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1 Late Life Depression 인제의대상계백병원정신건강의학과 이동우

2 Contents Depression & DM DM Depression Depression DM Late-Life Depression

3 DM Depression

4 DM & Risk of Depression ; Cross-sectional studies Sex(%fem) /Age Depression assessment method Prevalence of Dep.(%) Overall Males Females Dep.scale score Amato et al 68 /73.9± /74.2±6.4 Viinamaki et al /66.9± /65.6±0.5 Palinkas et al /72.4± /68.5±9.5 GDS ±6.8 GDS ±6.5 Zung ±1.3 Zung ±0.8 BDI BDI

5 Sex(%fem) /Age Depression assessment method Prevalence of Dep. Overall Males Females Odd ratio (95%CI) Black 56 /72(65-85) CES-D /73(65-85) CES-D ( ) Gregg et al. 100 /72(65) GDS /72(65) GDS 5-5 ( ) Pouwer et al. 55 /74(55-85) CES-D /68(55-85) CES-D ( )

6 NIDDM is a/w a greater prevalence of depression in the elderly. The Osservatorio Geriatrico of Campania Region Group Amato L. Paolisso G et al. (1996) Subjects: 1339 elderly subjects randomly selected from electoral rolls Scale : Geriatric Depression Scale to detect depression NIDDM is significantly associated with depression in the elderly

7 Mental well-being in people with NIDDM Viinamaki H, Niskanen L et al. (1995) Subjects community-based group of patients with DM for 10 years(n = 82) nondiabetic control subjects (n = 115) Scales General Health Questionnaire(GHQ) for minor mental disorder Zung Self-rating Depression scale for depression Results The mean scores of GHQ and Zung scores tended to be higher in diabetic than in control subjects But the frequency of case subjects was not different between the diabetic (GHQ: 40%; Zung: 11%) and nondiabetic groups (GHQ: 36%; Zung: 7%)

8 T2DM & depressive symptoms in older adults: a population-based study Palinkas LA, Barrett-Connor E et al. (1991) A population-based study of 1586 men and women aged 50 years or older Beck Depression Inventory total, somatic subscale, and affective subscale scores The age- and sex-adjusted rates of Inventory scores of 13 or greater among individuals with previously diagnosed diabetes was 3.7 times greater than the rates among individuals with newly diagnosed diabetes (p less than 0.05) The number of other chronic conditions and age were significant independent predictors of depressive symptoms in all diabetic men and women

9 Black SA. (1999) Increased health burden a/w comorbid depression in older diabetic Mexican Americans. Results from the Hispanic Established Population for the Epidemiologic Study of the Elderly survey 636 older diabetic Mexican Americans, in comparison with 2,196 older nondiabetic Mexican Americans Measured with the Center for Epidemiologic Studies of Depression scale 31.1% of the older diabetic individuals reported high levels of depressive symptoms The presence of concomitant depressive symptoms among older diabetic Mexican Americans is associated with a substantially greater health burden than is seen among diabetic individuals without depression or depressed individuals without diabetes

10 Rates and risks for co-morbid depression in patients with T2DM: results from a community-based study Pouwer F, Beekman AT et al. (2003) Subjects community-based Dutch adults (N=3107, years of age) Diagnosis Pervasive depression was defined as a CES-D score greater than 15. Diagnosis of Type 2 diabetes was obtained from self-reports and data from general practitioners. Results A number of 216 patients (7%) were identified as having T2DM. The prevalence of pervasive depression was increased in people with Type 2 diabetes and co-morbid chronic disease (20%).

11 DM & Risk of Depression ; Prospective studies T2DM as a risk factor for the onset of depression : A Nouwen et al ; Diabetologia (2010) 53: systematic review and meta-analysis of 11 prospective studies pooled data including 48,808 cases of T2 DM without depression at baseline pooled RR ;1.24 (95% CI ) Compared with non-diabetic controls, people with type 2 diabetes have a 24% increased risk of developing depression

13 DM could play a causal role in development of depression (Jacobson et al. 2000) Metabolic problems of diabetes (increased rates of hypoglycemia and hyperglycemia) accelerated vascular change white matter abnormalities in regions of the brain involved in affect regulation (e.g., the limbic system) Depression

14 Depression DM

15 (-) Impact of Depression on DM Depression in DM is associated with poorly controlled diabetes an increased risk of complications higher mortality increased healthcare costs

16 Depression and Poor Glycemic Control ; Lustman PJ et al, Diabetes Care Jul;23(7): meta-analysis of 24 studies Depression was significantly associated with hyperglycemia (Z = 5.4, P < ). ES was in the small-to-moderate range (0.17) ES was similar in studies of either type 1 or type 2 diabetes (ES 0.19 vs. 0.16)

18 Depression & Hyperglycemia Stress increases glucose level SNS activation pancreas : increase glucagon decrease insulin adrenal medulla : increase NE/Epinephrine ACTH stimulates adrenal cortex : cortisol

Major Depressive Disorder May Have Systemic Consequences 2.

Increase in catecholamines can lead to myocardial ischemia, diminished heart rate variability, and

Hypothalamus stimulates the pituitary gland to release excessive ACTH, continuously driving the

Cortisol antagonizes insulin and contributes to dyslipidemia, type 2 diabetes, and obesity; increases

19 Major Depressive Disorder May Have Systemic Consequences 2. The adrenal gland releases excessive amounts of catecholamines and cortisol 3. Increase in catecholamines can lead to myocardial ischemia, diminished heart rate variability, and can contribute to ventricular arrhythmias ACTH 1.Hypothalamus stimulates the pituitary gland to release excessive ACTH, continuously driving the adrenal gland 5. Cortisol antagonizes insulin and contributes to dyslipidemia, type 2 diabetes, and obesity; increases in cortisol also suppress the immune system' 4. Increase in catecholamines causes platelet activation; increase in cytokines and interleukins may also contribute to atherosclerosis and eventual hypertension ACTH=Adrenocorticotropic hormone. Adapted from Musselman et al. Arch Gen Psychiatry 1998;55(7):

20 Increased Release of Counter-Regulatory Hormones in Depression Major depression as stress response gone awry ; a/w perturbations of counter-regulatory hormones.

Hippocampal Dysfunction Contributes to Neuroendocrine Dysregulation Hypothalamus - Hippocampus CRF - - + Pituitary ACTH Hippocampus Amygdala

21 Hippocampal Dysfunction Contributes to Neuroendocrine Dysregulation Hypothalamus - Hippocampus CRF Pituitary ACTH Hippocampus Amygdala Glucocorticoids Dexamethasone Adrenal cortex CRF=Corticotropin-releasing factor; ACTH=Adrenocorticotropic hormone. Nestler et al. Neuron 2002;34(1):13 25.

22 Depression & Diabetes Complications Mary de Groot et al(2001) Association of Depression and Diabetes Complications: A Meta-Analysis to examine the strength and consistency of the relationship between depression and diabetes complications Depression was significantly a/w a variety of diabetes complications (diabetic retinopathy, nephropathy, neuropathy, macrovascular complications, and sexual dysfunction).

24 Association of Comorbid Depression With Mortality in Patients With Type 2 Diabetes Katon WJ et al. Diabetes Care 28: , 2005 Objective ; To assess whether pt with comorbid Depression(minor & major) & T2DM had a higher mortality rate over a 3-year period compared with patients with & T2DM alone. Subjects : 4,154 pt with T 2 DM were followed for up to 3 years. Analysis : Cox proportional hazards regression models were used Results : 275(8.3%) deaths in 3,303 patients without depression c/w 48 (13.6%) deaths in 354 patients with minor depression & 59 (11.9%) deaths among 497 patients with major depression. A proportional hazards model with adjustment for age, sex, race/ethnicity, & education found that c/w nondepressed group, minor depression was a/w 1.67-fold increase in mortality(p= 0.003) & major depression was a/w 2.30-fold increase (P <0.0001) Conclusions ; Among patients with diabetes, both minor and major depression are strongly associated with increased mortality.

26 Comorbid Depression is a/w Increased Health Care Use & Expenditures in Individuals With Diabetes LEONARD E et al, Diabetes Care 25: , 2002 OBJECTIVE To investigate the relation between depression and health care use and expenditures. Methods : In 825 patients with diabetes, we compared depressed and nondepressed individuals to identify differences in health care use and expenditures. Results ; Pt with DM and depression had higher ambulatory care use(12 vs 7, P<0.0001) & filled more prescriptions(43 vs 21, P< ) than their counterparts without depression. Among individuals with diabetes, total health care expenditures for individuals with depression was 4.5 times higher than that for individuals without depression ($247,000,000 vs. $55,000,000, P< ). CONCLUSIONS ; Depression in individuals with diabetes is a/w increased health care use and expenditures, even after adjusting for differences in age, sex, race/ethnicity, health insurance, & comorbidity.

29 Late Life Depression

30 Public Health Significance of Late-Life Depression healthcare utilization and costs quality of life poorer prognosis for comorbid conditions survival suicide Lebowitz BD et al. JAMA. 1997, 278:1186; Lenze EJ et al. Am J Psychiatry. 2000(Oct), 157:722

32 Etiology Biological Neuroantomical / neurochemical Genetic Psychological Dependency Self cohesiveness Social (= losses of late life) Poverty Retirement Bereavement

33 The Role of Epigenetic Modulation External environment Maternal care Social experiences Genetic background EARLY EXPERIENCES Epigenetic modifications 1 REVERSIBILITY Epigenetic modifications 2 Behavioral phenotype Fertilization Peripartum Postpartum Post-weaning Adult Champagne et al. Cur Opin Neurobiol 2005;15(6): Copyright Elsevier (2005).

34 Neurobiology of Major Depressive Disorder Stress Genetic Vulnerability Injury Network Level: Dysregulation of Neural Circuitry Functional Changes Structural Changes Neuroendocrine, Autonomic, and Immune Dysregulation Cellular and Subcellular Level Impact on: Intracellular Signaling Gene Transcription Neurotrophic Support Neuropsychiatric Symptoms Emotional Cognitive Behavioral Physical Systemic Manifestations Epigenetic Modulation Based on Maletic et al. Front Biosci 2009;14:

35 AS&K1 Neuroanatomy & Neurochemistry of Depression Limbic System Hippocampus Prefrontal Cortex Amygdala Raphe Nuclei (5-HT source) 1 Locus Coeruleus (NE source) Descending 5-HT pathways Descending NE pathways

36 슬라이드 35 AS&K1 The image in this slide is not in the Cooper reference provided and is also not found in the slide notes references. Please can you provide a reference that supports this image. For the slide notes, key points, first bullet point, the spinal tract details are not specified in the Mega or Hales references. Please can you provide a reference that supports this. In the slide notes, the third key point "Each of these midbrain nuclei has ascending tracts..." is not mentioned in the reference provided. Please can you provide a reference that supports this. AS&K Mercury,

37 Vascular Depression Hypothesis More WMH in depressed vs. non More WMH in late onset depression Less guilt, less agitation, less insight

38 주요우울증의진단기준 (DSM-IV) ( 5/9 증상 ) X ( 2 주 ) : 적어도증상의하나는 (1) 또는 (2) 1) 우울감 2) 흥미나즐거움의상실 3) 식욕저하 4) 불면증 5) 정신운동지체 / 초조 6) 에너지저하 7) 죄책감 8) 집중력장애 / 우유부단함 9) 자살사고

39 증상의비전형성 노인우울증의증상 주관적우울감의호소가적다. 인지기능장애의호소가흔함 신체증상의호소가두드러짐 기력의저하 불안, 초조 불면 식욕상실 * 자살사고의호소는적으나가장자살율이높은연령군

40 " 우울하거나슬프지않으십니까?" 라는질문에부정적인대답이나왔다고해서우울증이배제되는것은아니며다음영역에대한질문이필요하다. 1. 관심이나흥미의저하를평가한다 2. 활동정도의변화에대해묻는다 3. 자기자신, 주변상황, 미래에대해어떻게생각하는지물어본다

41 노인우울증선별검사 한국어판 " 노년기우울증척도 " 의단축형 ( 배재남등 : 15 문항 ) 을이용. : 합산점수가 8 점이상이면우울증을의심할수있으며, 정확한진단을받도록의뢰한다.

42 노년기우울증척도 : 밑줄친부분과일치하는답을한경우 1 점을준다 1. 현재의생활에대체적으로만족하십니까? 예 / 아니오 2. 요즈음들어활동량이나의욕이많이떨어지셨읍니까? 예 / 아니오 3. 자신이헛되이살고있다고느끼십니까? 예 / 아니오 4. 생활이지루하게느껴질때가많습니까? 예 / 아니오 5. 평소에기분은상쾌한편이십니까? 예 / 아니오

43 노년기우울증척도 : 밑줄친부분과일치하는답을한경우 1 점을준다 6. 자신에게불길한일이닥칠것같아불안하십니까? 예 / 아니오 7. 대체로마음이즐거운편이십니까? 예 / 아니오 8. 절망적이라는느낌이자주드십니까? 예 / 아니오 9. 바깥에나가기가싫고집에만있고싶습니까? 10. 비슷한나이의다른노인들보다기억력이더나쁘다고느끼십니까? 예 / 아니오 예 / 아니오

44 노년기우울증척도 : 밑줄친부분과일치하는답을한경우 1 점을준다 11. 현재살아있다는것이즐겁게생각되십니까? 12. 지금의내자신이아무쓸모없는사람이라고느끼십니까? 예 / 아니오 예 / 아니오 13. 기력이좋은편이십니까? 예 / 아니오 14. 지금자신의처지가아무런희망도없다고느끼십니까? 15. 자신이다른사람들의처지보다더못하다고생각하십니까? 예 / 아니오 예 / 아니오

45 High index of suspicion is needed! Some features that suggest depression frequent office visits or use of medical services persistent reports of pain, fatigue unexplained gastrointestinal symptoms delayed recovery from a medical or surgical condition refusal of treatment

46 Depression vs. Dementia Depressive Pseudodementia Subacute onset Early family recognition early Rapid progression Impairment inconsistent over time Pt admits deficits I don t know response to questions Pt often unconcerned Abstract thought usually normal Appears depressed Anhedonia Dementia Insidious onset Delayed family recognition Slow progression Impairment consistent Pt denies/unaware of deficits Near miss answers Pt tries to cover up Abstract thought impaired Not depressed Can experience pleasure

47 노인우울증의치료 병발질환과이차성우울증의원인질환을치료 자살가능성에대한주의 사회심리적요인에대한개입 약물치료 : START LOW, GO SLOW 정신치료

48 Classification of Antidepressants TCA MAOI SSRI SARI(serotonin antagonist/reuptake inhibitor) NaSSA(noradrenergic and specific serotonergic antidepressant) SNRI(serotonin/norepinephrine reuptake inhibitor) NDRI (norepinephrine/ dopamine reuptake inhibitor) NRI(norepinephrine reuptake inhibitor)

49 Optimizing Monoaminergic Drugs Dopamine Norepinephrine Methylphenidate Dexmethylphenidate DARI TRIP NERI Desipramine Reboxetine Maprotiline Viloxazine Fluoxetine Citalopram Escitalopram Fluvoxamine Paroxetine Sertraline SDRI SSRI Serotonin SNRI Bupropion Duloxetine Venlafaxine Milnacipran DARI=Dopamine reuptake inhibitor; NERI=Norepinephrine reuptake inhibitor; SDRI=Serotonin-dopamine reuptake inhibitor; SNRI=Serotonin-norepinephrine reuptake inhibitor; SSRI=Selective serotonin reuptake inhibitor; TRIP=Triple reuptake inhibitor. Adapted from Chen et al. Exp Opin Invest Drugs 2007;16:

50 TCA & SSRI Therapeutic Effect Side Effect 5-HT NE Antihistaminic Antiadrenergic Anticholinergic TCA SSRI

51 TCA : Side Effects Anti-histaminic Anti-adrenergic Anti-cholinergic Sedation Wt. gain Postural hypotension Delirium Blurred vision Dry mouth Cardiotoxicity Constipation Urinary retention

52 SSRI : Side Effects Stimulation of 5-HT2 receptors Anxiety (2-15%) Insomnia (5-15%) Sexual dysfunction Stimulation of 5-HT3 receptors Nausea (around 15%) Diarrhea (around 10%)

53 Inhibition of Cytochrome P450 by SSRI 1A2 2C9 2C19 2D6 3A4 Fluoxetine Paroxetine Fluvoxamine Sertraline Citalopram + Drugs metabolized by isoenzyme TCA Clozapine Wafarin Theophyll. NSAID Wafarin phenytoin Diazepam Omeprazole TCA neuroleptic bupropion ß-blocker CBZ BDZ TCA

54 Dosages of SSRI in the elderly Dosages Starting (4-7days) Average Fluoxetine 10 mg 20 mg Sertraline 25 mg mg Paroxetine 10 mg mg Fluvoxamine 50 mg mg Citalopram 10 mg mg Escitalopram 5 mg 5-10 mg

55 Newer Antidepressants Drugs with Serotonergic antagonism SARI(serotonin antagonist/reuptake inhibitor) NaSSA(noradrenergic and specific serotonergic antidepressant) Drugs with 2 mechanisms of action NaSSA(noradrenergic and specific serotonergic antidepressant) SNRI(serotonin/norepinephrine reuptake inhibitor) NDRI (norepinephrine/ dopamine reuptake inhibitor)

56 Use of Newer Antidepressants in the Elderly Starting dose Average Mirtazapine 15 mg 30 mg Venlafaxine mg 150 mg Bupropion mg 300 mg

57 Tx. of Nonresponders(I) Optimization Switching Augmentation Combination ECT

58 Tx. of Nonresponders(II) Little / no response(< 25% change in sx) by 4wks Increase the dose OR if the dosage is optimal, switch to another class Partial response(25 50 % change in sx) by 4wks Increase the dose(if possible) Carry on for a furthur 2-4 weeks If little further improvement Augment OR Switch to another class At any stage ECT may be the preferred option.

59 5 R s : Response, Remission, Recovery, Relapse, Recurrence Remission Recovery Mood Response Relapse Recurrence Acute treatment Continuation treatment Maintenance treatment Time

60 Psychotherapy Psychodynamic Psychotherapy Drive Theory Object Relations Theory Cognitive Behavioral Therapy Interpersonal Psychotherapy

61 Drive Theory Aggression turned inward ( = anger converted into self-hatred ) Self depreciation

62 Aggression turned inward Inconsistent, neurotic parents (both overindulgent & demanding), lacking in warmth & driven by their own selfish needs create a unpredictable, hostile world for a child. The child feels alone, confused, helpless, and ultimately, angry. The child, knowing that the powerful parents are his or her only means of survival, represses anger. toward the parents out of fear, love, or guilt The repressed anger is turned inward & directed towards him or herself.

63 Self-depreciation Despised vs Idealized Self Overindulgent & demanding parenting results in a "despised" self-concept. "I am an unlovable and unacceptable person." At the same time, the child also strives to present a perfect, idealized self as a means of compensating for perceived weaknesses that make him or her "unacceptable Depression - proneness Caught between the belief that he or she is unacceptable, & the imperative to act perfectly to obtain parental love a perpetual sense that he or she is not good enough, no matter how hard he or she tries. prone to experiencing exaggerated anxiety and/or depression

64 Object Relations Theory Depression is caused by problems people have in developing representations of healthy relationships an ongoing struggle that depressed people endure in order to try and maintain emotional contact with desired objects. 2 basic ways that this process can play out: anaclitic pattern introjective pattern

65 Anaclitic depression occurs when a person who feels dependent upon relationships with others and who essentially grieves over the threatened or actual loss of those relationships caused by the disruption of a caregiving relationship with a primary object characterized by.. feelings of helplessness and weakness. intense fears of abandonment desperate struggles to maintain direct physical contact with the need-gratifying object.

66 Introjective depression occurs when a person feels that they have failed to meet their own standards or the standards of important others and that therefore they are failures. arises from a harsh, unrelenting, highly critical superego that creates feelings of worthlessness, guilt and a sense of having failure. characterized by intense fears of losing approval, recognition, and love from a desired object.

67 Goal of Psychodynamic Psychotherapy To help the child (now an adult in therapy) to gain insight into the mistaken foundations of the mis-belief that he or she is bad/unlovable or inadequate so that the need to punish oneself/ to be perfect decreases.

68 Take Home Message Major complications of DM retinopathy, nephropathy, neuropathy & Depression High index of suspicion is needed! Features suggesting depression frequent office visits or use of medical services persistent reports of pain, fatigue unexplained GI symptoms delayed recovery from a medical or surgical condition refusal of treatment

69 Identification & Tx of Depression in DM Ask repeatedly about Mood Motivation & pleasure Activity level Pharmacotherapy : SSRI >> TCA Start low, go slow drug interaction : sertraline & (es)citalopram

00약제부봄호c03逞풚

00약제부봄호c03逞풚 경희대학교 동서신의학병원 약품 정보지 2 0 0 7. S P R I N G. V O L. 0 1 신약 소개 02 Journal Review 03 Special Subject 04 복약 지도 06 의약품 안전성 정보 07 약제부 알림 07 약제부 업무 소개 08 E A S T - W E S T N E O M E D I C A L C E N T E R 본 약품