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Recognition and Treatment of Depression: Reducing Suicide and Misery in Difficult Times Charles B. Nemeroff, MD, PhD Leonard M. Miller Professor and Chairman Department of Psychiatry and Behavioral Sciences Director, Center on Aging University of Miami, Miller School of Medicine Miami, Florida 33136 CHARLES B. NEMEROFF, M.D., PH.D. DISCLOSURES • Research/Grants: National Institutes of Health (NIH), Agency for Healthcare Research and Quality (AHRQ) • Speakers Bureau: None • Consultant: Xhale, Takeda, SK Pharma, Shire, Roche, Lilly • Stockholder: CeNeRx BioPharma, Inc., PharmaNeuroBoost, Revaax Pharma, Xhale • Other Financial Interest: CeNeRx BioPharma, PharmaNeuroBoost • Patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1), Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2) • Scientific Advisory Board: American Foundation for Suicide Prevention (AFSP), CeNeRx BioPharma, National Alliance for Research on Schizophrenia and Depression (NARSAD), PharmaNeuroBoost, Anxiety Disorders Association of America (ADAA), Skyland Trail • Board of Directors: AFSP, Gratitude America 3 Canst thou not minister to a mind diseased? Pluck from the memory a rooted sorrow, Raze out the written troubles of the brain, And with some sweet oblivious antidote Cleanse the stuffed bosom of that perilous Stuff which weighs upon the heart? MACBETH 4 All his life he suffered spells of depression, sinking into the brooding depths of melancholia, an emotional state which, though little understood, resembles the passing sadness of the normal man as a malignancy resembles a canker sore. William Manchester, The Last Lion, Winston Spencer Churchill, Vol. I: Visions of Glory (New York: Little, Brown & Company, 1989, p. 23) 5 Major Depressive Episode: DSM-IV Diagnostic Criteria • • Characterized by clinically significant distress and/or impairment in social, occupational, or other important areas of functioning Symptoms must persist for most of day, nearly every day, for 2 consecutive weeks DSM-IV. 1994. 6 DSM-IV Diagnostic Criteria for Major Depression • • 5 symptoms including depressed mood and/or anhedonia – Other symptoms may include: – Significant weight change – Psychomotor agitation/retardation – Pervasive loss of energy/fatigue – Feelings of worthlessness/excessive or inappropriate guilt – Difficulty concentrating – Sleep disturbance – Recurrent thoughts of death/suicide Symptoms present for 2 weeks DSM-IV. 1994. 7 Prevalence of Depression in United States Katon W. Schulberg H. Gen Hosp Psychiatry. 1992; 14: 237-247 8 Global Burden of Disease and Injury Series THE GLOBAL BURDEN OF DISEASE A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020 EDITED BY CHRISTOPHER J. L. MURRAY Harvard University Boston, MA, USA ALAN D. LOPEZ World Health Organization Geneva, Switzerland Published by The Harvard School of Public Health on behalf of The World Health Organization and The World Bank Distributed by Harvard University Press 5/24/2017 9 Depression—A Major Cause of Disability Worldwide DALYs—2000 and 2020 Rank 20001 1 Lower respiratory infections 2 Perinatal conditions 3 HIV/AIDS 4 Unipolar major depression 5 Diarrheal diseases 2020 (Estimated)2 Ischemic heart disease Unipolar major depression Road traffic accidents Cerebrovascular disease Chronic obstructive pulmonary disease 1.World Health Report 2001. Mental Health: New Understanding, New Hope. Geneva, World Health Organization, 2001. 2. Murray CJL, Lopez AD, eds. The Global Burden of Disease. Boston: Harvard University Press; 1996. DALYs=disability-adjusted life-years. 10 The leading causes of disease burden for women, aged 15-44, 1990 Percent of all causes in developed or developing regions CAUSES Unipolar major depression Schizophrenia Road traffic accidents Bipolar disorder Obsessive-compulsive disorder Alcohol use Osteoarthritis Chlamydia Self-inflicted injuries Rheumatoid arthritis Tuberculosis Iron-deficiency anaemia Obstructed labour Maternal sepsis War Abortion 11 11 Postpartum Depression (PPD) • 10% to 15% in adults* • 26% of adolescents† *Stowe and Nemeroff. Am J Obstet Gynecol. 1995; 173: 639-645. †Troutman and Cutrona. J Abnorm Psychol. 1990; 99: 69. 13 Depressive Disorders After Miscarriage • >33% severely depressed* • duration of pregnancy = risk of depressive disorder* • Treat depressive disorders if reaction beyond expected grief and bereavement *from Janssen et al. Am J Psychiatry. 1996; 153: 226-30. 5/24/2017 14 Depressive Disorders in Children Prevalence of Depressive Disorders in Children* • • • Preschool children – 0.8% School-aged prepubertal children – 2.0% Adolescents – 4.5% Key Issues† • • • Distinguish between depressive disorders and behavioral disorders Depressive disorders before age 20 often associated with recurrent mood disorders in adulthood 30% of adolescents hospitalized with severe major depressive disorder develop bipolar disorder *Weller EB, Weller RA. In: Psychiatric Disorders in Children and Adolescents. 1990: 3-20. †Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. 1993: 1-65. Giles DE, Jarrett RB, Biggs MM, et al. Am J Psychiatry. 1989; 146: 765-767. Strober M, Carlson G. Arch Gen Psychiatry. 1982; 39: 549-555. 15 Depressive Disorders in Older Age • Occur in approximately 15% of population >65 years old • May mimic dementia • Comorbid somatic symptoms • Not due to “old age” • Require appropriate treatment Data from NIH Consensus Development Panel on Depression in Late Life. JAMA. 1992; 288: 1018-24. 16 Depression is Often Under Diagnosed and Inadequately Treated • Less than 1/2 of patients with major depression are explicitly recognized as being depressed1 • Only about 1/2 of all depressed patients receive some form of therapy for their illness2 • Only about 1/4 of depressed patients receive an adequate dose and duration of antidepressant treatment3 1. AHCPR. Rockville, Md: US Dept of Health and Human Services; 1993. Publication 93-0550. 2. Lepine JP, et al. Int Clin Psychopharmacol. 1997;12(1):19-29. 3. Katon W, et al. Med Care. 1992;30(1):67-76. 17 Mania Depression Total mood variation The Mood-Disorders Spectrum Normals Cyclothymia Bipolar I Disorder Bipolar II Disorder Dysthymia Unipolar Depression 18 19 FACING THE FACTS… The suicide rate was 11.8/100,000 in 2008. It exceeds the rate of homicide greatly. Suicide is the 10th leading cause of death in the United States. Of the 50 states, Florida is # 15 in suicide rate in 2007. 20 FACING THE FACTS… 21 FACING THE FACTS… Suicide is considered to be the second leading cause of death among college students. 1100 college students died by suicide in 2009. Suicide is the third leading cause of death for youth, 5-24 years old. Suicide is the fourth leading cause of death for adults between the ages of 18 and 65. 22 FACING THE FACTS… Research shows that during our lifetime: 20% of us will have a suicide within our immediate family. 60% of us will personally know someone who dies by suicide. 23 SUICIDE DEATHS AND MAJOR PSYCHIATRIC SYNDROMES <10% without Major Psychiatric Syndromes >90% with Major Psychiatric Syndromes A number of psychological autopsy studies have found that approximately 90% of all completed suicides could be retrospectively diagnosed with a major mental disorder. 24 SUICIDE IS AN OUTCOME THAT REQUIRES SEVERAL THINGS TO GO WRONG ALL AT ONCE. -- There is no one cause of suicide and no single type of suicidal person. Biological Factors Familial Risk Predisposing Factors Proximal Factors Immediate Triggers Major Psychiatric Syndromes Hopelessness Public Humiliation Shame Serotonergic Function Substance Use/Abuse Intoxication AccessTo Weapons Neurochemical Regulators Personality Profile Impulsiveness Aggressiveness Severe Defeat Demographics Abuse Syndromes Negative Expectancy Major Loss Severe Medical/ Neurological Illness Severe Chronic Pain Worsening Prognosis Pathophysiology 25 TRIGGERING EVENTS ― Loss of social support (friends, family) ― Loss of identity/meaning (job, career, financial, legal problems) ― Loss of independence/autonomy, or function (major health problem) ― Acute psychiatric symptoms (psychosis, depression, panic…) ― Loss of hope/Sense of failure ― Date of a significant past interpersonal loss: Anniversary reaction 26 27 Comorbidity Lifetime comorbidity of mood and anxiety disorders 48% of patients with PTSD1 Up to 65% of patients with Panic Disorder2 Post-Traumatic Stress Disorder Social Anxiety Disorder Up to 70% of patients with Social Anxiety Disorder5 Panic Disorder DEPRESSION GAD OCD 67% of patients with Obsessive–Compulsive Disorder4 42% of patients with Generalised Anxiety Disorder3 Kessler et al. Arch Gen Psychiatry 1995; DSM-IV-TR™ 2000; Brawman-Mintzer et al. Am J Psychiatry 1993; Rasmussen et al. J Clin Psychiatry 1992 ; Dunner, Depression and Anxiety 2001 28 Outcome of Depression Treatment The Five Rs Reproduced with permission from Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34. Copyright 2002, Physicians Postgraduate Press. 29 21st Century Medicine 30 Etiology of Major Depression • Over a third of the liability for developing MDD comes from genetic factors • Genes likely mediate risk as well as resilience • Environmental stressors interact with genes to influence the likelihood of developing MDD 31 Genetics and Environmental Factors • Studies of identical twins have Strong revealed that some conditions, such Genetic as psoriasis, have a strong genetic Influence component and are less influenced by environmental and lifestyle Psoriasis factors—identical twins are more MDD Bipolar disorder likely to share these diseases; but IQ Schizophrenia other conditions, such as MS, are only weakly influenced by genetic Neurotic/ extrovert makeup and therefore twins may Asthma Diabetes show differences depending on their exposure to various Cardiac conditions environmental factors • “We used to think our fate was in our stars. Now we know, in large measure, our fate is in our genes.” —J. D. Watson Chakravarti A, Little P (2003), Nature 421(6921):412-414 Multiple sclerosis Cancers Weak Genetic Influence 32 Depression anxiety are are ultimately ultimatelyabout about Depression and and anxiety how to the the environment environment howthe thebrain brainresponds responds to cognition The Wisconsin Card Sorting Task mood and anxiety disorders temperament Genes: Cells: Systems: Behavior: sequence variants and variable gene processing molecular pathways activity in emotion processing circuitry Clinical phenotype 33 Risk Factors for Depressive Disorders • • • • • • • • • • • Family History of depressive disorders Prior personal history of a depressive disorder Female gender Life stressor (eg, bereavement, chronic financial problems) Certain personality traits Loss of parents at an early age Childhood abuse Alcohol or drug abuse Anxiety disorders Neurologic disorders (eg, Parkinson’s, Alzheimer’s, stroke) Primary sleep disorders Hirschfeld RMA, Goodwin FK. In: The American Psychiatric Press Textbook of Psychiatry. 1987: 403-441 Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. 1993: 1-65 34 Depressive Disorders: The Essentials Stress is an important risk factor for depression Early life stress is an important risk factor Genes account for a substantial variation in risk Brain systems related to the regulation of emotion are functionally impaired during an episode Monoaminergic drugs are therapeutic 35 Neurotransmitters and Depression • There are disturbances in the monoamine systems – Serotonin (5-hydroxytryptamine, 5-HT) – Norepinephrine (NE) – Dopamine (DA)?? • There are also disturbances in other neurotransmitter systems (e.g., corticotropinreleasing factor [CRF] and substance P) • Serotonin and norepinephrine have been the most extensively studied in the clinical setting 36 Axon Terminals of Serotonergic Neurons Project to Virtually All Portions of the Brain Thalamus Striatum Neocortex Cingulum Cingulate Gyrus To Hippocampus Ventral Striatum Amygdaloid Body Hypothalamus Cerebellar Cortex Olfactory and Intracerebellar Nuclei Entorhinal Caudal Raphe Nuclei Cortices Hippocampus Rostral Raphe Nuclei To Spinal Cord Kaplan HI, Sadock BJ (1991), Synopsis of Psychiatry: Behavioral Sciences, Clinical Psychiatry, 6th ed. New York: Lippincott Williams & Wilkins 37 38 39 Serotonin Transporters Measured With 123I -CIT and SPECT 5-HTT 5-HTT Sagittal Image Through Brainstem and Basal Ganglia Coronal Image SPECT = single photon emission-computed tomography 40 Reduced Brainstem [123I]β-CIT Binding in Depression 6 Brainstem V3" Drug free 5 Drug naive 4 3 2 1 Healthy Depressed *p=0.02; V3" = [brainstem-occipital]/occipital; Malison RT et al. (1998), Biol Psychiatry 44(11):1090-1098 41 Influence of Life Stress on Depression 0.7 Probability of Major Depression Episode • Results of regression analysis estimating the association between childhood maltreatment (between the ages of 3-11) and adult depression (ages 1826), as a function of 5-HTT genotype 0.6 0.5 s/s s/l 0.4 0.3 l/l 0.2 0 No Probable Severe Maltreatment Maltreatment Maltreatment Caspi A et al. (2003), Science 301(5631):386-389 42 43 Dopamine and Depression • Role of dopamine neurons in behavioral and physiological areas altered in depression • High rate of comorbidity of Parkinson’s disease and depression • Pathophysiological involvement of DA systems in depression Imaging Studies Postmortem Studies Biological Fluids Studies • Role of DA circuits in the actions of antidepressants MAOIs Effects on the DA transporter 44 Dopamine Transporter Binding Potential in Depression Healthy Depressed Linear (healthy) Linear (depressed) Dopamine Transporter Binding Potential • Dopamine transporter binding potential in bilateral striatum is lower in depressed patients. Data was analyzed using analysis of covariance with age as a covariate, examining effect of diagnosis (effect of diagnosis: F1,29 = 7.1, p=0.01) 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 15 Age 35 55 Meyer JH et al. (2001), Neuroreport 12(18):4121-4125 45 Cg25-Frontal Interactions in Negative Mood Regulation Recovery With SSRI Transient Sadness FDG PET CBF PET R F9 F9 F9 Cg25 Cg25 Cg25 +4z Cg31 Cg31 - 4z Cg25 Cg25 Cg25 Depressed Patients Healthy Volunteers FDG = [18F] fluorodeoxyglucose; Numbers (i.e., 25, 31) are Brodmann area designations; Mayberg HS et al. (1999), Am J Psychiatry 156(5):675-82 Mapping Treatment Effects: Isolate Potentially Most Relevant Regions Paroxetine (Paxil) N=13 Age 36+10 HAM 22+3 post 6+4 F9 - dec mF9 F9 Cg24 mF9 F9 mF10 pCg +inc Cg25 hc P40 CBT N=14 Age 41±9 HAM 20±3 post 6.7±4 th th vF hc hc Cg24 pCg F11 Different Treatments; Different Targets HAM = HAM-D Score; P = inferior parietal; th = thalamus; hc = hippocampus; pCg = posterior cingulate; mF = medial frontal; vF = ventral prefrontal; Goldapple K et al. (2004), Arch Gen Psychiatry 61(1):34-41 Miller et al (2009) Biol Psychiatry 65:732-741. 48 PTSD Symptom Score (PSS) Current Treatment Options for Depression Goal = reduce symptoms of depression and return patient to full, active life Nonpharmacologic • Psychotherapy - Cognitive behavioral therapy - Interpersonal therapy - Psychodynamic therapy • Electroconvulsive therapy • Phototherapy Pharmacologic • Antidepressant medications Depression Guideline Panel. Depression in Primary Care: Vol 1. Detection and Diagnosis. Clinical Practice Guideline No. 5. 1993. 49 Binder et al (Submitted) Potential Consequences of Failing to Achieve Remission • Increased risk relapse and treatment resistance • Continued psychosocial limitations • Decreased ability to work and decreased workplace productivity • Increased cost for medical treatment • Sustained risk suicide, substance abuse • Sustained depression can worsen morbidity/mortality of other conditions Paykel ES, et al. Psychol Med. 1995;25:1171-1180; Thase ME, et al. Am J Psychiatry. 1992;149:1046-1052. Judd LL, et al. J Affect Disord. 1998;59:97-108; Miller IW, et al. J Clin Psychiatry. 1998;59:608-619. Simon GE, et al. Gen Hosp Psychiatry. 2000;22:153-162; Druss BG, et al. Am J Psychiatry. 2001;158:731-734. Frasure-Smith N, et al. JAMA. 1993;270:1819-1825; Penninx BW, et al. Arch Gen Psychiatry. 2001;58:221-227. Rovner BW, et al. JAMA. 1991;265:993-996. 50 THE NEED FOR OUTREACH TO COLLEGE STUDENTS Only 15-19% of students who die by suicide had been treated at campus counseling center (Gallagher, Annual Survey of Counseling Center Directors, 1995-2006) Why is this figure so low? 51 BARRIERS TO HELP-SEEKING Negative attitudes toward treatment Fear of negative reactions from parents, friends Concerns about confidentiality and potential impact of treatment on academics and career Concerns about administrative sanctions Worries about costs/issues with parents’ insurance Beliefs that problems will resolve on their own Perception that problems don’t impact functioning Resistance to giving up “control” of own choices Too overwhelmed to take necessary steps 52 CONFIDENTIALITY AND NEGATIVE CONSEQUENCES “This may sound silly but it has held me back from trying to talk to someone earlier: are there any repercussions for coming in? Last year I overdosed on a bunch of pills and I cut up my body. My father flew down here to kind of help me out…he said that it was probably a good thing that I did not go to the hospital because they would have to report a suicide attempt or something and it could get me kicked out of school. If I admit to that or talk about my depression will I get in trouble?” 53 COST “I wouldn’t mind meeting you…One thing is bothering me, though: my parents used to pay for my therapists back home, but if I tell them now that I’m thinking of going back to therapy they would get really worried about me and might want me to withdraw or something…But then, I wouldn’t be able to pay on my own if it’s as expensive as seeing private psychiatrists were…What do you think I should do?” 54 DIALOGUE AS THERAPY ”I’ve had a really bad year and it seems like I am either super happy or super sad, like right now I am sitting here crying on my bed and I couldn’t even tell you why exactly…I think what I am most stressed out [about] (which makes me contemplate whether I should even live any more or not) is really stupid and even I can recognize that it is dumb. I feel like I am so lost because I am so undecided about my future that I lose sleep at night. My parents will not stop bugging me about a major or a career and I’m beginning to think that no matter what major or career I choose I will hate it. My friends would probably never guess I’m depressed. I try very hard to hide it…but in the end it makes it worse because I feel like I’m not being who I really am. I think the depression questionnaire was a God-send before I did something stupid. People looking at my life from the outside in would see a very normal happy childhood and I have a great family and people who love me, so I almost feel guilty about being so sad. I don’t have a real reason to be I guess... This is really long, but it’s nice to get it all out. Thanks for listening.” 55 STUDENTS CAN COME BACK FOR HELP AT LATER DATE I filled out your survey last semester. You emailed me multiple times, but I thought I had a handle on things and was starting to feel better. My friend committed suicide last week and I am finding it really hard to even get out of bed. It’s just,… I don't know. I thought I could handle this on my own, but I may need help. 56 STEPS: Factors to Consider in Antidepressant Selection • • • • • Safety - Drug-drug interaction potential Tolerability - Acute and long term Efficacy - Onset of Action - Treatment and prophylaxis Payment (cost-effectiveness) Simplicity - Dosing - Need for monitoring Preskorn SM. J Clin Psychiatry. 1997; 58(suppl 6): 3-8. 58 Pharmacotherapy of Depression Antidepressant agent classes • Monoamine oxidase inhibitors (MAOIs) • Tricyclic (TCAs) and tetracyclic • • antidepressants Selective serotonin reuptake inhibitors (SSRIs) Atypical antidepressants - Bupropion - Venlafaxine - Nefazodone - Mirtazapine Rossen EK, Buschmann MT. Arch Psychiatr Nurs. 1995; 9: 130-136. 59 Benefits of Remission • • • • Better prognosis Better function Less treatment resistance Better outcomes in comorbid general medical conditions • Fewer complications – Substance abuse – Relationship problems – Lower morbidity from general medical conditions 60 Depression: Recurrence Risks 1 Episode 50% 2 Episodes 80% - 90% 3 Episodes >90% Depression Guideline Panel. Depression in Primary Care, Volume 2: Treatment of Major Depression. Clinical Practice Guidelines, Number 5. 1993. Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34. 61 Optimizing current treatments • ECT effective for depression1 – Limitations include side effects and high relapse rate (even with continuation ECT)2 – Increasingly focal ECT may be efficacious with fewer side effects3,4 • Magnetic seizure therapy – Convulsive therapy with a very focal initial stimulation – Preliminary efficacy suggested with fewer cognitive side effects than ECT5,6 1The UK ECT Review Group, Lancet, 2003; 2Kellner et al., Arch Gen Psychiatry, 2006; 3Sackeim et al., Arch Gen Psychiatry, 2000; 4Bakewell et al., J ECT, 2004; 5Lisanby et al., Neuropsychopharmacology, 2003; 6White et al., Anesth Analg, 2006 62 Remission Is Associated with Fewer Missed Work Days Mean days of work missed 18 16 14 12 10 8 6 * 4 2 0 Persistent† Improved† Remission† *P<0.001 †Clinical depression status at 12-month assessment. Persistent = still meeting diagnostic criteria for MDD; Improved = HAM-D 8, but not meeting diagnostic criteria; Remission = HAM-D 7 Simon GE, et al. Gen Hosp Psychiatry. 2000;22:153-162. 63 Depression Decreases Workplace Productivity • Absenteeism may represent only a small fraction of the cost of depression in the workplace • Persistently depressed workers are 7 times less productive on the job • Impact of depression on function at work is substantially higher than its association with missed days at work Druss BG, et al. Am J Psychiatry. 2001;158:731-734. 64 Depression Worsens Outcomes of Many General Medical Conditions • Depression worsens morbidity and mortality after myocardial infarction1,2 • Depression increases risk for mortality in patients in nursing homes3 • Depression worsens morbidity post-stroke4 • Depression can worsen outcomes of cancer, diabetes, AIDS, and other disorders5 1.Frasure-Smith N, et al. JAMA. 1993;270:1819-1825. 2. Penninx BW, et al. Arch Gen Psychiatry. 2001;58:221227. 3. Rovner BW, et al. JAMA. 1991;265:993-996. 4. Pohjasvaara T, et al. Eur J Neurol. 2001;8:315-319. 5. Petitto JM, Evans DL. Depress Anxiety. 1998;8(suppl 1):80-84. 65 Depression Increases Risk of Cardiac Mortality RR cardiac mortality (and 95% CI) 5 4 Nondepressed Minor depression Major depression 3 2 1 0 No pre-existing cardiac disease Pre-existing cardiac disease Penninx BW, et al. Arch Gen Psychiatry. 2001;58:221-227. 66 Vagus Nerve Stimulation (VNS) • FDA-approved (1997) for treatment of medicationrefractory epilepsy • FDA-approved (2005) for treatment of depression that has not responded to four or more medications • Achieved by implanting a pulse generator attached to (usually) the left vagus nerve 67 rTMS • Studied for treatment of depression since 1993 – Multiple open and sham-controlled studies have been performed; meta-analyses support antidepressant effects for high frequency left-sided rTMS1,2 – Some studies have suggested a favorable comparison to ECT, but data are mixed3,4 – Low frequency right-sided rTMS may also have antidepressant effects5,6 • Side effects are generally mild; serious adverse events (seizures) from TMS performed within current safety guidelines are very rare7 1Holtzheimer et al., Psychopharm Bull, 2001; 2Kozel et al., Journal of Psychiatric Practice, 2002; 3Grunhaus et al., Biol Psychiatry, 2000; 4Eranti et al., Am J Psychiatry, 2007; 5Fitzgerald et al., Arch Gen Psychiatry , 2003; 6Januel et al., Prog Neuropsychopharmacol Biol Psychiatry, 2006; 7Wassermann, Electroencephalogr Clin Neurophysiol, 1998 68 Geracioti et al (2006) AJP 163:637-643. 69