s quality of relationship between patient and psychiatrist, and the environment in which help was sought Successful treatments can not depend on the su bjective quality of healthcare. A biological approach should be enough to elicit recovery. For example, c ancer patients cannot depend on the subjective nature of their treatment to survive, their disease necessitates accurate treatment. Why does depression treatment require less? According to Petty et al., (2008), placebo patients have an incredibly high 30% 40% response rate with antidepressant treatment According to another placebo meta analysis, response in antidepressant trials, placebo rates account for up to 68% of drug groups. Thus, clinicians are encouraged to depend on placebo efficacy (Rief et al. 20 09). D espite sixt y years of expensive control group research, the psychiatric industry ultimately relies heavily on the subjective response of drug treatment. In addition, because of unintended side effects,

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19 three months after the beginning of treatment 56% of patients have poor compliance rates (Myint 2007). Many must change medication more than once to find an efficient medication. Psychiatrists combine antidepressants with antipsychotics, mood stabilizers and sedatives to compensate for the short com ings of antidepressants. Even then, many individuals suffer from recurring depressive symptoms (Olfson and Marcus 2009). The purported efficacy of antidepressants is controversial. Publication bias in the treatment of adult depressive disorder has been ov erstated. Furthermore, antidepressant studies only represent efficacy in severe depression. Patients with mild or moderate depression are excluded from research (Olfson and Marcus 2009). Kirsch et al. (2009) evaluated all antidepressant drug trials, publi shed and unpublished, submitted to the Food and Drug Administration. A ntidepressant efficacy decreases with increasing severity of depression. N ew generation antidepressants elicit effects below the recommended levels of clinical significan ce (Kirsch et al 2009) Despite the increasing popularity of psychotropic medication, the treatment of depression has not improved since the release of the first TCA in 1958 (Myint 2007). Although pharmaceutical companies continue to release better alternatives, depressi on rates are still rising (Olfson and Marcus 2009).

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20 Chapter III II I Major Advances & Systematic Errors in Treatment Methodology 3.1 Diagnostic and Statistical Manual of Mental Disorders, DSM IV TR T he goals and guidelines of the American Psychiatri c Association (APA) must be explored to facilitate public health education and to substantiate the necessity for biological parameters of depression Since its inception in 1892, the association has provided medical treatment for patients suffering from ps ychiatric illness To ensure that the A ssociation is accurately represented, I purposefully quote directly from the diagnostic manual. To facilitate diagnosi s and treatment of depression my aim is to highlight advances and introduce potential amendments. The goal of the diagnostic manual of language and explicit statements of the constructs embo ( APA 200 0 ). It enables clinicians to diagnose people with mental disorders. Th e diagnostic manual presents several systematic shortcomings. O nce a patient is shuffled to a psychiatrist, the psychiatrist has no professional motivation to explore the physiological ological determinants, diagnostic practice is highly subjective. In most cases, psychological symptoms can overlap in more than one category of disease. Diagnostic experience and interpretation can vary from doctor to doctor ( APA 200 0 ). Thirdly, because tr eatment options have not changed since the 1950s the broad expansion of behavioral quantification is im practical (Myint 2007). Although psychotropic medication remains the main method of treatment, the diagnostic manual has expanded its nomenclature from

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21 106 disorders in 1952 to 297 disorders in 1994 (Grob 1991). In addition, all antidepressants work similarly ( APA 2010). Because antidepressants are not distinguishable extensive diagnostic criteria does not affect treatment selection or efficacy Without a thorough understanding of etiology, the psychiatric community is compromising the development of comprehensive and safe treatment s for depression mechanism, associated with a gene PA 200 0 ) in Major Depressive, Bipolar, and Adjustment Disorders. The overwhelming comorbidity of physiological conditions with mental disorders suggests that physicians must comprehensively evaluate the patient for physiological, as well as psychological symptoms. In one paragraph, the DSM IV asserts that many general medical conditions ascular disease (e.g., stroke) metabolic conditions (e.g., vitamin B12 deficiency), endocrine conditions (e.g., hyper and hypothyroidism, hyper and hypoparathyroidism, hyper and hypoadrenocorticism), autoimmune conditions (e.g., systemic lupus erythemat osus), viral or other infections (e.g., hepatitis, mononucleosis, HIV and certain cancers (e.g., carcinoma of the APA 200 0 ). Do patients who cannot establish the etiol ogical origin of their disorder have an entirely unique mood condition? Alth ough neurotransmitters cannot be measured directly in brain synapses, accurate neurotransmitter and metabolite concentrations can be measured in cerebrospinal fluid, urine, blood and saliva (Garlow 2004). Unfortunately, psychiatrists do not use these measu rements (APA 2000). Many physiological conditions associated

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22 with psychiatric symptoms are used to help diagnose mental disorders (Petty 2008). (APA 2010). These condit ions an d diagnostic tests are not used as medical standards. Instead psychiatrists are fully motivated and allowed to distribute psychiatric medication without an extended physiological examination P sychiatrists dissuade patients from e xploring biologica l treatments. A lthough counseling and psychiatric treatments could not substantially improve the health of a 25 year old university graduate suffering from treatment resistant depression his psychiatrist did not encourage further physiological investigati ons (Parker 2002). In another case stu dy a 51 year old woman diagnosed with atypical depression failed to respond to 51 different drug s psychopharmacologist assured her the mental symptoms could not possibly be caused by ld et al 2007). If accepted treatments of chronic depression do not yield positive results, the quest for biological treatments should not be trivial ized as a superfluous fixation. Medical professionals should be held accountable for the safest and most c omprehensive treatment for depression 3.2 Practice Guidelines for the Treatment of Patients with Major Depression In addition to a diagnostics manual, the American Psychiatric Association provides an updated guideline for clinical practice, the 2010 P ractice Guidelines for the Treatment of Patients with Major Depressive Disorder. Published by the APA for

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23 clinicians, the practice guidelines are available to the public online. Although depression diagnostics have become more precise over the past 40 year s, clinicians employ various systematic errors in the treatment of major depression (Garlow and Nemeroff 2004). First, a ntidepressant criteria do not represent acute treatment goal s established by the APA. Second, a ntidepressant selection is based on subje ctive criteria, rather than extensive physiological parameters. Third, t reatment approach should change when psychotropic medication does not garner sufficient improvement. Fourth, most importantly guidelines for alternative therapies should be reassessed These shortcomings lead to an unrealistic public un derstanding of depression and treatment efficacy The practice guidelines strive to acks research on topics such as immunology, although some of the respective research dates back to as early as 2001. Thus, bias towards the psychiatric and pharmacological model of depression is inherently and consistently predominant. Unfortunately, the APA claims that not ensure a successful outcome for every individual, nor should they be interpreted as including all proper methods of care or excluding other acceptable methods of care aimed at th e same resul although the association provides a clinical rubric, it absolves itself from responsibility if the recommended treatments prove insufficient.

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24 3.2.1 Major Advance s The APA is expanding the physiological implications of d epression. Previously, psychiatrists have ignore d alternative studies. However, t he 2010 Practice G uidelines state analyses is limited, the level of confidence may also incorporate other clinic al trials and case reports as well as clinical consensus with regard to a particu lar clinical decision Thus, psychiatrists are currently encouraged to implement clinical research and case reports. A century after Professor v on Jauregg the APA acknowledges the role of infectious disease in depr essive disorders As of 2010 gene ral medical conditions associated with depression are neurological conditions, thyroid disorders, metabolic conditions, malignancy and infectious disease (APA 201 0). However, infectious disease is only mentioned once In the future, t he association should improve the specificity of physiological diagnostic criteria 3.2.2 Treatment Selection Unfortunately, antidepressant selection is highly subjective and does no t reflect the goals of the APA. The purpose of treatment is return to ba seline functioning, although antidepressant success is defined by a 50% or more symptom improvement In addition, t he APA states that antidepressant efficacy is comparable between and within classes of medication. D rug de effects, the safety or tolerability of side effects for the individual patient, pharmacological

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25 s a highly subjective practice informed mainly by side effects and patient comfort. In addition, the excessive specificity of diagnostic specifiers do es not influence psychotropic medication selection The APA relies on methodology that strictly adheres t o the pharmacological and psychotherapeutic model of treatment. In the s cientific community, nonresponse to treatment is addressed with an entirely new and different methodology. Unfortunately the APA consistently uses the same methodology that d oes not g arner adequate treatment results If psychotropic medications do not work adequately the most logical approach would be to use an entirely different therapy, rather than switching subjectively from medication to medication. If all antidepressants functio n similarly, it is useless to change medications and expect highly different results. It is illogical and ridiculous to employ the same technique, but expect different results. As previously mentioned a 51 year old woman diagnosed with atypical depression failed to respond to 51 different drug trials. Bransfield et al 2007). After nonresponse to 51 different dr ug s would it not be medically and scientifically justified to attempt a different biological approach to treatment?

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26 3.2.3 Monotherapy Accepted treatme nt employs a narrow methodology, erroneously considered monotherapuetic. The complementary and alter native treatments suggested by the Adenosyl methione (SAM e), Omega 3 fatty modalities can be recommended with enthusiasm for their ge neral health benefits; however, patients should be informed that evidence for their antidepressant efficacy as Mentioned continuously, this is the guideline s greatest argument against complementary treatments. T he APA downplays the contributions of these complimentary therapies because they cannot work as a solitary therapy. In many cases, antidepressants, psychotherapy, and psychotropics do not work as monotherapies. A ntidepressants are increasingly being pre scribed with sedatives, antipsychotics, and other drugs to overcome side effects (Olfson 2009). Thus, like psychotropic medication, these alternatives should not be considered monotherapies. These complementary approaches, proven to improve the well being and health of the patient, without creating deleterious side effects, should not be treated to a higher standard than the efficacy rates used for psychotropic medication psychotherapy and treatment Furthermore, as evidenced by increasing research, Major Depression implies multi systemic dysfunction. Therefore, it would make logical and scientific sense to treat a multi syst emic disease multi systemically. To support every weakened biological

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27 system equally, multi systemic support requires more than one t herapy. Thus, the monotherapuetic and pharmacological model of depression is therefore an inade quate and unrealistic treatment. M ulti systemic illness must be supported multi systemically and substantial results may require much time. The psychiatric indu stry is d angerously promoting an illusory stigma regarding mental health. By blatantly disregarding potential sources of neurotransmitter dysfunction, they potentiate an artificial dichotomy between mental and physical dysfunction s and stigmatize the latter They promote the idea that function is so completely mysterious, that people suffering from mental illness cannot fully recover without pharmacological and counseling dependence. I f we continue to propagate the idea that our b rain is disconnected from our biological sys tems, we are only furthering medical and social ignorance. In order to treat depression more comprehensively we must be willing to redefine mental health. That definition must not only be based on symptomatic psychological terminology, but multi systemic biological criteria.

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28 Chapter IV IV Systemic Background 4.1 Stress Hans Selye (1907 1982) introduced stress as a biological and psychological concept. Selye, searching for new female hormones, observed a repetitive pattern of effects in his experime ntal rats. When inject ed with hormonal extracts the rats developed a unique syndrome in response to the substances. T he rats developed organ ulcerations and atrophy. He continued experimenting with other noxiou s agents such as drugs, exposure to cold, sur gical injury and excess exercise. He concluded that the rats responded identically, indiscriminately of the toxin. In 1936, Selye attributed this non specific response, the General Adaptation Syndrome, to stress. He defined health and disease as an organic agents (Viner 1999). The General Adaptation Syndrome contains three phases. During the General Alarm Reaction (6 48 hours after the initial stressor), several organs shrink, fat and mu scle tissue is lost, and body temperature decreases. During the resistance stage, body growth decreases, the gonads atrophy and the adrenals enlarge. If the body is exposed to small doses of the stressor, the body will build up resistance, adapt, and ultim ately return to its initial condition. In contrast, after one to three months of continued stress, symptoms intensify and lead to exhaustion and death. Because the syndrome has profound similarities with histamine toxicosis, Selye recommended that the resp onse be

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29 compared to inflammation and immune system function. With these astute observations, Selye laid the foundation for the biological study of the stress response (Neylan 1998). or flight mechanism in the 1930s stimula ted research, the fight or flight response describes the Alarm Phase of sympathetic arousal. This immediate response is characterized by an increase in circulating adrenergi c hormones. The second, prolonged response represents the Resistance phase. In an effort to increase energy supplies, circulating cortisol levels increase. If the body cannot be restored to homeostasis, it can enter a state of prolonged resistance and chro nic hyperactivity. Unfortunately, stress has come to represent a broad psychological analysis of our extern al environment, without much releva nce to less obvious exogenous factors. Diet, industrial and environmental toxicity and infection are rarely defin ed as mediators of stress, although they are damaging. Ultimately, stress is incorporated into modern 1999).

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30 4.2 Nervous System 4.2.1 Neurons and Neurotransmitter s Figure 4 Typical N euron (McCance 1998 ) Neuron size and structure varies greatly in the central nervous system. As shown in Fig ure 4 a neuron consists of an axon, cell body and multiple dendrites. Typically, a neuron has one axon. Neurons, fueled mai nly by glucose, are capable of generating new extensions and synaptic connections. Dendrites bring external nerve impulses to the neuron, while axons transmit impulses to neighboring neurons (Jessel et al 2000). Neuroglia are non excitable support cells of the central nervous system. These cells compose half the spinal and brain substance. They are ten times more plentiful than nerve cells (Jessel et al 2000). Illustrated in Figure 5 m icroglia, t he smallest neuroglia, are crucial to phagocytosis and the neuroinflammatory process T version of a macrophage (Masliah 2008).

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31 Figure 5 Microglia (McCance 1998) As illustra ted in Figure 1 neurons communicate via chemical messengers known as neurotransmitters. Presynaptic neurons carry an electrical signal towards a synapse. Stored in the presynaptic axon, the neurotransmitters are released into the synaptic cleft when initiated by action potentials. Then, the neurotransmitters bind to receptors in postsynaptic neurons. Neurons may have mor e than one neurotransmitter receptor and may produce more than one neurotransmitter type. Monamine oxidase MAO, is responsible for recycling neurotransmitters in the synapse, after their function is complete (Jessel et al 2000). Neurotransmitters are che mical messengers used to relay neuronal messages The n eurotransmitters are divided into acetylcholine, the monoamines, the amino acids, neuropeptides and neuroactive steroids (Jessel et al 2000). The monamines are divided into the catecholamine group and s eroto nin and histamine. The c atecholamines dopamine, norepinephrine and epinephrine, act as hormones and neurotransmitters. They response (Shepard 1988). Dopamine, a precursor of norepinephrine, is involved in m ultiple brain functions, including mood, cognition, sleep and attention ( Campbell et al 2007 ). Because neurotransmitters are

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32 involved in multiple pathways in the body they require a delicate inter connected balance to function properly. Figure 6 S erotonin Function in Central Nervous System (Berger et al. 2009) Discovered 60 years ago, the neurotransmitter s erotonin (5 HT) is involved in most major organ systems The public widely assumes that serotonin originates in the C entral N ervous S ystem (CNS ) In reality, 95% of serotonin originates in the gastrointestinal system (McLean et al 2006) The majority of serotonin is found outside of the CNS. S erotonin is implicated in most behavioral functions in the CNS (Berger et al. 2009). Outside the CNS, se rotonin accounts for multiple hormonal, circulatory, reproductive, respiratory, urinar y and gastrointestinal function Much more than a mood regulator, serotonin is a multi systemic regulator of physiological processes throug hout the entire body (Berger et al. 2009).

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33 4.2.2 The Central and Peripheral Nervous Systems The central nervous system is composed of the brain and spinal cord, while the peripheral nervous system (PNS) is composed of neurons and ganglia (bundles of cell bodies) spread throughout the body (Kande l et al 2000). The brain is composed of billions of neurons that work simultaneously to orchestrate voluntary and involuntary behavior. In the brain, the cerebrospinal fluid (CSF), which contains glucose and white blood cells, provides structur al and nutritive support for the brain and spinal cord (Jessel et al 2000). Composed of neurons that transmi t motor and sensory information, the spinal cord serves as a communication junction to the peripheral nervous system (PNS). Afferent signals move fr om the peripheral nervous system to the central nervous system, while e fferent signals travel from the central nervous system t o the periphery (Purves et al. 2001). The administration of laxatives to patients with mental illness is reported before the Mi ddle Ages (Shorter 1998). Connected to the CNS by the vagus nerve, the enteric nervous system (ENS) of the gastrointestinal system is an auto nomic and highly adaptable system. Comparable to the spinal cord, i t has over 100 million neurons. Lined with infla mmatory cells in the esophagus, stomach, small intestine and colon the walls of the tract are frequently exposed to acute intestinal inflammation (Rubin 2002, Sharkey and Kroese 2001) Thus, the central nervous system is incredibly sensitive t o gastrointe stinal fluctuations.

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34 4.3. Immune System 4.3.1 Innate & Adaptive Response s mechanism against foreign microscopic invaders. V iruses, bacteria, fungi, parasites, pollen, food, drugs, vaccines and tran splanted tissues can stimulate an immune reaction The strength of the immune response depends on a ge, gender trauma, disease, radiation, drugs and toxicity. The skin is t mechanical defense. Internally, the immune system attempts to inhibit the pathogen (Campbell et al 2007). The primary, innate response is activated once the microbe has entered the body The nonspecific response does not differentiate between micro organisms Exposure to chemical molecules on the surface of foreign cells, called antigens, stimulates infla mmation in the infected tissues. The white blood cells leukocytes, increase in the affected area Phagocytic macrophages among others, attempt to surround, destroy and remove the pathogens and damaged tissue from the body. In m any instances, the body creates a low grade fever to stimulate phagocytosis and inhibit pathogen growth (Campbell et al 2007) In addition, w hite blood cells circulate and promote immunity throughout the entire body. Macrophages are scattered in connecti ve tissues, but are also found in t he liver and central n ervous system (Kumar 200 4 ) Because of this cellular aggregation, the physical response of inflammation may el icit redness, heat, and swelling. Eventually, the response becomes widespread; toxins and microorganism s circulate through the bloodstream (Campbell et al 2007).

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35 When a localized inflammatory reaction fails to eliminate an antigen, the infection spreads t o the lymphatic system. Lymphocytes, macrophages, cell debris, pathogens, and cancer cel ls are transported throug h the lymph (Campbell et al 2007 ). Lymph nodes may swell, isolating pathogens and increasing lymphocyte production. I f the lymph nodes cannot stop the spread of infection pathogens move into the vascular circulation (Kumar 200 4 ). The second specific stage of the immune system amplifies the first response Immune cells trigger a heightened response for previously encountered antigens that evaded the innate immune response. T he specific antigen either stimulates an increase of pha gocytic cells (cellular immunity) or the production of antibodies in the blood, lymph and interstitial fluid (humoral immunity) Orchestrating cellular and humoral immunity, T lymphocyte cells attack the foreign invaders directly in blood and lymph. Origin ating in the thymus, t hese lymphocytes are vital to stimulating B cell induced humoral immunity (Kumar et al. 2004). The Type 1 (Th1) and Type 2 (Th2) helper T cells an integral s ubset of lymphocytes, release pro inflammatory cytokines and anti inflammato ry cytokines respectively ( McNally 2008 ). In contrast to T cells B cells create antibodies that immobilize antigens (Campbell et al 2007). B lymphocytes, derived from the bone marrow, are found in lymph tissue and other organs (Poleuktova 200 8 ). Stimul ation from infection leads to B cell secretion of immunoglobulins commonly known as antibodies (Kumar et al. 2004). A ntibodies circulate throughout the body in response to B cell secretion (Kumar et al. 2004). Antibodies promote the phagocytosis of bacte ria, the extermination of

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36 bacterial toxins, and the neutralization of viruses After inflammation subsides, memory cells in lymph tissues record antigen to enhance immune memory (Campbell et al 2007). Abnormal antibody levels are an indication of immune dysfunction If acute inflammation is not resolved, a state of chronic inflammation may subsist. Inflammation, tissue necrosis and regeneration occur simultaneously if inflammation persists. Macrophages and lymphocytes infiltrate the inflamed area. T cells work reciprocally with macrophages in chronic inflammation. Macrophages present antigens to lymphocytes. The activated lymphocytes secrete inflammatory mediators and cytokines to reciprocally activate macrophages. The intensity of the inflammation destroy s tissue. Under healthy conditions, immunological feedback mechanisms prevent host cell damage. Persistent exposure to certain toxic agents and chronic infection can directly cause chronic inflammation (Kumar et al. 2004). Chronic activation of the immune system leads to a weakened immune response. 4.3.2 Cytokines As previously mentioned, an immune response requires either direct cell to cell interactions or secretion of soluble mediators by white blood cells such as macrophages and lymphocytes To regula te the immune response, these soluble mediators, known as cytokines, bind to receptors on the target cell to elicit a response (Kumar 200 3 ). In immunology, cytokine research has progressed rapidly and significantly In the past 25 years of medicine, cytok ines have been used for diagnostic and therape utic purposes in the study of a utoimmune disease virology, cancer and immunology

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37 Although there are many studies correlating cytokines with disease, a causative role of cytokines can only be demonstrated by b lockade in humans or animals ( Dinarello 2007 ) Cytokines are unique in their pleiotropic properties. Involved in most biological events, incl uding infection, inflammation, and degenerative disease, these proteins have diverse functions. Their properties are associated with the presentation of disease symptoms. The cytokine family is classified in to many functional groups among t he se are interferon (IFN) interleukin (IL) and tumor necrosis factor families (TNF) (Dinarello 2007). Within those group s, cytokines are divided into pro inflammatory and anti inflammatory functions. For example, IL 1, IL 2, IL 6, TNF, and IFN inflammatory; IL 4 and IL 5 are anti inflammatory (Kumar 2003). Type 1 helper T cells regulate pro inflammatory release, while Type 2 helper T cells regulate anti inflammatory cytokines (McNally 2008) To achieve optimal balance, anti inflamm atory cytokines antagonize pro inflamm atory cytokine behavior (Myint 2007). D uplicate function enhances host defense and immunity. During microbial invasion, the body initiates multiple defense mechanisms to ensure success. During infection, cytokines are responsible for ass isting in antigen presentation regulation of T cells and B cells and phagocytic activity, among others Additionally, s ome cytokines function to repair cell damage after infection In states of chronic inflammation, cytokines function continuously, leading to chronic activation of the immune system and tissue damage ( Dinarello 2007 )

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38 Chapter V V Chronic Inflammation in D epression 5.1 Proinflammatory Cytokine Imbalance in Depression As previously mentioned, the classical symptoms o f inflammation include fever, redness, local swelling and pain. Interestingly, in those persons that do not exhibit regular inflammatory symptoms, personality and behavioral changes may also be manifestations of chronic inflammation. Patients with major d epression exhibit changes in many inflammatory markers, including microglia l and cytokine elevations ( Mller and Schwarz 2008 Miller et al 2009) In depressed patients IL 6 and TNF are elevated in the CNS and circulating plasma (Irwin 2007). In additi on depressed patients demonstrate elevated levels of IL 1 in the cerebrospinal fluid. Therefore, there is excess inflammation both centrally and peripherally in depressed patients (McNally 2008). th depression ha ve elevated plasma levels of pro inflammatory mediators IL 1, IL 2, IL 6, and TNF (2008). Because these proinflammatory cytokines are released from Th1 cells, depressed patients also have a Th1/Th2 imbalance, leading to an ove rabundan ce of Th1 cells. Under healthy conditions, the anti inflammatory Th2 response balance s the pro inflammatory response. In another study, the ratio of pro inflammatory IFN inflammatory IL 4 was elevated (McNally 2008).

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39 In addition, i ncreased levels of baseline inflammation were noted to predict later onset of depression in the elderly (McNally 2008). Patients with late life depression have been found to have elevated levels of IL 1 and TNF (Irwin 2007). Because a causal relationship between cytok ines and depression is difficult to establish, cytokine correlations with depression remain associative rather than causal (Dinarello 2007). To further this connection, researchers study antidepressant effects on cytokines. According to Murrin, antidepre ss ants potentially alter pro inflammatory and anti inflammatory cytokines. In an antidepressant study, patients with previously elevated IL 6 levels exhibited normal IL 6 levels after drug treatment (2008). Antidepressants also increase the an ti inflammatory cytokine IL 10 (Myint 2003). Thus, antidepressant success may be partially attributed to an improvement of immune function. Thus, pro inflammatory cytokine involvement in the etiology of depression is well established (Myint 2007) The condition may repre sent a state in which inhibitory feedback loops have become dysfunctional. feedback mechanisms would inhibit chronic inflammation (Irwin 2007 ) W ithout assuming inhibitory feedback dysfunction can scientists identify e xogenous factors perpetuating chronic inflammation ? 5.2 Co morbidity of Depression in P atients Undergoing Cytokine T herapy The immune system is continually activated during chronic disease C hronically ill patients with tissue damage, infection, or auto immunity show high rates of depression. Depressed patients suffering from different types of cancer and Metabolic Syndrome demonstrate elevated levels of IL 6 (Irwin 2007). Patients with Metabolic Syndrome,

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40 categorized by insulin resistance, type 2 diabete s with central obesity and high blood pressure, exhibit depressive symptoms. Thus inflammation occurs comorbidly with depression in patients with Metabolic Syndrome (Capuron et. al. 2008). As previously mentioned, cytokine therapy is used to treat chroni c and infectious diseases such as cancer and AIDS. IFN and IL 2 are the most commonly used cytokines According to Myint, twenty to sixty percent of patients undergoing cytokine therapy develop a mental disorder which subsides after termination of treatment (Myint 2007). Administered pro infla mmatory cytokines alter CNS function (Murrin 2008). These alterations in neurotransmission may lead to sickness behavior (Haddad 2008). Cytokine induced sickness behavior describes the behavioral symptoms induced by cytokine therapy. The first phase of sic kness behavior manifests as a fever, nausea and flu like symptoms. The second phase includes depressive symptoms similar to major depression (Pfaff 2002). Frequently up to 50% of patients undergoing cytokine therapy develop major depression (Irwin 2007). Hepatitis C patients receiving IFN ve increased levels of IL 6 in the CSF (McNally 2008). Capur o n et al compared symptoms in twenty depressed patients with malignant melanoma undergoing IFN treatment, and twenty eight depressed patients c between depressive symptoms in both conditions (2009).

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41 5.3 Use of Anti inflammatory Drugs for Depressive Symptoms Reduction of inflammation through the administration of anti inflammatory m edication has reduced depressive symptoms in patients with various chronic diseases. Celecoxib, a rheumatoid arthritis drug, was more efficacious than placebo in treating depression. Etanercept, a TNF antagonist, is commonly used to treat arthritis. Etaner cept reduced depressive symptoms in patients with psoriasis. B locking TNF can potentially treat depressive symptoms (McNally 2008). Unfortunately, this treatment, along with SSRI treatment before it, does not address the potential sources of excess inflamm ation in depressed individuals. In conclusion, there is an overwhelming amount of data substantiating the association of depression with inflammation. An overabundance of proinflammatory cytokines in depressed patients exemplifies this correlation (McNally 2008) Furthermore, depressed patients with other chronic diseases exhibit elevated cytokine levels. Of those with chronic diseases, half of patients undergoing cytokine therapy develop depression (Irwin 2008).

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42 Chapter VI V I Conclusion Over a cent ury ago, Professor v on Jauregg received the Nobel Prize for his work on the immunological implications of psychiatry. Unfortunately psychiatric interest ignoring immunological connections, shifted to pharmacological and psychotherapeutic treatments. P sychoneuroimmunology specifically endeavors to explain the bidirectional relationship of the nervous and immune systems. Established by the APA the Diagnostic and Statistical Manual of Mental Disorders, DSM IV TR, contains similar criteria for Major Dep ressive Episode, Major Depressive Disorder, and Depressive Personality Disorder. Most common symptoms include a depressed mood, loss of interest, insomnia or hypersomnia, fatigue, inability to concentrate, suicidality, psychomotor retardation and weight ch ange. While no clear etiological explanation has been discovered, the pathophysiology of depression involves neurotransmitter imbalance (APA 2000). Worldwide incidence of major depression occurs irrespective of any cultural or ethnic divisions (Myint 2007 Petty et al. 2008). Chronic and treatment resistant depression remain unresolved obstacles to efficient treatment (Myint 2007). Because depression has a high comorbid rate with other mental illness and chronic disease, common physiological characteristi cs of these diseases should be explored. T he most investigated etiological model is the neurotransmitter hypothesis. Fueled by the discovery of psychotropic medication, the hypothesis was created to explain antidepressant mechanisms. Because this hypothe sis indirect ly explains depressive symptoms and cannot account for multiple phenomena, the psychiatric

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43 community is promoting a narrow avenue of research (Myint 2007) On the other hand, multi systemic immunological implications of depression may more adeq uately assess the physiological etiology of the disorder. The most popular form of treatment is antidepressants. If response proves insufficient, psychotherapy, anti psychotics, and electroconvulsive therapy are jointly recommended (APA 2010). Unfortunate ly, these psychotropic medications demonstrate limited eff icacy, with undesirable side effects. Although pharmaceutical companies release new psychotropic medication, the treatment of depression has not improved since the introduction of the neurotransmitt er hypothesis in the 1960s (Myint 2007). The APA makes several systematic errors in treatment methodology In the DSM IV TR, excessive diagnostic criteria lead to heightened diagnostic subjectivity and the miseducation of etiology. Fortunately, the A ssoc iation is becoming increasingly accepting of different research In 2010, the etiological role of infectious disease in depression is acknowledged Despite this advance, treatment methodology remains narrow, ill defined and unscientific. The APA, rather th an expanding etiological examinations of depression, promotes psychotropic dependence and mental health exclusivity. To validate the need for physiological markers of depression, the nervous and immune systems are briefly explored. Because depression is l argely assumed to be a response to chronic stress, the concept of stress is clearly defined. In developing the General Adaptation Syndrome concept, t he endocrinologist Hans Selye de fined the term stress Unfortunately, the physiological implications of th e term were replaced by psychosocial interpretations (Viner 1999)

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44 The nervous system is responsible for voluntary and involuntary movement, behavior, cognition and learning. At a cellular level, neurons communicate with neurotransmitters to activate a s pecific response (Kande l et al 2000) In contrast to public opinion, serotonin has multiple hormonal, circulatory, reproductive, respiratory, urinary and gastrointestinal functions outside of the brain. On a systemic level, the central nervous system rela ys information to and from the peripheral nervous system. composed of an innate and adaptive response. If adaptive mechanisms c annot sq uelch an invade r, inflammation may result and become c hronic. Cytokines, identified as immune messengers, proliferate in response to inflammation. These chemical messengers interact with multiple systems and have unique pleiotropic properties throughout the body. Patients with depression exhibit a 50% 100% el evation in cytokines and other inflammatory m arkers (Mller and Schwarz 2008, Miller et al 2009 Myint 2007). In addition, patients exhibit an imbalance in the Th1 helper cells / Th2 helper cells ratio (McNally 2008). Patients undergoing cytokine therapy develop depressive symptoms as well (Irwin 2007, Haddad 2008, Myint 2007, McNally 2008) In addition, antidepressants and anti inflammatory medications exhibit immune stimulating and anti depressant effects respectively (McNally 2008) Thus, awareness of t he relationship between depression and chronic inflammation is growing. Although these links are purely associative and not causal, treatments that address depression as an immunological disorder may be safer and more effective. I f depression is approached as a multi systemic immunological disorder, a more physiologically comprehensive etiology may be un covered.

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