Treatment of Depression and Schizophrenia Presented by: Charles B. Nemeroff, MD, Ph. D Reunette W. Harris Professor and Chairman Department of Psychiatry & Behavioral Sciences Emory University School of Medicine Atlanta, GA Annotated for Bi 1 by Henry Lester May 21, 2002
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
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)
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.
Prevalence of Depression in United States 6%-25% 10%-14% 5%-10% 2%- 4% Community Primary Care Clinic Katon W. Schulberg H. Gen Hosp Psychiatry. 1992; 14: 237 -247 Medical Inpatient Setting Nursing Home
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.
Epidemiology of Major Depression • 17% of US population reported a major depressive episode in their lifetime • Average of onset: late 20 s - >50% of patients have first episode by age 40 • Duration: 6 months – 2 years if left untreated - Episodes continue in up to 80% of untreated patients Depression Guideline Panel. Depression in Primary Care: Vol 1. Detection and Diagnosis. Clinical Practice Guideline No. 5. 1993.
“He asked me if I was suicidal, and I reluctantly told him yes. I did not particularize -- since there seemed no need to -- did not tell him that in truth many of the artifacts of my house had become potential devices for my own destruction: the attic rafters (and an outside maple or two) a means to hang myself, the garage a place to inhale carbon monoxide, the bathtub a vessel to receive the flow form my open arteries. The kitchen knives in their drawers had but one purpose for me. Death by heart attack seemed particularly inviting, absolving me as it would of responsibility, and I had toyed with the idea of self-induced pneumonia -- a long, frigid, shirt sleeved hike through the rainy woods. Nor had I overlooked an ostensible accident, a la Randall Jarrell, by walking in front of a truck on the highway nearby. These thoughts may seem outlandishly macabre -- a strained joke -- but they are genuine. They are doubtless especially repugnant to healthy Americans, with their faith in self-improvement. Yet in truth such hideous fantasies, which cause well people to shudder, are to the deeply depressed mind what lascivious daydreams are to persons of robust sexuality. ” William Styron, Darkness Visible: A Memoir of Madness, 1990.
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
Leading Causes of Disability, World, 1990 All Causes Total (millions) Per cent of total 472. 7 1) Unipolar major depression 50. 8 10. 7 2) Iron-deficiency anaemia 22. 0 4. 7 3) Falls 22. 0 4. 6 4) Alcohol Use 15. 8 3. 3 5) Chronic obstructive pulmonary disease 14. 7 3. 1 6) Bipolar Disorder 14. 1 3. 0 7) Congenital anomalies 13. 5 2. 9 8) Osteoarthritis 13. 3 2. 8 9) Schizophrenia 12. 1 2. 6 10) Obsessive-compulsive disorders 10. 2 2. 2
The leading causes of disease burden for women, aged 15 -44, 1990 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 Percent of all causes in developed or developing regions
The burdens of mental illness, such as depression, alcohol dependence, and schizophrenia, have been seriously underestimated by traditional approaches that take account only of deaths and not disability. While psychiatric conditions are responsible for little more than one per cent of deaths, they account for almost 11 per cent of disease burden worldwide.
Depression harms more women than AIDS or cancer In 1990, suicide was the number-one cause of death and disability for women ages 15 to 44 worldwide. By the year 2020, it will rank second only to heart disease as the world’s leading cause of death and disability for men and women of all ages, predicts a five-year study by the World Health Organization, the World Bank and the Harvard School of Public Health.
Among adults aged 15 – 44 worldwide, road traffic accidents were the leading cause of death for men and the fifth most important for women. For women aged between 15 – 44, suicide was second only to tuberculosis as a cause of death. In China alone, more than 180, 000 women killed themselves in 1990. In India, women face an appallingly high risk of dying in fires: in 1990 alone, more than 87, 000 Indian women died this way. In Sub-Saharan Africa, by contrast, the most important cause of injury deaths for both women and men is war.
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.
Rates of Completed Suicide* 80 Male Female 70 60 50 No. of Suicides 40 Per 100, 000 30 20 10 tal To >85 84 80 - 79 75 - 74 70 - 69 65 - 64 60 - 59 55 - 54 50 - 49 45 - 44 40 - 39 35 - 34 30 - 29 25 - 24 20 - 19 15 - 10 - 14 0 Age (years) *In the United States, 1994. Reproduced with permission from Hirschfeld RMA and Russell JM. N Engl J Med. 1997; 337: 910 -915. © Copyright 1997, Massachusetts Medical Society. All rights reserved.
Postpartum Depression (PPD) • 10% to 15% in adults* • 26% of adolescents† • Second in frequency only to C-section *Stowe and Nemeroff. Am J Obstet Gynecol. 1995; 173: 639 -645. †Troutman and Cutrona. J Abnorm Psychol. 1990; 99: 69.
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.
Anxiety Disorders Panic Disorder Specific Phobias Social Phobia Generalized Anxiety Disorder Posttraumatic Stress Disorder Comorbid Depressive Disorder Obsessive. Compulsive Disorder
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.
Current Treatment Options for Depression Goal = reduce symptoms of depression and return patient to full, active life Nonpharmacologic • Psychotherapy - Cognitive behavioral Pharmacologic • Antidepressant medications therapy - Interpersonal therapy - Psychodynamic therapy • Electroconvulsive therapy • Phototherapy Depression Guideline Panel. Depression in Primary Care: Vol 1. Detection and Diagnosis. Clinical Practice Guideline No. 5. 1993.
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.
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.
Evidence for the Undertreatment of Depressive Disorders Medical Outcomes Study N = 634 Minor tranquilizer only 19% No antidepressant or tranquilizer 59% 12% Antidepressant* only 11% Antidepressant* and minor tranquilizer *39% of patients using antidepressants were receiving subtherapeutic doses Data are rounded to nearest percentage Adapted from Wells KB, Katon W, Rogers B, et al. Am J Psychiatry. 1994; 151: 694 -700.
Outcome of Depression Treatment The Five Rs Remission Recovery Relapse Recurrence Response x x Symptoms Syndrome Treatment Phases x Acute 6 -12 Weeks Continuation 4 -9 Months Maintenance ? 1 Year Reproduced with permission from Kupfer DJ. J Clin Psychiatry. 1991; 52(suppl 5): 28 -34. Copyright 2002, Physicians Postgraduate Press.
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.
Recurrent Depression: Treatment Implications Continue antidepressant for first 4 - 9 months Continue antidepressant indefinitely after 3 episodes or 2 episodes in patients with risk factors Depression Guideline Panel. Depression in Primary Care, Volume 2: Treatment of Major Depression. Clinical Practice Guidelines, Number 5. 1993. Schulberg HC et al. Arch Gen Psychiatry. 1998; 55: 1121 -1127.
Primary Care Patients with Depression % of Patients Who Filled Antidepressant Prescriptions * % of Patients Time Period (months) * P<. 001; statistical significance assessed only at 1 year. Katon W et al. Arch Gen Psychiatry. 2001; 58: 241 -247.
Primary Care Patients with Depression Discontinuation Rate of Antidepressant Medication % of Patients Discontinuing Medication Weeks After Medication Initiation Adapted with permission from Lin EHB et al. Med Care. 1995; 33: 67 -74.
SSRIs Available for Treatment of Depression in the United States • Fluoxetine: • Paroxetine: • Sertraline: • Citalopram: Prozac®, Eli Lilly Paxil®, Glaxo. Smith. Kline Zoloft®, Pfizer Celexa. TM, Forest & Parke-Davis Physicians’ Desk Reference. 1998. Celexa Package Insert. Forest Pharmacueticals, Inc.
SSRI Structures O NC O HN CH 3 O O CH 2 CH 2 N(CH 3)2 HBr CH 2 Citalopram F Paroxetine N Cl F 3 C C CH 2 O CH 3 Sertraline N Fluvoxamine Cl O CH 2 NH 2 Celexa package insert, Forest Laboratories, Inc. Physicians’ Desk Reference. 1998. O Fluoxetine H C CH 2 N CH 3 H
% Patients with >50% Reduction in Baseline HAMD Total Score Response to Paroxetine and Fluoxetine in Patients with Major Depression *P<. 05 De. Wilde et al. Acta Psychiar Scand. 1993; 87: 141 *
Proportion Remaining Well Relapse of Depression During Continuation Study of Sertraline Days of Continuation Treatment Doogan et al. Br J Psychiatry. 1992; 160: 217
SSRIs: Tolerability Issues Early-onset effects (headache, GI) Sexual dysfunction Weight change Discontinuation Drug interactions
Most Common Adverse Effects Paxil (N=4126) • Nausea • Headache • Somnolence • Dry Mouth • Insomnia 23% 18% 17% 13% Prozac (N=2938) • Nausea • Headache • Nervousness • Insomnia • Anxiety Boyer et al. J Clin Psychiatry. 1992; 53 (suppl 2): 61. Doogan. Int Clin Psychopharmacol. 1991; 6(suppl 2): 47. Stokes. Clin Ther. 1993; 15: 216. 23% 18% 17% 16% 13% Zoloft (N=4126) • Nausea 21% • Headache 18% • Dry Mouth 16% • Diarrhea/Loose Stools • Insomnia 15% 14%
SSRIs and Sexual Dysfunction Common, class effect Affects men and women Reduced libido Orgasmic dysfunction – delayed ejaculation – anorgasmia Erection difficulties minimal Associated with anxiety/depression Keller Ashton A et al. J Sex Marital Ther. 1997; 23: 165 -175. Segraves RT. J Clin Psychiatry. 1998; 59(suppl 4): 48 -54.
Strategies for Antidepressant Nonresponse Optimization: Full Dose and Duration Drug Substitution Combination: Addition of Second Antidepressant Agent Electroconvulsive Therapy Augmentation: Addition of Second Agent (Not an Antidepressant)
Antipsychotic Indications and Uses – Schizophrenia/Psychosis – Bipolar Disorder Mania Depression – Unipolar Depression Psychotic Treatment Resistant – Dementia Agitation/psychosis
Schizophrenia Chronic, “lifelong” condition Very high morbidity Very high mortality High personal/family impact High societal/medical system cost
The Course of Schizophrenia Affects approximately 1. 3% of the population* Onset generally occurs during young adulthood* Early treatment predicts better long-term outcomes* Majority of patients experience at least one relapse† Higher incidence of comorbid conditions including hypertension, diabetes, cardiac concern, STDs, substance abuse disorders, smoking*‡ Mortality higher than in the general population‡ – 10% incidence of suicide‡ *Mental health: a report of the surgeon general. Department of Health and Human Services. December 1999. †Robinson D, Woerner MG, Alvir JMJ, et al. Arch Gen Psychiatry. 1999; 56: 241 -247. ‡Goldman LS. J Clin Psychiatry. 1999; 60(suppl 21): 10 -15.
Risk of Relapse in Patients With Schizophrenia Rate of relapse among patients treated with conventional antipsychotics for first-episode schizophrenia and schizoaffective disorder – 16% at 1 year – 54% at 2 years – 82% at 5 years Stable patients were allowed the option to discontinue antipsychotic medication after 1 year of treatment The risk for a first and second relapse was almost 5 times greater than when not taking medication* – Risk is diminished by maintenance antipsychotic drug treatment *Based on a survival analysis of relapse using medication status as a time-dependent covariate. Source: Robinson D, Woerner MG, Alvir JMJ, et al. Arch Gen Psychiatry. 1999; 56: 241 -247.
Barriers to Adherence to Antipsychotic Therapy Cognitive impairment Complex drug regimen (eg, BID dosing) Adverse events (eg, weight gain, EPS, diabetes, QTc prolongation) Monitoring of selected adverse events (eg, ECG, blood, glucose, liver functioning, electrolyte, slit-lamp testing) Cost of medication Substance abuse Source: Perkins DO. J Clin Psychiatry. 1999; 60(suppl 21): 25 -30.
All Antipsychotics Efficacious, but not perfect High side effect burden Potential catastrophic adverse events Acceptable in the balance between treatment vs no treatment
Typical Antipsychotics Discovered by accident – Chlorpromazine All cause same side effects – Byproduct of drug discovery process Not Obsolete
Atypical Antipsychotics Discovered by accident – Clozapine (Clozaril) Significant improvement over typical Improved “effectiveness”
Typical vs. Atypical Typical – – High D 2 Low 5 -HT 2 A D 1=D 2 Increases neurotensin in caudate and nucleus accumbens Atypical – – High 5 -HT 2 A a peptide neurotransmitter Lower D 2 Low D 1 Increases neurotensin in nucleus accumbens only
Atypical Antipsychotics Clozapine (Clozaril) Risperidone (Risperdal, Consta) Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon)
Atypical Antipsychotics All efficacious Differing levels of effectiveness – Patient response characteristics – Side effects – Use limitations (Clozapine) All have significant side effects – Similar magnitude – Different specifics
Significant Improvement Across a Full Range of Symptoms* Negative Positive Hostility/ symptoms excitement symptoms Mood Cognition 0. 5 0. 47 0. 0 -0. 19 -0. 28 -0. 65 -0. 5 -1. 0 Improvement Mean PANSS change score at Week 1† 0. 1 -1. 23 -1. 28 P<0. 025 -1. 5 -2. 0 -2. 56 -2. 5 -3. 0 -3. 5 P<0. 001 -3. 29 P<0. 02 Risperidone (n=85) -3. 16 -3. 07 P<0. 001 Placebo (n=86) PANSS=Positive and Negative Syndrome Scale. *The Positive and Negative Syndrome Scale (PANSS) is a composite scale consisting of items used to assess overall psychopathology. Conclusions as to efficacy outcomes of individual items should not be drawn. † 6 mg/day. Source: Marder SR, Davis JM, Chouinard G. J Clin Psychiatry. 1997; 58: 538 -546.
Risperidone Provides Rapid and Sustained Efficacy* 0 -1. 0 -2. 0 Improvement Mean Total PANSS change score Significant improvement in symptom scores at week 1 Significant improvement maintained through 1 year -3. 0 -4. 0 -5. 0 P<0. 001 -6. 0 -7. 0 Week P<0. 001 1 2 4 12 28 PANSS=Positive and Negative Syndrome Scale. 1 -year, double-blind trial (n=365) – Average dose was 4. 9 mg/day at 1 year *Data on file, 2000. Submitted for publication. 52
Reduction of Hostility in Schizophrenia Week 1 Week 8 0. 5 0. 3 0. 2 0. 1 0. 0 -0. 1 -0. 2 -0. 3 -0. 4 P<0. 001 -0. 5 -0. 6 Placebo (n=86) Risperidone (n=85)† *Change from baseline to weeks 6 and 8 (last observation carried forward). † 6 mg/day. PANSS=Positive and Negative Syndrome Scale. Source: Marder SR, Davis JM, Chouinard G. J Clin Psychiatry. 1997; 58: 538 -546. P<0. 001 Improvement Mean PANSS change score* 0. 4
Improvement of Symptoms Associated With Cognition* 0. 10 0. 00 -0. 15 Improvement Mean PANSS change score† -0. 05 -0. 20 -0. 25 -0. 30 -0. 35 -0. 40 P<0. 001 -0. 45 -0. 50 -0. 55 P<0. 001 -0. 60 -0. 65 Week 1 2 3 Placebo (n=86) 4 5 6 7 Risperidone (n=85)‡ *Symptoms of disorganized thought from the PANSS scale. † Change from baseline to weeks 6 and 8 (last observation carried forward). ‡ 6 mg/day. PANSS=Positive and Negative Syndrome Scale. Source: Marder SR, Davis JM, Chouinard G. J Clin Psychiatry. 1997; 58: 538 -546. 8
Improvement of Mood* Symptoms in Schizophrenia 0. 10 0. 00 -0. 15 -0. 20 Improvement Mean PANSS change score† -0. 05 -0. 25 -0. 30 -0. 35 P<0. 025 -0. 40 -0. 45 -0. 50 P<0. 001 -0. 55 -0. 60 -0. 65 Week 1 2 3 Placebo (n=86) 4 5 6 7 ‡ Risperidone (n=85) *Symptoms of anxiety/depression from the PANSS scale. †Change from baseline to weeks 6 and 8 (last observation carried forward). ‡ 6 mg/day. PANSS=Positive and Negative Syndrome Scale. Source: Marder SR, Davis JM, Chouinard G. J Clin Psychiatry. 1997; 58: 538 -546. 8
Emerging Safety Concerns With Selected Antipsychotics Diabetes – Glucose elevations Weight Gain Cardiac Safety – QTc prolongation
Weight Change After 10 Weeks on Standard Drug Doses, Estimated From a Random Effects Model 5 4 3 Placebo Conventional antipsychotics Novel antipsychotics Nonpharmacologic controls 2 1 0 – 1 – 2 – 3 pl ac eb m o ol in do ne zip ra sid on flu ph e en az in no ha e np lo pe ha rid rm ol ac o po co log n i ly ph tro c ar l m ac ris y pe ch rid lo on rp e ro m az in e se rti n m thio do ez ri l or da e id zin az e in / ol an e za pi ne cl oz ap in e 95% confidence interval for weight change (kg) 6 Allison et al. Am J Psychiatry 156: 1686 -1696, 1999
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