Depression and PTSD Treatments Improve HIV Treatment Outcome

1. Depression and PTSD Treatments Improve HIV Treatment Outcome Eric Avery, MD Assistant Clinical Professor of Psychiatry Director, HIV Psychiatry Services The University of Texas Medical Branch Galveston, Texas

2. Objectives 1. To understand the relationship between the increasing prevalence of psychiatric disorders in HIV patients and the changing epidemiology of the epidemic. 2. To review Depression and Post Traumatic Stress Disorder (PTSD): Prevalence Diagnosis Impact on adherance and mortality Treatment of Depression and PTSD 3. To review HIV and psychiatric drug/drug interactions.

3. HIV is a Psychiatric Epidemic • Psychiatric illness increases risk for HIV. • HIV increases risk for psychiatric illness. • Effective treatment for psychiatric illness can improve patient outcome. • Effective treatment for psychiatric can decrease HIV transmission.

4. Psychiatric Illness Increases Risk of HIV Infection • Substance Abuse. • Mood Disorders (Major Depression, Bipolor D/O) • Post Traumatic Stress Disorder (PTSD) • Psychotic Disorders • Impulsive behavior and personality factors

5. HIV Increases Risk for Psychiatric Illness • Increased major depression. • Increased mania. • HIV dementia (AIDS Dementia Complex). • Increased psychosocial stressors.

6. Depression 1. Prevalence 2. Diagnosis 3. Impact on ARV Treatment: • Initiation • Discontinuation • Adherance 4. Impact on HIV Mortality 5. Treatment of Depression

7. 100 Patients with HIVHow many are depressed?

8. Depressed Mood and HIV: Name the 11 types: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Why is the diagnosis important?

9. Differential Diagnosis of Depressed Moods in HIV Patients • Despondency/demoralization. • Dysthymia (chronic low mood). • Adjustment disorder/minor depression. • Major depression, recurrent major depression. • General anxiety disorder. • Bipolar disorder -- depressed phase. • Organic mood disorder “secondary depression” (infections, medication side-effects, and mass lesions of CNS). • Malnourishment/weight loss associated with HIV. • Sleep disorder. • Psychoactive substance abuse. • Bereavement.

10. Depression: Multicenter AIDS Cohort Study % Depressed Time of AIDS Onset 55- 49- 43- 37- 31- 25- 19- 13- 7-12 0-6 0-6 7-12 13- 19- 60 54 48 42 36 30 24 18 mo mo mo mo 18 24 mo mo mo mo mo mo mo mo mo mo Percentages of Multicenter AIDS Cohort Study participants who met syndromal criteria for depression, or who had a score of 22 or greater on the Center for Epidemiologic Studies Depression scale (CES-D) or 14 or greater on the CES-D minus its “somatic” items (CES-D-NS), as AIDS developed. Lyketos et al, Psych Ann 31: 1 Jan 01

11. Depression and Progression to AIDS – PreHAARTLyketos, Hoover, Guccione et al JAMA 1993 • MACS Cohort: 1718 participants • 21% depressed at baseline • Cox proportional hazards analysis controlling for sociodemographics, CD4, AIDS related symptoms • Depression did not predict AIDS or death

12. Depression and Progression to Death – PreHAARTBurack, Barret, Stall, Chesney, Estrand, Coates JAMA 1993 • San Francisco Men’s Health Study: 277 participants • 20% depressed at baseline • Cox proportional hazards analysis of progression to death • Depression predicted ARV use but not mortality

13. Depression and Progression to AIDS – PreHAARTMayne, Vittinghoff, Chesney, Barrett, Coates Arch Int Med 1996 • SF Men’s Cohort: 1032 participants over 102 months • Cox proportional hazards with time dependent variables • 58% had significant depressive symptoms (CES-D) • Longitudinal measurement of depression every 6 months • Predictors of Mortality • CD4 cell count • B2 microglobulin • P24 antigen • WHO HIV stage • Depression (RR=1.67 P<0.05)

14. Depression and Progression to AIDS: Post-HAARTIckovics, Hamburger, Vlahov et alJAMA 2001 • HERS Cohort: 765 Participants • Longitudinal depression (CES-D) • 42% chronic • 35% intermittent • 23% none • Mortality predictors: depression (RR=2), CD4, HAART duration, age

15. Depression, Mortality by CD4 and Viral load: Post-HAARTIckovics, Hamburger, Vlahov et alJAMA 2001

16. Why Does Depression Speed Progression to AIDS and Death? • Stress alters cellular and humoral immune response • Kieclot-Glaser Proc Nat Acad Sci 1996 • Vedhara Lancet 1999 • Glaser Psychosom Med 1992 • Jabaaij J Psychosom Res 1993 • Glaser Ann NY Acad Sci 1998 • Azciati Psychosomatics 2001 • Delay in HAART initiation • Early HAART Discontinuation • Sub-optimal adherence to HAART

17. Factor Hazard 95% CI p Value CD4 cell count <200 1.00 200-500 2.63 1.61, 4.17 <.001 >500 11.11 3.57, 33.33 <.001 Tenfold increase in initial        elevated viral load 0.66 0.45, 0.98 .038 History of pneumocystis 0.57 0.37, 0.90 .016 Depression (53%) 1.49 1.03, 2.13 .032 History of injection drug use 2.70 1.35, 5.56 .005 Model adjusted for calendar date of first elevated viral load. Depression and Delay in HAART InitiationFairfield JGIM 1999 199 Patients New England Deaconnes with VL>10,000

18. What Degree of AdherenceIs Needed to PreventDrug-Resistant Virus Adherence to a PI-Containing Regimen CorrelatesWith HIV RNA Response at 3 Months 100 80 60 Patients With HIV RNA <400 (%) 40 20 0 <70 70-80 80-90 90-95 >95 PI Adherence (%) (MEMScaps) Paterson. 6th CROI; 1999; Chicago. Abstract 92.

19. Amiodarone Irvine Psychosom Med 1999 General medicine Botelho J Fam Pract 1992 Aspirin for angina Carney Behavioral Med 1998 Renal diet De-Nour Transplantation 1993 ESRD Diet Katz Psychol Reports 1998 ESRD Diet Schnieder Health psychol 1991 ESRD Medical Regimen Brownbridge Ped Neph 1994 Cyclosporine Renal Transplant Kiley Transplantation 1993 Cyclosporine Renal Transplant Rodriguez Trans Proc 1991 Rheum arthritis treatment plan Taal Pt Ed Counsel 1992 Oral cytoxan Lebovits Cancer 1990 Asthma Cochrane Drugs 1996 Depression Predicts Adherence to Non-HIV Treatment

20. Depression and HIV Medication Adherence • Singh AIDS Care 1996 • Holzmer AIDS Patient Care STDs 1999 • Peterson Annals Int Med 2000 • Schulz 38th ICAAC 1998 • Bangsberg #1721 41st ICAAC 2001

21. Depression is Under-Treated • 475 HIV+ men • 37% moderate-severe depressive symptoms • 40% of depressed received mental health care (12 mo) • 3.4% of depressed received antidepressant medications (12 mo) Katz et al AIDS Care 1996

22. Depression: Diagnosis

23. Simple Depression Assessment • During the past month, have you often been bothered by feeling down, depressed, or hopeless? • Yes No • During the past month, have you often been bothered by having little interest or pleasure in doing things? • Yes No If “no” to both, patient is unlikely to have major depression. If “yes” to either, proceed with the follow-up clinical interview. Whooley MA, Simon GE. N Engl J Med, 2000.

24. Follow-up Interview for Diagnosis: SIGECAPSS SSleep Disruption in sleep patterns nearly every day? I Interests Decreased interest and pleasure in usual activities G Guilt Feelings of worthlessness or guilt? E Energy Decreased energy? C Concentration Diminished ability to concentrate? AAppetite Change in appetite or weight? PPsychomotor Psychomoror retardation or agitation/irritable? SSuicidal Recurrent thought of death or suicide? SSex drive Diminished sex drive?

25. 1 0I do not feel sad. 1I feel sad. 2I am sad all the time and I can’t snap out of it. 3I am so sad or unhappy that I can’t stand it. 20I am not particularly discouraged about the future. 1I feel discouraged about the future. 2I feel I have nothing to look forward to. 3I feel that the future is hopeless and that things cannot improve. 30I do not feel like a failure. 1I feel I have failed more than the average person. 2As I look back on my life, all I can see is a lot of failures. 3 I feel I am a complete failure as a person. 8 0 I don’t feel I am any worse than anybody else. 1 I am critical of myself for may weaknesses or mistakes. 2 I blame myself all the time for my faults. 3 I blame myself for everything bad happens. 90 I don’t have any thoughts of killing myself. 1 I have thoughts of killing myself, but I would not carry them out. 2 I would like to kill myself. 3 I would kill myself if I had the chance. 100 I don’t cry any more than usual. 1 I cry more now than I used to. 2 I cry all the time now. 3 I used to be able to cry, but now I can’t cry even though I want to. To order forms: 1-800-228-0752 Beck Depression Inventory Date__________________Name:__________________________________________________ Marital Status:_______ Age:____ Sex:___Occupation:_____________________________________________ Education:___________________________This questionnaire consists of 21 groups of statements. After reading each group of statements carefully, circle the number (0,1,2 or 3) next to the one statement in each group which best describes the way you have been feeling the past week, including today. If several statements within a group seem to apply equally well, circle each one. Be sure to read all the statements in each group before making your choice.

26. Depression: Treatment

27. Medication Response Author Journal Year Imipramine 74% Rabkin Am J Psych 1994 Imipramine 87% Elliot Am J Psych 1998 Desipramine 50% Schwartz Dep and Anxiety 1999 Tricyclic Antidepressants Treatment of Depression in HIV+ Individuals

28. Treatment of Depression With Other Agents in HIV+ Individuals Drug Response Author Journal Year Dextroamphetamine 73% Wagner J Clin Psych 1999 Testosterone 74% Rabkin Arch Gen Psych 2000 Testosterone (Sx decrease) Grinspoon J Clin Endo Metab 2000 Grinspoon 2000

29. Medication Response Author Journal Year Fluoxetine 83% Rabkin J Clin Psych 1994 Fluoxetine 64% Zisook J Clin Psych 1998 Fluoxetine 67% Elliot Am J Psych 1998 Fluoxetine 90% Ferrando Gen Hosp Psych 1997 Fluoxetine 75% Schwartz Dep and Anxiety 1999 Fluoxetine/ Sertraline 78% Ferrando J Clin Psych 1999 Sertraline 86% Ferrando Gen Hosp Psyh 1997 Nefazodone 73% Elliot J Clin Psych 1999 Paroxetine 86% Ferrando Gen Hosp Psych 1997 SSRI Treatment of Depression in HIV+ Individuals

30. TCA Narrow therapeutic window Requires drug monitoring Anticholinergic effects Dry mouth, Constipation, dizziness, hypotension 41% discontinue at 6 months (Rabkin Amer J Psych 1994) Pill burden SSRI Mild side effects Anticholinergic, agitation/sedation, sexual dysfunction Drug interactions (Rx + ritonavir) Bupropion - seizures Side Effect/Toxicity Profile TCA vs SSRI

31. SSRI FDA Approvals * FDA approved to age 6 years;

32. Half Lives of 4 SSRIs

33. Serotonin Discontinuation Syndrome • Somatic symptoms • Disequilibrium, dizziness, unsteadiness, vertigo • Feeling “spacey”, confusion, memory dysfunction • Flulike symptoms (myalgia, chills, fatigue, nausea) • Sensations of electric shocks, parethesia, tremor • Insomnia, overactivity, vivid dreams • Psychological symptoms • Agitation, anxiety, irritability • Mood lability, crying spells • Cognitive fog

34. Hepatic Isoenzyme Inhibition of the SSRIs (Cytochrome P450)

35. HIV-Related Medications and Psychotropic Agents Involving the Cytochrome P450 Isoenzyme

37. Staging HIV and Antidepressant Treatment:Treat Depression First Whenever Possible • Depression is common • Depression is the strongest modifiable predictor of adherence to all medical therapy • Adherence is the strongest predictor of disease progression and death after CD4 cell count • Depression should be treated prior to starting antiretroviral therapy • Depression screen, CD4, VL • Patients with severe HIV disease may need concurrent initiation of antidepressant therapy and antiretroviral therapy Bangsberg JGIM 1999;14:446-8

38. Comorbid Mood and Anxiety Disorders Panic Disorder 50% - 65%1 Generalized Anxiety Disorder 8%- 39%1 Depression Social Anxiety Disorder 70%2 PTSD 48%4 OCD 67%3 1American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC; American Psychiatric Press; 1994. 2 Van Ameringen M et al. J Affect Disord. 1991;21:93-99. 3 Rasmussen SA, Eisen JL. J Clin Psychiatry. 1992;53(suppl):4-10. 4 Coryell W Et al. Am J Psychiatry 1988;155:895-898.

39. Post Traumatic Stress Disorder • Prevalence • Childhood abuse, PTSD and HIV risk behaviors • Proposed association between PTSD and HIV treatment nonadherance • Treatment of PTSD

40. PTSD Prevalence • Over half the U.S. population has been exposed to a severe trauma • 10-20% of trauma survivors will develop PTSD • Lifetime prevalence 8% overall. 12% in women (Kessler 1995) • Increased rates in HIV +, incarcerated • Limited studies: • HIV + 30% (1/3 after HIV dx) (Kelly 1998) • Incarcerated women lifetime 33%, current 15-22% (Hutton 2001) • PTSD is the 5th most prevalent major psychiatric illness

41. Most Prevalent Anxiety Disorders in the General Population Lifetime Prevalence (%) Kessler et al, National Comorbidity Survey, 1994 MalesFemales Hutton (2001) 177 Prison Women Kelly (1998) 61 HIV+ Gay/Bi men

42. Comorbidity • Comorbid psychiatric illness is about 80% • Patients with PTSD are 2 - 4X more likely to have depression, anxiety disorders or substance abuse • They are 90X more likely to have a somatization disorder

43. Common Traumatic Events • Witnessing injury/death • Sexual molestation/rape • Natural disaster/fire • Physical attack or abuse/threatened with a weapon • Life threatening accident • Combat

44. PTSD - Clinical Course • PTSD symptoms usually present within the first 3 months following the trauma • Less frequently, symptoms may be delayed for months or years after the traumatic event • Symptoms of PTSD may persist for months or years after the trauma • Approximately 50% of all cases of PTSD are chronic

45. Connection Between Childhood Abuse and HIV Infection Reported Abuse & Survivor Characteristics (N= 52 HIV +Adults Atlanta Social Service Agency) Note. Survivor characteristic categories are not independent. Allers C. J Counsel Devel. 1991; 70: 309-13

46. Frequency of PTSD Disorders Among 177 Women Prisoners in an HIV Risk Behavior Study Compared with participants who did not have PTSD, those with lifetime diagnosis of PTSD were 71% more likely to have engaged in anal sex and 56% more likely to have engaged in prostitution. The association between lifetime PTSD and other HIV risk behaviors were not significant in this study. Hutton, Psych Services 2001, 52/4:508-13

47. PTSD Predicts Adherence to Non-HIV Treatment Survivors of Myocardial Infarction • 102 s/p MI • 10% PTSD (intrusion/avoidance) • significant association with decreased adherence Shemesh Gen. Hosp. Psych 2000

48. PTSD is Under-Treated 47 HIV+ women • 42% full, current PTSD • 59% not receiving mental health care • 22% partial PTSD • 78% not receiving mental health care Martinez AIDS Patient Care and STDs 2002

49. PTSD: Diagnosis

50. Screening questions • Have you ever had anything happen to you where you thought you would be seriously injured or might die? • Have you ever been in a life threatening accident? Fire? Disaster? • Have you ever been attacked or raped? • Have you ever seen these things happen to someone else?