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  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; MDD, major depressive disorder.
  • IFN, interferon.
  • pegIFN, peginterferon; MADRS, Montgomery Åsberg Depression Rating Scale; MFI, Multidimensional Fatigue Inventory; RBV, ribavirin.
  • pegIFN, peginterferon; RBV, ribavirin.
  • ACTH, adrenocorticotropic hormone; HPA, Hypothalamic-Pituitary-Adrenal; IFN, interferon; IL-6, interleukin-6; MDD, major depressive disorder.
  • CNS, central nervous system.
  • IFN, interferon.
  • PegIFN, peginterferon; RBV, ribavirin; SDS, Zung self-rating depression scale.
  • HTR1A, 5-hydroxytryptamine (serotonin) receptor 1A; IFN, interferon; HADS, Hospital Anxiety and Depression Scale.
  • IFN, interferon; RBV, ribavirin.
  • IFN, interferon; HADS-D, Hospital Anxiety and Depression Scale; PegIFN, peginterferon.
  • PegIFN, peginterferon; RBV, ribavirin.
  • IFN, interferon; RBV, ribavirin; SDS, Zung Self-rating Depression Scale.
  • RBV, ribavirin.
  • SVR, sustained virologic response.
  • EOT, end of treatment; pegIFN, peginterferon; Pts, patients; RBV, ribavirin; SVR, sustained virologic response.
  • PegIFN, peginterferon; RBV, ribavirin; SDS, Zung Self-Rating Depression Scale .
  • CES-D, Center for Epidemiologic Studies Depression Scale; IV, intravenous; SVR, sustained virologic response.
  • IFN, interferon; PegIFN, peginterferon; SVR, sustained virologic response.
  • IFN, interferon.
  • IFN, interferon.
  • GT, genotype; IDEAL, Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy; IFN, interferon; PegIFN, peginterferon; Tx, treatment.
  • MADRS, Montgomery Åsberg Depression Rating Scale; pegIFN, peginterferon; RBV, ribavirin.
  • DSM, Diagnostic and Statistical Manual of Mental Disorders.
  • DSM, Diagnostic and Statistical Manual of Mental Disorders.
  • ICD-10, International Statistical Classification of Diseases and Related Health Problems 10th Revision.
  • BDI, Becks Depression Inventory; DSM-IV, Diagnostic and statistical manual of mental disorders, Fourth Edition ; HADS, Hospital Anxiety and Depression Scale; HAMD, Hamilton Depression Scale; MADRS, Montgomery-Åsberg Depression Scale; SCID, Structured Clinical Interview; Z-SDS, Zung Self-Rating Depression Scale.
  • IFN, interferon.
  • AUDIT, alcohol use disorders identification screen; CAGE, CAGE assessment; SVR, sustained virologic response.
  • IFN, interferon; Pts, patients; SSRIs, selective serotonin reuptake inhibitors.
  • IFN, interferon.
  • IFN, interferon; MADRS, Montgomery Åsberg Depression Rating Scale; MDD, major depressive disorder; RBV, ribavirin.
  • HADS, Hospital and Anxiety Depression Scale; SSRI, selective serotonin reuptake inhibitor.
  • BDI, Becks Depression Inventory; HAMD-17, Hamilton Depression Rating Scale ; MADRS, Montgomery Åsberg Depression Rating Scale ; SSRIs, selective serotonin reuptake inhibitors.
  • IFN, interferon; F/U, follow-up; HADS, Hospital Anxiety and Depression Scale; NS, not significant; RBV, ribavirin.
  • IFN, interferon.
  • IFN, interferon; SSRIs, selective serotonin reuptake inhibitors.
  • RBV, ribavirin.
  • GI, gastrointestinal; IFN, interferon; TCAs, tricyclic antidepressants; SSRIs, selective serotonin reuptake inhibitor; WBC, white blood cell.
  • IFN, interferon; SSRI, selective serotonin reuptake inhibitor.
  • IFN, interferon; SSRI, selective serotonin reuptake inhibitor.
  • PegIFN, peginterferon.
  • RVR, rapid virologic response.
  • IFN, interferon; RBV, ribavirin.

    1. 1. Michael R. Kraus, MD, PhD Associate Professor of Medicine Department of Gastroenterology and Hepatology Medizinische Klinik II Kreiskliniken Altötting – Burghausen Burghausen, Germany Answering the Questions: Depression Related to HCV and Its Treatment This program is supported by an educational grant from
    2. 2. About These Slides <ul><li>Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent </li></ul><ul><li>These slides may not be published or posted online without permission from Clinical Care Options </li></ul><ul><li>We are grateful to Michael R. Kraus, Medizinische Klinik II, Kreiskliniken Altötting – Burghausen, Burghausen, Germany , who aided in the content creation of these slides </li></ul>Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
    3. 3. Epidemiology and Mechanisms How common is depression in HCV-infected patients and among patients receiving HCV therapy? What is known about the mechanism of depression development in these 2 instances?
    4. 4. Depression More Common in HCV Patients vs General Population <ul><li>Depression significantly more prevalent in chronically HCV-infected patients than in the general population [1] </li></ul><ul><li>Reported prevalence rates for MDD (according to DSM-IV ) [2-4] </li></ul><ul><ul><li>6% to 10% for the general population </li></ul></ul><ul><ul><li>24% to 70% for HCV-infected patients </li></ul></ul>1. Coughlan B, et al. Br J Health Psychol. 2002;7:105-116. 2. Lang CA, et al. J Pain Sym Manage. 2006;31:335-344. 3. Lee D, et al. Dig Dis Sci. 1997;42:186-191. 4. World Health Organization.
    5. 5. HCV May Lead to Changes in Brain Metabolism <ul><li>HCV infection leads to changes in brain metabolism and in the serotonin-dopamine transporter [1-5] </li></ul><ul><ul><li>Significant decrease in N-acetyl-aspartate/creatinine ratio [5] </li></ul></ul><ul><ul><li>Increased choline and decreased N-acetyl-aspartate levels [3] </li></ul></ul><ul><ul><li>Hypometabolism in the prefrontal cortex [6] </li></ul></ul><ul><ul><li>Significant reduction of regional cerebral blood flow in areas associated with memory and language function [7] </li></ul></ul>1. Forton DM, et al. AIDS. 2005;19:S53-S63. 2. Forton DM, et al. 2007 Hepatology. 2002;45;433-439. 3. McAndrews MP, et al. Hepatology. 2005;41:801-808. 4. Weissenborn K, et al. Metab Brain Dis. 2000;15:173-178. 5. Weissenborn K, et al. J Hepatol. 2004;41:845-851. 6. Juengling FD, et al. Psychopharmacology. 2000;152:383-389. 7. Tanaka H, et al. Clin Exp Med. 2006;6:124-128.
    6. 6. Variation Among Results of Studies Examining IFN-Related Depression <ul><li>Systematic review analyzed 21 clinical trials of HCV-infected patients experiencing IFN-related depression </li></ul><ul><ul><li>Definition of depression, treatment strategy, and duration differed among trials </li></ul></ul>Schafer A, et al. Int J Methods Psychiatr Res. 2007;16:186-201. 0 16 17 17 20 20 23 24 24 26 33 34 35 36 37 41 44 82 0 20 40 60 80 100 Mulder 2000 Davis 1998 Renault 1987 Scalori 2005 Hunt 1997 Pariente 1999 Horikawa 2003 Scalori 2000 Castera 2002 Schafer 2003 Hauser 2002 Bernstein 2002 Kraus 2003 McHutchinson 1998 Kraus 2005 Bonaccorso 2002 Miyaoka 1999 Reichenberg 2005 Patients With Depression (%)
    7. 7. Worsened Depression and Fatigue Scores Following HCV Treatment <ul><li>32 HCV-infected patients randomized to no treatment or pegIFN alfa-2a/2b + RBV </li></ul><ul><li>Depression and fatigue evaluated at baseline and at ~ 12 weeks </li></ul><ul><li>HCV treatment associated with development of depressive symptoms, fatigue </li></ul>P < .01 -10 -5 0 5 10 15 20 Depression (MADRS) Fatigue (MFI) Mean Change at Follow-up Majer M, et al. Brain Behav Immun. 2008;22:870-880. 8.1 -0.9 19.2 -4.0 P < .01 PegIFN + RBV (n = 20) Control (n = 12)
    8. 8. De Novo Depression in Patients Treated With PegIFN + RBV <ul><li>176 HCV-infected patients beginning pegIFN alfa-2a + RBV therapy evaluated for depressive and anxiety disorders at baseline and throughout treatment </li></ul><ul><ul><li>Patients with baseline mood disorders excluded (n = 30) </li></ul></ul><ul><li>High incidence of depression and anxiety syndromes during treatment </li></ul>Martin-Santos R, et al. Alimen Pharmacol Ther. 2008;27:257-265. Type of Depressive Disorder, % Patients Any depression or anxiety 37 Major depression 6 Major or minor depression 35 Anxiety with/without depression 11
    9. 9. HPA Axis Response to Interferon in Nondepressed Patients <ul><li>ACTH, cortisol, IL-6 levels evaluated in malignant melanoma patients following IFN administration (N = 14) </li></ul><ul><ul><li>Immediately before, and 1, 2, and 3 hours after IFN administration </li></ul></ul><ul><ul><li>Presence of major depression evaluated throughout therapy </li></ul></ul><ul><li>ACTH and cortisol levels following IFN injection higher in those who eventually developed MDD vs those who did not ( P < .01) </li></ul><ul><ul><li>No differences in IL-6 responses </li></ul></ul><ul><li>HPA axis response indicates a vulnerability to IFN-induced depression </li></ul>Capuron L, et al. Am J Psychiatry. 2003;160:1342-1345.
    10. 10. Epidemiology and Mechanisms What are the risk factors for developing depression during HCV therapy? Does a past history of depression increase risk of developing depression during HCV therapy?
    11. 11. Factors Possibly Influencing Depressive Symptoms in HCV Other Factors Therapy options Nonresponse Social support Host Factors Sex Time since diagnosis Comorbidities Age Viral Factors HCV RNA? HCV genotype? CNS involvement Kraus MR, et al. Psychosomatics. 2000;41:377-384. Loftis JM, et al. Drugs. 2006;2:155-178. McDonald EM, et al. Lancet. 1987;2:1175-1178. Viral Factors Viral load? HCV genotype? CNS involvement
    12. 12. Patient-Related Risk Factors for Depression During IFN-Based Therapy <ul><li>Key risk factor for depression during HCV therapy is presence of depressive symptoms right before antiviral treatment </li></ul><ul><li>Other factors that may be associated </li></ul><ul><ul><li>History of drug abuse </li></ul></ul><ul><ul><li>HIV coinfection </li></ul></ul><ul><ul><li>Older age </li></ul></ul><ul><ul><li>Organic brain impairment </li></ul></ul><ul><ul><li>Genetic polymorphisms in the serotonergic system </li></ul></ul><ul><li>Patient sex is risk factor for depression in the general population but is not risk factor for IFN-induced depression </li></ul>Raison CL, et al. J Clin Psychiatry. 2005;66:41-48. Capuron L, et al. N Engl J Med. 1999;340:1370. Kraus MR, et al. Gastroenterology. 2007;132:1279-1286. Martin-Santos R, et al. Aliment Pharmacol Ther. 2008; 27:257-265.
    13. 13. Depression History Associated With Depression at Baseline, on Treatment <ul><li>Patients with past history of depression had higher risk of </li></ul><ul><ul><li>Becoming depressed during pegIFN/RBV therapy </li></ul></ul><ul><ul><li>Having a higher depression score at baseline </li></ul></ul>Raison CL, et al. J Clin Psychiatry. 2005;66:41-48. 0 20 40 60 80 100 Past History of Depression Yes No Patients With SDS Index ≥ 60 on Treatment (%) Chi Square = 10.6, df = 1 P < .005 Yes Past History of Depression 30 40 50 60 Mean Depression Score at Baseline (SDS Index) No t = 4.5, P < .0001 64.5 32.8 48.7 40.3
    14. 14. HTR1A Polymorphism Predisposes Patients to IFN-Induced Depression <ul><li>HTR1A, serotonin receptor gene </li></ul><ul><ul><li>C1019G polymorphism linked with IFN-induced depression </li></ul></ul>HTR1A Max (Δ HADS) P = .011 C/C C/G G/G 0 2 4 6 Reprinted from Gastroenterology, 132, Kraus MR, Al-Taie O, Schäfer A, Pfersdorff M, Lesch K-P, Scheurlen M, Serotonin-1A Receptor Gene HTR1A Variation Predicts Interferon-Induced Depression in Chronic Hepatitis C, 1279-1286, Copyright (2007), with permission from Elsevier.
    15. 15. Epidemiology and Mechanisms Are depressive symptoms increased among patients receiving standard vs pegylated IFN? Is there an association between RBV use and depression? Are there any data on depression in patients receiving novel HCV therapies?
    16. 16. Rates of Depression With Standard vs PegIFN alfa-2b + Weight-Based RBV <ul><li>Little information on depression in patients receiving novel HCV treatments </li></ul>Kraus MR, et al. World J Gastroenterol. 2005;11:1769-1774. Conventional IFN (n = 48) PegIFN (n = 50) Total sample (N = 98) Clinically Relevant Scores for Depression (HADS-D) (Score ≥ 9) Patients (%) Evaluation Time Points Baseline Week 4 Months 3-4 Months 6-8 Week 4 Posttreatment 0 20 40 60 80 100
    17. 17. Depression Among Patients Receiving 48 vs 72 Weeks of PegIFN + RBV <ul><li>327 HCV-infected, treatment-naive patients with detectable HCV RNA after 4 weeks of pegIFN alfa-2a 180 μg/week plus ribavirin 800 mg/day randomized to continue treatment for 48 or 72 weeks </li></ul>Duration of Therapy (Weeks) 12 19 0 20 40 Patients (%) 60 80 100 48 72 Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451-460.
    18. 18. RBV Dose Associated With Depressive Symptom Scores During IFN Treatment Raison CL, et al. J Clin Psychiatry. 2005;66:41-48. Mean ( ± SE) SDS Index P < .01 Weight-Based RBV (800-1400 mg/day) Fixed-Dose RBV (800 mg/day) 46.8 0 20 40 60 51.5 n = 86 n = 76 80 100
    19. 19. ↑ Risk of Moderate/Severe Depressive Symptoms With Weight-Based RBV Raison CL, et al. J Clin Psychiatry. 2005;66:41-48. * P < .05 † P < .01 Risk of Moderate or Severe Depression According to RBV Dosage Risk Factor: RBV Dosage Weight-Based vs Fixed-Dose RBV Odds Ratio 95% CI Controlling for baseline depressive symptom score 2.4* 1.1-5.4 Not controlling for baseline depressive symptom score 2.7 † 1.3-5.6
    20. 20. Epidemiology and Mechanisms Are depressive symptoms at baseline and during therapy associated with lowered rates of adherence and lower rates of virologic response, including SVR?
    21. 21. EOT, SVR, and Dropout Rates Similar Between Controls and Psychiatric Pts <ul><li>70 HCV-infected patients prospectively evaluated for response to HCV therapy based on presence of psychiatric disease or drug addiction </li></ul><ul><ul><li>PegIFN alfa-2b + RBV administered for 24 weeks (genotypes 2/3) or 48 weeks (genotypes 1/4) </li></ul></ul>Schaefer M, et al. Hepatology. 2007; 46:991-998. 64 72 0 20 40 60 80 100 EOT SVR Dropout Psychiatric (n = 22) Methadone (n = 18) Former drug abuse (n = 13) Control (n = 17) 54 77 50 72 54 59 9 28 15 6 Patients (%)
    22. 22. Depressive Symptoms and Viral Clearance at 24 Weeks <ul><li>PegIFN alfa-2b 1.5 µg/kg/week + fixed-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV </li></ul><ul><li>Higher baseline SDS depression scores associated with lower rates of HCV RNA negativity at Week 24 ( P < .05) </li></ul>Raison CL, et al. Brain Behav Immun. 2005;19:23-27. Baseline SDS Depression Score, % HCV RNA Negative at Week 24 < 10 (n = 32) 69 10-19 (n = 41) 59 ≥ 20 (n = 29) 34
    23. 23. Depressive Symptoms, Virologic Outcome, and Treatment Adherence Guadagnino V, et al. Dig Liver Dis. 2006;38:119-124. Patients with higher CES-D depression scores at baseline and Month 1 were less likely to achieve SVR vs patients with lower CES-D scores Predictors of SVR in Univariate Model Variables SVR (n = 25) Nonresponse (n = 18) Odds Ratio (95% CI) P Value Mean age, yrs ± SD 29.9 ± 6.1 36.9 ± 6.5 0.83 (0.73-0.94) .004 Mean duration of IV drug addiction, mos ± SD 71.4 ± 52.13 137.8 ± 76.8 0.98 (0.97-0.99) .006 HCV genotype 1 or 4, % 32.0 66.7 0.24 (0.06-0.86) .03 <ul><li>CES-D score </li></ul><ul><li>Baseline </li></ul><ul><li>Month 1 </li></ul><ul><li>Month 3 </li></ul>14.68 ± 8.71 14.0 ± 6.91 15.86 ± 8.43 21.43 ± 13.31 25.18 ± 11.91 22.87 ± 13.86 0.94 (0.88-1.01) 0.88 (0.80-0.97) 0.93 (0.86-1.02) .09 .008 .13
    24. 24. Conflicting Results on Impact of IFN-Induced Depression on SVR Rates <ul><li>28.5% of 39 patients developing major depression on IFN-based therapy attained SVR vs only 11.5% of patients without depression [1] </li></ul><ul><ul><li>Possible caveat: high rate of antidepressant use in group of patients with major depression </li></ul></ul><ul><li>Depression did not predict response in the 64% of 29 pegIFN-treated patients who achieved SVR [2] </li></ul><ul><ul><li>Depression may adversely effect SVR rates due to need for dose reductions or discontinuations </li></ul></ul><ul><ul><li>Conversely, high HCV RNA due to nonresponse possibly associated with inflammation and cytokine release, which induces fatigue and depression [3] </li></ul></ul>1. Loftis JM, et al. Neurosci Lett. 2004;365:87-91. 2. Maddock C, et al. Mol Psychiatry. 2005;10:332-333. 3. Raison CL, et al. Brain Behav Immun. 2005;19:23-27. Depression Associated With Increased SVR Depression Associated With Decreased SVR
    25. 25. Epidemiology and Mechanisms Is depression occurrence during HCV therapy dependent on IFN dose received?
    26. 26. IFN Dose May Increase Incidence of Depression, Further Data Needed <ul><li>Evidence suggests higher IFN doses increase risk of cytokine-induced depression </li></ul><ul><ul><li>Both dosage and duration (cumulative dose) increase risk of depression </li></ul></ul><ul><ul><li>Linear relationship: higher IFN dose generally correlates with more severe depression </li></ul></ul><ul><li>Association remains to be confirmed by future prospective studies </li></ul>Schafer M, et al. Int J Methods Psychiatr Res. 2007;16:186-201. Raison CL, et al. CNS Drugs. 2005;19:105-123. Raison CL, et al. Trends Immunol. 2006;27:24-31.
    27. 27. IDEAL: Depression With Standard IFN vs Standard- vs High-Dose PegIFN Week 72 Tx-naive genotype 1 HCV – infected patients (N = 3070) PegIFN alfa -2b 1.5 µg/kg/week + RBV 800-1400 mg/day (n = 1019) PegIFN alfa-2b 1.0 µg/kg/week + RBV 800-1400 mg/day (n = 1016) PegIFN alfa- 2a 180 µg/week + RBV 1000-1200 mg/day (n = 1035) Week 48 24-Week Follow-up Incidence of Depression* 26 19 21 0 20 40 Patients (%) 60 80 100 Sulkowski M, et al. EASL 2008. Abstract 919. * P value not reported.
    28. 28. Screening and Identification of Depression What is the typical time course of HCV treatment adverse effects, including psychiatric adverse effects?
    29. 29. Time Course of Treatment-Associated Psychiatric Adverse Effects Months Incidence/Severity Depression Fatigue Influenza-like symptoms 1 2 3 4 0 0 20 40 60 80 100 Dan A, et al. J Hepatol. 2006;44:491-498. Constant A, et al. J Clin Psychiatry. 2005;66:1050-1057.
    30. 30. Time Course of Mood Changes in Patients Treated With PegIFN + RBV <ul><li>17 patients without psychiatric diseases or drug addiction treated with pegIFN + RBV </li></ul><ul><li>Majority of depressive symptoms occurred during first 1-3 months of HCV therapy </li></ul>*P < .001 vs baseline. 3.65 13.12* 16.94 12.88 0 5 10 15 20 25 30 Baseline 1 Month 3 Months 6 Months Mean MADRS Score Schaefer M, et al. Hepatology. 2007; 46:991-998.
    31. 31. Persistence of Psychiatric Symptoms After Discontinuation of HCV Therapy <ul><li>Symptoms often reversible </li></ul>Persistent adverse effects common up to 3 months after discontinuation According to clinical experience, in some cases, symptoms persist over years (depression, cognitive disturbance) Discontinuation of IFN ± RBV Meyers, CA. Neurology. 1991;41:672-676. Dieperink E, et al. Am J Psychiatry. 2000;157:867-876.
    32. 32. Screening and Identification of Depression What are the tools available for diagnosing depression? How is depression defined by each of the screening tools? At what scores is treatment warranted? How should patients be screened for depression before and during therapy?
    33. 33. Diagnostic Instruments: DSM-IV Criteria for Major Depression <ul><li>Presence of ≥ 1 of the elements below for ≥ 2 weeks </li></ul><ul><li>It is sufficient to have only 1 of these plus </li></ul><ul><ul><li>≥ 4 additional symptoms listed in the next slide over a 2-week period </li></ul></ul>APA. Diagnostic and statistical manual of mental disorders revision IV-TR, 4th ed. 2000. or Depressed mood Anhedonia
    34. 34. Diagnostic Instruments: DSM IV Criteria for Major Depression (cont’d) <ul><li>Feelings of overwhelming sadness and/or fear or emptiness </li></ul><ul><li>Decrease in the amount of interest or pleasure in all, or most, daily activities </li></ul><ul><li>Changing appetite and marked weight gain or loss </li></ul><ul><li>Disturbed sleep patterns </li></ul><ul><li>Psychomotor agitation or retardation nearly every day </li></ul><ul><li>6. Fatigue, mental or physical; also loss of energy </li></ul>7. Intense feelings of guilt, helplessness, hopelessness, worthlessness, isolation/loneliness, and/or anxiety 8. Trouble concentrating, keeping focus, or making decisions, or a generalized slowing and obtunding of cognition, including memory 9. Recurrent thoughts of death (not just fear of dying), desire to just “ lay down and die ” or “ stop breathing, ” recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide APA. Diagnostic and statistical manual of mental disorders revision IV-TR, 4th ed. 2000.
    35. 35. Diagnostic Instruments: ICD-10 Criteria for Depression <ul><li>Mild: 2 typical symptoms + 2 additional symptoms </li></ul><ul><li>Moderate: 2 typical symptoms + ≥ 3 additional symptoms </li></ul><ul><li>Severe: 3 typical symptoms + ≥ 4 additional symptoms </li></ul>WHO. Available at: Typical Symptoms Additional Symptoms <ul><li>Depressed mood </li></ul><ul><li>Loss of interest and enjoyment </li></ul><ul><li>Reduced energy leading to increased fatigability and diminished activity </li></ul><ul><li>Reduced concentration and attention </li></ul><ul><li>Reduced self-esteem and self-confidence </li></ul><ul><li>Ideas of guilt and unworthiness </li></ul><ul><li>Bleak and pessimistic views of the future </li></ul><ul><li>Ideas or acts of self-harm or suicide </li></ul><ul><li>Disturbed sleep </li></ul><ul><li>Diminished appetite </li></ul>
    36. 36. Screening Instruments for Depression: Physician Rating Scales <ul><li>Depression scales can be used before and during treatment to assess baseline, changes in symptoms </li></ul>Hamilton Depression Rating Scale (HAM-D) Montgomery-Åsberg Depression Rating Scale (MADRS) 21 items; gold standard symptom severity measure in clinical trials 10 items; commonly used in antidepressant trials <ul><li>Mild depression: ≥ 8-14 </li></ul><ul><li>Moderate depression: ≥ 15-24 </li></ul><ul><li>Severe depression: ≥ 25 </li></ul><ul><li>Mild depression: ≥ 10-13 </li></ul><ul><li>Moderate depression: ≥ 18-20 </li></ul><ul><li>Severe depression: ≥ 32 </li></ul>
    37. 37. Screening Instruments for Depression: Self-Rating Scales <ul><li>Depression scales can be used before and during treatment to assess baseline, changes in symptoms </li></ul>Center for Epidemiologic Studies Depression Scale (CES-D) Zung Depression Scale (SDS) Hospital Anxiety and Depression Scale (HADS) Beck Depression Inventory (BDI) 20 items; most frequently used in hepatology setting 20 items; requires index scoring conversion 14 items; self report 21 items; patient administered <ul><li>Mild depression: ≥ 16-26 </li></ul><ul><li>Moderate/severe depression: ≥ 27 </li></ul><ul><li>Mild depression: ≥ 50-59 </li></ul><ul><li>Moderate depression: ≥ 60-69 </li></ul><ul><li>Severe depression: ≥ 70 </li></ul><ul><li>Clinically relevant ≥ 9 </li></ul><ul><li>Mild depression: ≥ 10-11 </li></ul><ul><li>Moderate depression: ≥ 17 </li></ul><ul><li>Severe depression: ≥ 27-30 </li></ul>
    38. 38. How to Use Diagnostic Scales <ul><li>Depression rating scales </li></ul><ul><ul><li>Show changes in depressive symptoms over time </li></ul></ul><ul><ul><li>Try to quantify the severity of depressive symptoms </li></ul></ul><ul><li>Diagnosis of a “major depression” must be confirmed by diagnostic criteria </li></ul><ul><ul><li>DSM-IV </li></ul></ul><ul><ul><li>ICD-10 </li></ul></ul><ul><ul><li>Or using the SCID as a diagnostic interview </li></ul></ul><ul><li>To diagnose major depression – specific symptoms, they must be present over a period of ≥ 14 days </li></ul>APA. Diagnostic and statistical manual of mental disorders revision IV-TR, 4th ed. 2000. Iannuzzo RW, et al. Psychiatry Res. 2006;145:21-37. Shafer AB. J Clin Psychol. 2006;62:123-146.
    39. 39. When to Assess Depression in Patients Beginning HCV Therapy <ul><li>Initial evaluation </li></ul><ul><ul><li>Immediately prior to start of IFN treatment </li></ul></ul><ul><li>On-treatment screening </li></ul><ul><ul><li>At least every 8 weeks (preferably every 4 weeks) throughout the whole period of antiviral treatment </li></ul></ul><ul><li>In the case of depressive events or the onset of antidepressant treatment </li></ul><ul><ul><li>More frequently evaluations indicated </li></ul></ul><ul><ul><ul><li>At least weekly in the initial phase </li></ul></ul></ul>
    40. 40. Screening and Identification of Depression How should patients with current and past alcohol or substance abuse and HCV infection be screened for depression and managed?
    41. 41. Active Alcohol Use Should Be Moderated if Possible <ul><li>Current guidelines strongly recommend complete abstinence from alcohol during therapy </li></ul><ul><ul><li>Consider screening: CAGE, AUDIT </li></ul></ul><ul><ul><li>Patients with history of alcohol use should not be excluded from HCV therapy </li></ul></ul><ul><li>Recent alcohol use associated with higher rates of treatment discontinuation and lower SVR rates [1] </li></ul><ul><ul><li>Patients who use alcohol and complete treatment may have comparable SVR rates to nondrinkers </li></ul></ul><ul><li>Engage problem alcohol users during care to maximize their ability to complete treatment </li></ul><ul><ul><li>Treatment programs </li></ul></ul><ul><ul><li>Disulfiram—watch for hepatotoxicity </li></ul></ul><ul><ul><li>Acamprosate </li></ul></ul>1. Anand BS, et al. Gastroenterology. 2006;130:1607-1616.
    42. 42. Patients With Psychiatric Risk Factors Require Interdisciplinary Treatment <ul><li>Drug abuse disorders </li></ul><ul><ul><li>Methadone treatment improves adherence and compliance [1-2] </li></ul></ul><ul><ul><li>Recent studies suggest that buprenorphine [3-5] and naltrexone [6] improve adherence and response rates </li></ul></ul><ul><li>Psychiatric disorders </li></ul><ul><ul><li>Pretreatment with citalopram or mirtazapine reduces depressive episodes during treatment [7] </li></ul></ul>1. Mauss S, et al. Hepatology. 2004;40:120-124. 2. Schaefer M, et al. Hepatology. 2008;46:991-998. 3. Belfiori B, et al. Gastroenterol Hepatol. 2007;19:731-732. 4. Bruce RD, et al. Am J Drug Alcohol Abuse. 2007;33:869-874. 5. Krook AL, et al. Eur Addict Res. 2007;13:216-221. 6. Jeffrey GP, et al. Hepatology. 2007;45:111-117. 7. Schaefer M, et al. J Hepatol. 2005;42:793-798.
    43. 43. Prevention of Depression When is prophylactic treatment for depression recommended in HCV patients with or without a history of depression? Are there nonpharmaceutical methods for preventing depression?
    44. 44. Managing Psychiatric Issues During HCV Treatment <ul><li>Education, monitoring, and support </li></ul><ul><ul><li>Information and psychoeducation before and during treatment </li></ul></ul><ul><ul><li>Monitoring of patients and psychiatric issues </li></ul></ul><ul><ul><li>Supportive psychotherapy </li></ul></ul><ul><ul><li>Regulation of sleep </li></ul></ul><ul><li>Pharmaceutical strategies </li></ul><ul><ul><li>Antidepressant treatment </li></ul></ul><ul><ul><li>Other treatments: antipsychotics, benzodiazepines (mood stabilizers, amphetamines, naltrexone, tryptophan, etc) </li></ul></ul><ul><ul><li>Antiviral therapy dose reduction, discontinuation as needed </li></ul></ul>
    45. 45. Prophylactic Antidepressant Therapy Should Be Considered in Subset of Pts <ul><li>Prophylactic treatment for depression indicated in </li></ul><ul><ul><li>Patients with previous IFN-associated depression [1] </li></ul></ul><ul><ul><li>Patients with increased depression scores immediately prior to initiation of IFN therapy [2,3] </li></ul></ul><ul><ul><li>Potentially also those with a demonstrated genetic risk for developing treatment-associated mood disorders or depression [4] </li></ul></ul><ul><li>Prophylactic treatment for patients starting HCV treatment generally not recommended </li></ul><ul><ul><li>Patients not developing IFN-induced depression (vast majority) would be unnecessarily exposed to SSRIs and their potential additional adverse effects </li></ul></ul>1. Kraus MR, et al. J Viral Hepatol. 2005;12:96-100. 2. Raison CL, et al. J Clin Psychiatry. 2005;62:41-48. 3. Hauser P, et al. Mol Psychiatry 2002;7:942-947. 4. Kraus MR, et al. Gastroenterology. 2007;132:1279-1286.
    46. 46. Early Studies: Benefit of Prophylactic Treatment for IFN-Induced Depression <ul><li>40 malignant melanoma patients received paroxetine or placebo starting 2 weeks before IFN therapy and continuing throughout treatment </li></ul><ul><ul><li>Reduced incidence of depression (P = .04) </li></ul></ul><ul><li>Fewer cases of depression requiring HCV treatment discontinuation ( P = .03) with paroxetine pretreatment </li></ul><ul><ul><li>Pretreatment with paroxetine associated with lower incidence of fear, cognitive impairment, and pain </li></ul></ul><ul><ul><li>Paroxetine did not reduce or prevent symptoms such as fatigue, sleeping disturbances, anhedonia, or irritability </li></ul></ul>Musselman DL, et al. N Engl J Med. 2001;344:961-966. Capuron L, et al. Neuropsychopharmacology. 2002;26:643-652.
    47. 47. Prophylactic Treatment Reduced Depression Symptom Severity <ul><li>Prospective, double-blind trial compared paroxetine vs placebo for 2 weeks before IFN + RBV therapy (N = 61) </li></ul><ul><li>No difference in rates of MDD with paroxetine vs placebo (13% vs 21%; P = .71) </li></ul><ul><li>Depression symptom severity reduced with use of paroxetine among patients with elevated baseline depressive symptoms </li></ul>Raison CL, et al. Aliment Pharmacol Ther. 2007;25:1163-1174. *P = .02 Placebo (n = 33) Paroxetine* (n = 28) Normal (MADRS < 15) Mild (MADRS ≥ 15 ) Moderate (MADRS ≥ 25) Severe (MADRS ≥ 31) 0 20 40 60 80 100 17 57 35 55 9 21 0 7 Patients (%) Rates of Mild, Moderate, Severe, Depression During IFN/RBV Therapy
    48. 48. Use of SSRI Pretreatment in Patients Receiving HCV Retreatment <ul><li>Patients experiencing major depression during first course of HCV treatment received SSRI pretreatment when retreated for HCV (N = 8) </li></ul><ul><ul><li>Reduced depressive symptoms severity with retreatment ( P = .036) </li></ul></ul>Kraus MR, et al. J Viral Hepatitis. 2005;12:96-100. 0 2 4 6 8 10 12 14 t1 t2 t3 t4 t5 Time Point of Examination HADS Depression Score First therapy Retreatment with SSRI
    49. 49. Antidepressant Use During HCV Therapy What are the preferred treatments for depression and why? What are the dosing schedules? How should psychotherapy be incorporated?
    50. 50. SSRIs Most Effective for IFN-Induced Depression <ul><li>Efficacy with SSRIs across multiple studies </li></ul>1. Gleason OC, et al. Prim Care Companion J Clin Psychiatry. 2005;7:225-230. 2. Schaefer M, et al. J Hepatol. 2005;42:793-798. 3. Hauser P, et al. Mol Psychiatry. 2002;7:942-947. 4. Kraus MR, et al. Aliment Pharmacol Ther. 2002;16:1091-1099. *In the case of nonresponse to the antidepressant, citalopram dose was elevated to 40 mg/day or citalopram up to 30 mg/day was combined with mirtazapine. Reference N Treatment Definition of Response Response, % Gleason [1] 18 Escitalopram 10-20 mg/day ≥ 50% reduction in HAMD-17 score 88.2 Schaefer [2] 14 Citalopram 20 mg/day* ≥ 40% reduction in MADRS score after 3 weeks 86.0 Hauser [3] 39 Citalopram 20-60 mg/day ≥ 50% reduction in BDI score 85.0 Kraus [4] 14 Paroxetine 20 mg/day Able to complete HCV therapy 78.6
    51. 51. Improved Depression Scores With Citalopram During HCV Treatment <ul><li>First prospective, controlled trial of citalopram 20 mg/day vs placebo for depression during HCV treatment with pegIFN + RBV </li></ul>HADS Depression Score Placebo (n = 14) Citalopram (n = 14) Baseline Depression Diagnosis 1 wk f/u 2 wks f/u 4 wks f/u After IFN Therapy 2 4 6 8 10 12 14 Citalopram Treatment Period P = NS P = .025 P = .016 Kraus MR, et al. Gut. 2008;57:531-536.
    52. 52. Patients With Psychiatric Problems: During HCV Therapy <ul><li>Psychiatric visits </li></ul><ul><ul><li>Every 2-4 weeks for first 3 months </li></ul></ul><ul><ul><li>Then every 4-8 weeks </li></ul></ul><ul><li>Encourage patient and confidant (relative, friend, etc) to look for psychiatric changes and in self-rating scores </li></ul>Loftis J, et al. Drugs. 2006;66:155-174. Raison C, et al. CNS Drugs. 2005;19:105-123.
    53. 53. Antidepressant Use During HCV Therapy How can a clinician determine if an antidepressant is effective? When should antidepressants be switched or an additional antidepressant added? How should patients starting depression treatment during HCV therapy be managed once HCV therapy is stopped?
    54. 54. Use of Antidepressants for IFN-Induced Depression <ul><li>Initiate antidepressants at lowered doses to reduce adverse events and increase adherence </li></ul><ul><li>Therapeutically relevant antidepressive effect can be expected at Day 8-14 of treatment </li></ul><ul><li>Adverse effects generally appear in first 8 days </li></ul><ul><li>In case of nonresponse </li></ul><ul><ul><li>Assess adherence </li></ul></ul><ul><ul><li>Monitor serum levels to determine if dose escalation is needed </li></ul></ul><ul><ul><li>Switch or add if current drug found to be ineffective </li></ul></ul><ul><ul><ul><li>Combination of 2 antidepressants with a different profile can be considered (eg, citalopram and mirtazapine) </li></ul></ul></ul>Raison C, et al. CNS Drugs. 2005;19:105-123. 61. Schaefer M, et al. Neuropsychobiology. 2000;42(suppl 1):43-45.
    55. 55. Patients With Psychiatric Problems: Management After HCV Therapy <ul><li>Continue antidepressant treatment ≥ 3 months after the end of HCV treatment </li></ul><ul><ul><li>Reduce the dosage of antidepressant slowly </li></ul></ul><ul><li>Attend to mental changes ≥ 6 months after end of HCV treatment </li></ul>Loftis J, et al. Drugs. 2006;66:155-174. Raison C, et al. CNS Drugs. 2005;19:105-123.
    56. 56. Antidepressant Use During HCV Therapy Are there antidepressant treatments that also manage specific symptoms (ie, fatigue or insomnia)? How should fatigue and insomnia be managed in patients not showing extensive depressive symptoms? What is the contribution of thyroid dysfunction?
    57. 57. Other Symptoms During IFN Treatment <ul><li>Sleep disturbances </li></ul><ul><ul><li>Administration of sleep medications (eg, benzodiazepines) or sedative antidepressants (eg, mirtazapine) may be indicated </li></ul></ul><ul><li>Irritability </li></ul><ul><ul><li>Antidepressants, mood stabilizers, or antipsychotics may be indicated depending on etiology </li></ul></ul><ul><li>Fatigue </li></ul><ul><ul><li>Thyroid dysfunction and anemia must be ruled out </li></ul></ul><ul><ul><li>SSRIs may be indicated </li></ul></ul><ul><li>Psychotic symptoms </li></ul><ul><ul><li>Psychiatric monitoring indicated </li></ul></ul><ul><li>Suicidal symptoms </li></ul><ul><ul><li>Dose reductions or treatment interruptions may be indicated </li></ul></ul><ul><ul><li>Referral to psychiatric, consideration of hospitaliztion </li></ul></ul>Dieperink E, et al. Gen Hosp Psychiatry. 2004;26:237-240. Constant A, et al. J Clin Psychiatry. 2005;66:1050-1057. Schaefer M, et al. Fortschr Neurol Psychiatr. 2003;71:469-476. Sockalingam S, et al. Int Clin Psychopharmacol. 2005;20:289-290. Schaefer M, et al. Current Drug Abuse Reviews. 2008;1:177-187.
    58. 58. Management of Neuropsychiatric Adverse Effects Other Than Depression <ul><li>Sleep disorders associated with depression </li></ul><ul><ul><li>Antidepressant with noradrenergic properties, such as reboxetine </li></ul></ul><ul><ul><li>Mirtazapine may be first choice, although amitriptyline or trimipramine can also be considered </li></ul></ul><ul><ul><li>Citalopram and escitalopram cause less insomnia than paroxetine and sertraline </li></ul></ul><ul><li>Sleep disorders not associated with depression </li></ul><ul><ul><li>Benzodiazepine-like drugs or sedative antidepressants preferred </li></ul></ul><ul><ul><ul><li>Caution in patients with history of drug addiction </li></ul></ul></ul><ul><ul><li>RBV-induced anemia: epoetin alfa therapy indicated </li></ul></ul><ul><ul><li>Thyroid dysfunction: treated under care of endocrinologist </li></ul></ul>
    59. 59. Managing Fatigue Not Associated With Depression, Thyroid Dysfunction <ul><li>Nonpharmacologic measures </li></ul><ul><ul><li>Fluid and electrolyte repletion </li></ul></ul><ul><ul><li>Aerobic exercise </li></ul></ul><ul><ul><li>Improved nutritional intake </li></ul></ul><ul><ul><li>Appetite stimulants </li></ul></ul><ul><li>Pharmacologic measures </li></ul><ul><ul><li>Epoetin alfa (if anemia is present) </li></ul></ul><ul><ul><li>Tryptophan </li></ul></ul><ul><ul><li>Ondansetron ( 5-hydroxytriptophan receptor antagonist) </li></ul></ul>
    60. 60. Antidepressant Use During HCV Therapy What are the adverse effects of antidepressants? Are there antidepressants that should not be used in the setting of HCV infection? Why?
    61. 61. Adverse Effects of Antidepressants Hansen RA, et al. Ann Intern Med. 2005;143:415-426. Hanje A, et al. Clin Gastroenterol Hepatol. 2006;4:912-917. Type Features SSRIs <ul><li>Sexual dysfunction, headache, dizziness, GI adverse effects, tremors, anxiety </li></ul>TCAs <ul><li>Potential for lethal overdose </li></ul><ul><li>Alpha-adrenergic effects </li></ul><ul><li>Delirium risk from anticholinergic/antihistamine adverse effects </li></ul><ul><li>Cardiac conduction prolongation </li></ul>Venlafaxine <ul><li>Minimal protein binding </li></ul><ul><li>Blood pressure risk </li></ul>Mirtazapine <ul><li>Risk of decreased WBC count </li></ul><ul><li>Risk of weight gain, sedation </li></ul>Nefazodone <ul><li>Risk of hepatic failure </li></ul>Bupropion <ul><li>May increase risk of IFN-associated seizures </li></ul>Duloxetine <ul><li>Risk of liver toxicity </li></ul>
    62. 62. Selecting an Antidepressant: Potential for Drug-Drug Interactions Crewe HK, et al. Br J Clin Pharmacol. 1992;34:262-265. Nemeroff CB, et al. Am J Psychiatry. 1996;153:311-320. von Moltke LL, et al. J Clin Psychopharmacol. 1994;14:1-4. von Motkle LL, et al. Clin Pharmacokinet. 1995;20(suppl 1):33. Potent P450 Blockers: Potential for strong impact on metabolism of other drugs Weak P450 Blockers: Likely to have little impact on metabolism of other drugs Citalopram Escitalopram Mirtazapine Venlafaxine Bupropion Duloxetine Modafinil Sertraline Methylphenidate Nefazodone Paroxetine Fluoxetine Fluvoxamine Antidepressants can interact with the cytochrome P450 enzyme in the liver and, therefore, interfere with the metabolism of other medications
    63. 63. Antidepressant Use During HCV Therapy What are the differences in SSRI efficacy (kinetics of therapeutic effects) in IFN-induced depression vs depressive symptoms of different etiology?
    64. 64. SSRI Efficacy in IFN-induced vs Non-Substance – Induced Depression <ul><li>Evidence of more rapid response to SSRIs in patients with IFN-induced depression vs depression not substance induced </li></ul><ul><ul><li>Response in patients with IFN-induced depression typically seen within 1-2 weeks </li></ul></ul><ul><ul><li>Response in patients with depression not substance induced typically seen in > 4 weeks </li></ul></ul><ul><li>SSRI response rates higher in patients with IFN-induced depression vs depression not substance induced </li></ul>Kraus MR, et al. Gut. 2008;57:531-536. Kraus MR, et al. N Engl J Med. 2001;345:375-376. Kraus MR, et al. Aliment Pharmacol Ther. 2002;16: 1091-1099. Kirsch I, et al. PLoS Med. 2008;5:e45.
    65. 65. Other Strategies for Managing Depression During HCV Therapy What team of experts should be involved in the care of HCV patients with psychiatric issues? When should patients be referred to a specialist vs treated by a general physician?
    66. 66. Multifactorial Care of HCV-Infected Patients With Psychiatric Issues <ul><li>Team of experts recommended for HCV-infected patients with psychiatric issues </li></ul><ul><ul><li>Hepatologist (or infectious diseases doctor with expertise in viral hepatitis and its treatment ) </li></ul></ul><ul><ul><li>Psychiatrist familiar with management of drug abuse, including alcohol detoxification and methadone substitution strategies </li></ul></ul><ul><ul><li>Nurses, nurse practitioners, or physician assistants with psychological expertise may be supportive and helpful for managing troubles in the family and job environment </li></ul></ul>
    67. 67. When to Refer the Patient to a Psychiatrist <ul><li>Identified or suspected risk of suicide </li></ul><ul><li>Alcohol or substance abuse </li></ul><ul><li>Primary physician not comfortable managing patient’s depression </li></ul><ul><li>Diagnosis is uncertain or complicated by other psychiatric factors </li></ul><ul><li>Complex social situation </li></ul><ul><li>Management is complex, response to medication is not optimal, or considering prescribing multiple agents </li></ul><ul><li>Psychotherapeutic treatment is required </li></ul>Michigan Quality Improvement Consortium. Management of adults with major depression. 2006. Guidance based on clinical data and experience; consensus guidelines not available
    68. 68. Other Strategies for Managing Depression During HCV Therapy When should HCV therapy be stopped or dose reduced in patients experiencing new or heightened depressive symptoms? When is hospitalization for depression required?
    69. 69. HCV Therapy Alterations in Presence of Depression <ul><li>Changes in treatment schedule not usually required for mild/moderate depression without psychotic symptoms or suicidal ideation </li></ul><ul><ul><li>Can typically be managed with supportive psychotherapy, counseling, and/or antidepressants </li></ul></ul><ul><li>PegIFN dosing should be promptly modified or withdrawn in presence of severe depression </li></ul>
    70. 70. When Might Hospitalization Be Required? <ul><li>High risk of suicide </li></ul><ul><li>Lack of response to appropriate therapy </li></ul><ul><li>Any psychotic symptoms significantly affecting patient’s thinking and behavior </li></ul><ul><ul><li>Psychotic depression, paranoid psychosis, etc </li></ul></ul><ul><li>Disorientation </li></ul><ul><li>Delirious symptoms </li></ul>Michigan Quality Improvement Consortium. Management of adults with major depression. 2006. Guidance based on clinical data and experience; consensus guidelines not available
    71. 71. Other Strategies for Managing Depression During HCV Therapy How should one balance optimal treatment duration with HCV therapy and depression management during HCV treatment?
    72. 72. Balancing Optimal Duration of HCV Therapy With Depressive Symptoms <ul><li>Genotypes 2/3 </li></ul><ul><ul><li>Recommended duration: 24 weeks </li></ul></ul><ul><ul><ul><li>Treatment may be stopped at 14-16 weeks in patients who develop depressive symptoms if RVR achieved and no advanced fibrosis </li></ul></ul></ul><ul><li>Genotype 1/4 </li></ul><ul><ul><li>Recommended duration: 48 weeks </li></ul></ul><ul><ul><ul><li>Treatment may be stopped at 24 weeks in patients who develop depressive symptoms if RVR achieved and low baseline HCV RNA </li></ul></ul></ul><ul><ul><ul><li>Treatment may be stopped at 38-40 weeks in patients who develop depressive symptoms if complete virologic response achieved </li></ul></ul></ul>Dalgard O, et al. Hepatology. 2004;40:1260-1265. Mangia A, et al. N Engl J Med. 2005;352:2609-2617. Shiffman ML, et al. N Engl J Med. 2007;357:124-134. Zeuzem S, et al. J Hepatol. 2006;44:97-103.
    73. 73. Suicidal Ideation— Identification and Management How often should a patient be assessed for suicidal ideation? How should they be evaluated, and how is suicidal ideation identified? Can all depression screening tests identify suicidal ideation? If suicidal ideation is identified, how should a patient be managed?
    74. 74. Risk of Suicide During Antiviral Therapy <ul><li>Treatment with IFN + RBV reported to be associated with suicidal thoughts, suicide attempts, and successfully completed suicides </li></ul><ul><ul><li>No robust estimates of suicide rates in IFN-exposed and untreated hepatitis C population </li></ul></ul><ul><ul><li>Most data from case reports </li></ul></ul><ul><li>Relative risk associated with treatment is unknown </li></ul><ul><li>Specific risk factors for suicide during IFN + RBV therapy are unknown </li></ul><ul><li>Consider risks associated with antidepressant use </li></ul>Dieperink E, et al. Gen Hosp Psychiatry. 2004;26:237-240.
    75. 75. How to Screen for Suicide Risk <ul><li>Assess risk of suicide by direct questioning about suicidal thoughts </li></ul><ul><li>If present </li></ul><ul><ul><li>Suicide planning </li></ul></ul><ul><ul><li>Identify potential means </li></ul></ul><ul><ul><li>Personal/family history of suicide attempts </li></ul></ul>Guidance based on clinical data and experience; consensus guidelines not available
    76. 76. Guidance for Preventing Suicide During IFN/RBV Therapy <ul><li>The following is based on clinical experience and expert opinion </li></ul><ul><li>Ask all patients about suicidal ideation and plan, obtaining as much specific information as possible </li></ul><ul><li>Treat underlying depressive and anxiety symptoms aggressively </li></ul><ul><ul><li>Such as use of benzodiazepines short term to suppress agitation/anxiety </li></ul></ul><ul><li>Prior to treatment, obtain permission to communicate with significant others </li></ul><ul><ul><li>Enlist their aid in monitoring patient and reducing danger in environment (eg, removing firearms) </li></ul></ul><ul><li>Encourage patients to concentrate on reasons for living </li></ul><ul><li>Hospitalize patients who are at high risk for suicide (based on self-report or severe symptoms such as agitation, anxiety, panic) </li></ul>
    77. 77. CME-certified modules and slidesets exploring the relationships among HCV infection, HCV therapy, and depression Interactive Case Challenges: review challenging cases and compare your answers to those of your peers Expert Viewpoints featuring European expert faculty opinions Downloadable slidesets Go Online for More of This Program!