September 26 28, 2013 Westin Tampa Harbour Island. Co-sponsored by

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1 September 26 28, 2013 Westin Tampa Harbour Island Co-sponsored by

2 Hepatitis C- Associated Depression Ondria C. Gleason, MD, FAPA, FAPM University of Oklahoma School of Community Medicine Tulsa, OK

3 Ondria C. Gleason, MD, FAPA, FAPM Disclosures Dr. Gleason has no disclosures to report.

4 Learning 1 Objective Counsel patients about the impact of depression on treatment outcomes in patients with hepatitis C virus infection

5 Learning 2 Objective Employ strategies for managing depression in patients with hepatitis C virus infection

6 Overview Epidemiology Prevalence of psychiatric illness in HCV IFN-induced depression Treatment of depression in HCV Role and duties of psychiatric consultant

7 Hepatitis C Virus (HCV): Facts Positive strand RNA virus 1 Characterized in Responsible for 8,000-10,000 deaths annually 2! More than from hepatitis A and B combined! More than from HIV Leading indication for liver transplantation 3 1. Liang TJ, et al. N Engl J Med. 2013;368(20): PMID: Clark PJ, et al. N Engl J Med. 2012;366(26): PMID: Merion RM. Semin Liver Dis. 2010;30(4): PMID:

8 HCV Infection Affects Many People Approximately 4 million Americans infected! 4 times more common than infection with hepatitis B virus! 1% to 2% of U.S. population carries HCV antibodies 170 million infected worldwide Liang TJ, et al. N Engl J Med. 2013;368(20): PMID:

9 The Prevalence of HCV Infection in Psychiatric Populations Patients with severe mental illness 8%-18% (4-9 times that in the general population, 2%) Patients in psychiatric hospitals 18% Veterans admitted to inpatient psychiatric services 12.7% Worldwide! Japan (4-5 times the general Japanese population [1%-2%]) 9.1%! Taiwan (6-7 times the general Taiwanese population [1%]) 6.8%! Northern Italy (1.5% in the general Italian population) 6.1% Rifai MA, et al. Prim Care Companion J Clin Psychiatry. 2010;12(6). PMID:

10 HCV Infection and Psychiatric Illness Psychiatric illness in 206 veterans with HCV 1! Alcohol or substance use disorder, 80%! Psychiatric disorder (primarily depression and PTSD), 60% Psychiatric illness in 306 veterans with untreated HCV infection 2 Depression 28% Bipolar 6% Personality disorder 30% Other mood disorder 4% PTSD 17% Alcohol 86% Psychotic disorder 17% IVDA 28% Anxiety 9% PTSD = posttraumatic stress disorder; IVDA = abuser of intravenously administered drugs. 1. Nguyen HA, et al. Am J Gastroenterol. 2002;97(7): PMID: Yovtcheva SP, et al. Psychosomatics. 2001;42(5): PMID:

11 Primary Psychiatric Disorders in 76 Patients With HCV Infection Referred for Psychiatric Consultation Percentage of Patients Substance Depression No Diagnosis Other Anxiety Adjustment Bipolar 5 0 Primary Psychiatric Disorders Yates WR and Gleason OC. Postgrad Med. 1998:26-33.

12 Prevalence Studies of HCV Infection and Depression Author Specific Population with Infection 1. Lee K, et al. Psychosomatics. 2013;54(1): PMID: Hunt CM, et al. Dig Dis Sci. 1997;42(12): PMID: Yovtcheva SP, et al. Psychosomatics. 2001;42(5): PMID: Dwight MM, et al. J Psychosom Res. 2000;49(5): PMID: Johnson ME, et al. Am J Gastroenterol. 1998;93(5): PMID: el-serag HB, et al. Gastroenterology. 2002;123(2): PMID: Yates WR and Gleason OC. Postgrad Med. 1998: Percentage with depression Lee 1 HCV 24 Hunt 2 HCV 30 Yovtcheva 3 Veterans with HCV 28 Dwight 4 HCV 28 Johnson 5 Substance abusers with HCV 57 el-serag 6 Hospitalized veterans with HCV 50 Gleason 7 HCV referred for psychiatric evaluation 25

13 Neuropsychiatric Adverse Events (AEs) Occurring During Treatment With Interferon (IFN) and Ribavirin in Patients With HCV Infection Neuropsychiatric AEs are among the most common reasons for treatment discontinuation 24%-49% of patients experience neuropsychiatric AEs! Anger, hostility! Anhedonia! Anxiety! Cognitive disturbances, delirium, psychosis! Depression! Fatigue! Irritability! Manic symptoms! Relapse in alcohol or drug abuse! Suicidal ideation Quelhas R, Lopes A. J Psychiatr Pract. 2009;15(4): PMID:

14 Neuropsychiatric AEs During Treatment With IFN and Ribavirin in Patients With HCV During clinical trials for the approval of peg-ifn-alpha-2a and -2b! Neuropsychiatric AEs among the most commonly reported AEs; 77% of patients! Suicidal ideation, suicide attempts, and actual suicides occurred in 2% of all patients studied Case reports of AEs with IFN and ribavirin therapy for HCV! Depression (ranging from 25%-34%)! Irritability and insomnia (possibly symptoms of mania) Quelhas R, Lopes A. J Psychiatr Pract. 2009;15(4): PMID:

15 Neuropsychiatric AEs During Treatment With Pegylated IFN-alpha Plus Ribavirin in 93 IFN-naïve Patients With HCV Infection Thirty patients (32%) developed a mood disorder! Hypomania, 50%! Depressive mixed states, 40%! Mania, 10% Of those who developed a mood disorder, 63% had prior history of psychiatric disorder Constant A, et al. J Clin Psychiatry. 2005;66(8): PMID:

16 Incidence of Major Depression During Treatment of HCV Infection With IFN-alpha Meta-analysis of published articles reporting the incidence of IFN-alphainduced major depression Of patients who started IFN and ribavirin, 25% developed a major depressive episode Udina M, et al. J Clin Psychiatry. 2012;73(8): PMID:

17 Sixty-six Patients With HCV Infection Undergoing IFN Therapy Diagnosis of major depressive disorder during IFN therapy! Total 44%! Baseline 4.5%! Week 4 22%! Week 12 38%! Week 24 27% Mean maximum Hamilton Depression Scale score, 20.5 ± 5.7 Four patients (6.6%) discontinued IFN due to severe depression Two patients had suicidal ideations but no attempts Miyaoka H, et al. Am J Psychiatry. 1999;156(7):1120. PMID:

18 Onset of Psychiatric AEs in Patients With HCV Infection Treated With IFN 20% within 1 week 40% within 2 weeks 60% within 1 month 90% within 3 months Yokoyama A, et al. J Toxicol Sci. 1996;21(1): PMID:

19 Risk Factors for Antiviralrelated Depression in Patients With HCV Infection High baseline levels of interleukin 7 Female History of major depression History of psychiatric disorder Subthreshold depressive symptoms Low education level Udina M, et al. J Clin Psychiatry. 2012;73(8): PMID:

20 Proposed Mechanisms of IFN-induced Depression Most likely to be multifactorial IFN Downregulates glucocorticoid receptors on immune cells glucocorticoids are unable to suppress the immune system, resulting in! Overexpression of proinflammatory cytokines! Hypersecretion of glucocorticoids Serotonin metabolism dysregulation! IFN and IL-1 Upregulate serotonin transport protein, resulting in decreased 5-hydroxytriptamine levels! Cytokines Upregulate indoleamine 2,3 deoxygenase production, resulting in decreased central serotonin production Papafragkakis H, et al. Int J Interferon, Cytokine Mediator Res. 2012;4:25-35.

21 Proposed Mechanisms of INF-induced Depression IFN-alpha decrease in tryptophan (TRP) and increase in kynurenine, resulting in the production of toxic neuroactive metabolites 1 IFN-alpha decrease in serum dipeptidyl peptidase IV (a membrane serine that modulates T-cell activity) that has been associated with higher MADRS and HAM-A scores and increased kynurenine/trp ratios and increased IL-8 1 Overproduction of reactive oxygen species 2 Alterations in cerebral metabolism 2! Decreased metabolism in prefrontal regions! Increased metabolism in putamen and left occipital lobes MADRS = Montgomery-Åsberg Depression Rating Scale; HAM-A = Hamilton Anxiety Scale; IL = interleukin 1. Papafragkakis H, et al. Int J Interferon, Cytokine Mediator Res. 2012;4: Juengling FD, et al. Psychopharmacology (Berl). 2000;152(4): PMID:

22 Outcomes of Poorly Treated or Unrecognized Depression in HCV Infection Denial of need for antiviral therapy for HCV Exacerbation of other (physical) side effects of antiviral therapy Poor adherence with treatment regimen, lab monitoring, etc., leading to poor response to antiviral agents Reduced quality of life Increased risk of substance abuse especially concerning with alcohol Other known complications of depression not unique to the depression caused by IFN Suicidal thoughts or behavior Sockalingam S, Abbey SE. Can J Psychiatry. 2009;54(9): PMID:

23 Psychiatric Illness and Substance Abuse - Barriers to IFN Treatment Patients with HIV and HCV who were ineligible for treatment with IFN 26% due to severe psychiatric illness! 20% due to drug or alcohol abuse! 4% due to both substance abuse and psychiatric illness Taylor LE, et al. AIDS. 2002;16(12):

24 Psychiatric Illness and Substance Abuse - Barriers to IFN Treatment 293 patients evaluated for treatment of HCV infection 72% were excluded! 34% due to a medical or psychiatric contraindication! Psychiatric illness was the most frequent! 13% due to substance abuse! 37% due to noncompliance! Complicating factors! Failed to have blood drawn! Missed more than 2 appointments! Homelessness! Incarceration Falck-Ytter Y, et al. Ann Intern Med. 2002;136(4): PMID:

25 Treatment of IFN-induced Depression Gleason 1! 3 patients responsive to antidepressant therapy (imipramine, sertraline, paroxetine)! 2 patients nonresponsive (sertraline and paroxetine) Schramm 2! Series of 10 patients with IFN-induced depression responsive to sertraline Kraus 3! Eleven of 14 patients who developed depression during IFN therapy responded to treatment with paroxetine and were able to complete IFN therapy 1. Gleason OC, Yates WR. Psychosomatics. 1999;40(6): PMID: Schramm TM, et al. Med J Aust. 2000;173(7): PMID: Kraus MR, et al. Aliment Pharmacol Ther. 2002;16(6): PMID:

26 Prospective Open-label Study of Citalopram for the Treatment of IFN-induced Depression 39 patients with HCV infection undergoing IFN therapy! Weekly Beck Depression Inventory! 13 patients (39%) developed major depressive disorder! Mean time of onset of depression, 12 weeks! 11 of the 13 (85%) patients responded to citalopram Hauser P, et al. Mol Psychiatry. 2002;7(9): PMID:

27 An Open-Label Trial of Citalopram for Major Depression in HCV Infection Community population recruited by advertisement or referred by local physicians Fifteen adults (18-65 y/o) HCV infection and major depressive disorder Given citalopram at a mean dose of mg/day Measured HAM-D scores, SF-36, SCL-90, and CGI- Severity Thirteen subjects experienced >50% reduction in HAM-D scores! No significant changes in liver function test HAM-D, Hamilton Depression Rating Scale; SCL = Symptom Checklist; CGI = Clinical Global Impression Gleason OC, et al. J Clin Psychiatry. 2002;63(3): PMID:

28 HAM-D Scores in Patients with Hepatitis C Infection 25 Citalopram HamD p = Baseline Visit 3 Visit 4 HAM-D = Hamilton Depression Rating Scale Gleason OC, et al. J Clin Psychiatry. 2002;63(3): PMID:

29 SF-36 Ratings in Patients with Hepatitis C Infection Role Limitations due to Physical Health Baseline Visit 4 Role Limitations Due to Emotional Health Gleason OC, et al. J Clin Psychiatry. 2002;63(3): PMID:

30 SF-36 Ratings in Patients with Hepatitis C Infection Social Functioning Baseline Visit 4 Emotional Well-being Gleason OC, et al. J Clin Psychiatry. 2002;63(3): PMID:

31 Liver Function Tests in Patients with Hepatitis C Infection 70 Baseline Visit AST ALT GGT AST = asparatate transaminase; ALT = alanine aminotransferase; GCT = gamma glutamyl transferase. Gleason OC, et al. J Clin Psychiatry. 2002;63(3): PMID:

32 Escitalopram for Major Depression in HCV Infection: HAM-D Scores 25 Escitalopram HamD Baseline Visit 2 Visit 3 Visit 4 HAM-D, Hamilton Depression Rating Scale. Gleason OC, et al. Prim Care Companion J Clin Psychiatry. 2005;7(5): PMID:

33 Escitalopram for Major Depression in Hepatitis C Infection: SF-36 Measures Emotional Wellbeing p =.002 Pain p =.01 Social Fxn p = Baseline Visit 4 Gleason OC, et al. Prim Care Companion J Clin Psychiatry. 2005;7(5): PMID:

34 Escitalopram for Major Depression in Hepatitis C: SCL-90 Measures Anxiety p =.004 Obsessive Compulsive p =.03 Interpersonal Sensitivity p =.002 Baseline Visit 4 SCL = Symptom Checklist. Gleason OC, et al. Prim Care Companion J Clin Psychiatry. 2005;7(5): PMID:

35 Escitalopram for Major Depression in Hepatitis C: Liver Function Tests 60 Baseline Visit AST ALT GGT AST = asparatate transaminase; ALT = alanine aminotransferase; GCT = gamma glutamyl transferase Gleason OC, et al. Prim Care Companion J Clin Psychiatry. 2005;7(5): PMID:

36 An Open-label Trial of Escitalopram for Prophylaxis of Major Depression in HCV Infection Before and During Combination Therapy with Pegylated IFN and Ribavirin Hypothesis: A patient with a past history of depression, not currently depressed, can successfully undergo a course of pegylated-ifn and ribavirin therapy if first treated with the antidepressant escitalopram. Methods: Ten patients were started on treatment with escitalopram before they began antiviral therapy and were followed throughout the course of antiviral therapy. Results: Depression remained in remission in 9 of the 10 patients; 6 patients completed the entire course of antiviral therapy. Gleason OC, et al. Dig Dis Sci. 2007;52(10): PMID:

37 Putting it all together.

38 Psychiatrist s Role Be conversant with the basic facts of IFN-alpha and ribavirin treatments Serve as the patient s advocate! Evaluate each patient and estimate his or her psychiatric risk, and communicate your findings with the physician treating the HCV infection! Treat the patient s underlying psychiatric illness; stabilize before beginning IFN therapy! Closely monitor the patient for recurrence of psychiatric illness during IFN therapy! Appropriately treat IFN-emergent psychiatric disorders

39 Goals of the Psychiatric Evaluation Assess for active psychiatric symptoms! Depression! Anxiety! Mania/hypomania! Psychosis Assess for active substance use! Alcohol! Opiates, stimulants, sedatives, cannabis, others Review past psychiatric history (diagnoses, suicide attempts, hospitalization) Evaluate current support systems Assess psychiatric risk and make recommendation whether or not to begin or continue IFN Provide psychoeducation! Psychiatric symptoms (particularly depression) related to IFN! Psychiatric emergency procedures! Educate family as well, if patient authorizes Treatment or provide treatment recommendationss

40 Pretreatment Assessment of Patients with HCV Infection: The Role of Integrated Care Work alongside gastroenterologists in deciding whether to offer IFN-alpha and ribavirin treatment to the patient Perform a multidisciplinary, pretreatment risk-benefit assessment of! Predictors of viral clearance! Likelihood of IFN-alpha and ribavirin-induced neuropsychiatric adverse effects! Patient s treatment preferences! Available psychosocial resource Seize the opportunity to reinforce patients knowledge of their disease and its treatment

41 HCV Infection / IFN-induced Depression: Management Prevention/ Early Detection! Review psychiatric history! Perform a retreatment psychiatric evaluation! Initiate antidepressant therapy in appropriate cases! Educate the patient! Listen to the patient many feel a sense of doom, guilt, contamination, and loss of control

42 HCV Infection / IFN-induced Depression: Management Treatment Options! Antidepressant therapy - dose/duration! Reduce the dose of or discontinue IFN! Individual or group psychotherapy may be helpful! Combination therapy or electroconvulsive therapy may be necessary in refractory cases! Referral for substance abuse treatment

43 Counseling of Patients with Psychiatric Illness and HCV Infection Offer HIV testing! 5%-10% of patients with HCV infection are co-infected with HIV Provide counseling about the need to! Prevent the spread of HCV to others! HCV can be transmitted through common household objects such as toothbrushes, shaving utensils, and other personal items.! Safe sex practices should include the use of barrier protection! Most importantly eliminate alcohol use! Alcohol, even in moderation, can accelerate the progression of HCVinduced liver disease or cirrhosis Outline treatment options

44 Patient Education

45 Clinical Connections HCV is common Depression is prevalent in HCV population IFN can induce depression It is important to treat depression in HCV Psychiatric consultant plays an important role in the management of the patient with HCV

46 Questions & Answers

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