Download Clinical Data and Best Practices for Managing Depression

Clinical Data and Best Practices for
Managing Depression in HCV-Infected
Patients Treated With Peginterferon
and Ribavirin
Martin Schaefer, MD
Associate Professor of Psychiatry
Charité University of Medicine
Berlin, Germany
Head, Department of Psychiatry,
Psychotherapy and Addiction Medicine
Kliniken-Essen-Mitte
Essen, Germany
This program is supported by an educational grant from
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
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Summary of HCV Epidemiology
and Treatment
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Epidemiology of HCV Infection
 Nearly 170 million persons infected with HCV worldwide
– Represents 2.5% of world population
– Approximately 3-4 million new cases each year
– 80% of new cases become chronic
 HCV infection responsible for
– Up to 76% of all HCC cases
– 65% of liver transplantations in developed world
 Cirrhosis develops in 20% to 30% over 20-30 years
– 5% annual incidence of HCC
World Health Organization. Available at:
http://www.who.int/mediacentre/factsheets/fs164/en/.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Common Adverse Effects of HCV
Infection
Adverse Event, %
Physical fatigue
Irritability
Depression
Mental fatigue
Abdominal discomfort
Poor memory
Sleep problems
Joint discomfort
Trouble concentrating
Generalized pain
Headache
Muscular discomfort
Nausea
Lang CA, et al. J Pain Sym Manage. 2006;31:335-344.
Estimated Proportion of Patients
86
74
70
70
68
65
65
64
62
57
56
54
52
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Current HCV Standard of Care
 Current standard of care for hepatitis C
– Combination therapy with pegIFN plus RBV
– Treatment length dependent on viral genotype and virologic response
on therapy
 Response rates vary according to genotype
 SVR > 50% overall in clinical trials
– 42% to 46% for genotype 1 infection
– 76% to 82% for genotype 2/3 infection
NIH Consens State Sci Statements. 2002;19:1-46.
Manns M, et al. Lancet. 2001;358:958-965.
Fried MW, et al. N Engl J Med. 2002;347:975-982.
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Relationship Among
Depression, HCV, and
HCV Treatment
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Depression More Common in HCV
Patients vs General Population
 Depression significantly more prevalent in chronically
HCV-infected patients than in the general population[1]
 Reported prevalence rates for MDD (according to
DSM-IV)[2-4]
– 6% to 10% for the general population
– 24% to 70% for HCV-infected patients
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.
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http://www.who.int/mediacentre/factsheets/fs265/en/.
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Variation Among Results of Studies
Examining IFN-Related Depression

Systematic review analyzed 21 clinical trials of HCV-infected patients
experiencing IFN-related depression
– Definition of depression, treatment strategy, and duration differed among trials
Patients With
Depression (%)
100
82
80
60
40
23 24 24 26
20
20
16 17 17
20
0
41 44
37
36
33 34 35
0
Schafer A, et al. Int J Methods Psychiatr Res. 2007;16:186-201.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Worsened Depression and Fatigue
Scores Following HCV Treatment
 32 HCV-infected patients
randomized to no treatment
or pegIFN alfa-2a/2b + RBV
 HCV treatment associated
with development of
depressive symptoms,
fatigue
Mean Change at Follow-up
 Depression and fatigue
evaluated at baseline and
at ~ 12 weeks
PegIFN + RBV (n = 20)
Control (n = 12)
P < .01
19.2
20
15
10
5
0
-0.9
-5
-10
Majer M, et al. Brain Behav Immun. 2008;22:870-880.
P < .01
8.1
-4.0
Depression
(MADRS)
Fatigue
(MFI)
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
De Novo Depression in Patients
Treated With PegIFN + RBV
 176 HCV-infected patients beginning pegIFN alfa-2a + RBV
therapy evaluated for depressive and anxiety disorders at
baseline and throughout treatment
– Patients with baseline mood disorders excluded (n = 30)
 High incidence of depression and anxiety syndromes during
treatment
Type of Depressive Disorder, %
Patients
Any depression or anxiety
37
Major depression
6
Major or minor depression
35
Anxiety with/without depression
11
Martin-Santos R, et al. Alimen Pharmacol Ther. 2008;27:257-265.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Time Course of Mood Changes in
Patients Treated With PegIFN + RBV
 17 patients without psychiatric diseases or drug addiction
treated with pegIFN + RBV
 Majority of depressive symptoms occurred during first 13 months of HCV therapy
Mean MADRS Score
30
25
20
16.94
13.12*
15
12.88
10
5
3.65
*P < .001 vs baseline.
0
Baseline
1 Month
Schaefer M, et al. Hepatology. 2007; 46:991-998.
3 Months
6 Months
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Risk of Suicide During Antiviral
Therapy
 Treatment with IFN + RBV reported to be associated with
suicidal thoughts, suicide attempts, and successfully
completed suicides
– No robust estimates of suicide rates in IFN-exposed and
untreated hepatitis C population
– Most data from case reports
 Relative risk associated with treatment is unknown
 Specific risk factors for suicide during IFN/RBV therapy
are unknown
 Consider risks associated with antidepressant use
Dieperink E, et al. Gen Hosp Psychiatry. 2004;26:237-240.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Risk Factors for Depression During
IFN-Based Therapy
 Key risk factor for depression during HCV therapy is presence
of depressive symptoms before or during treatment
 Other factors that may be associated
– History of drug abuse
– HIV coinfection
– Older age
– Organic brain impairment
– Genetic risk factors in the serotonergic system
 Sex is risk factor for depression in the general population but is
not risk factor for IFN-induced depression
Raison CL, et al. J Clin Psychiatry. 2005;66:41-48. 40. Capuron L, et al. N Engl J Med.
1999;340:1370. Kraus MR, et al. Gastroenterology. 2007;132:1279-1286. Martinclinicaloptions.com/hep
Santos R, et al. Aliment Pharmacol Ther. 2008; 27:257-265.
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Depressive Symptoms and Viral
Clearance at 24 Weeks
 PegIFN alfa-2b 1.5 µg/kg/week + fixed-dose (800 mg/day)
or weight-based (800-1400 mg/day) RBV
 Higher baseline SDS depression scores associated with
lower rates of HCV RNA negativity at Week 24 (P < .05)
Baseline SDS Depression Score, %
HCV RNA Negative at Week 24
< 10 (n = 32)
69
10-19 (n = 41)
59
≥ 20 (n = 29)
34
Raison CL, et al. Brain Behav Immun. 2005;19:23-27.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Antidepressant Use May Improve SVR
Rates Following HCV Therapy
 39 patients received IFN alfa-2b + RBV for
24-48 weeks
– Assessed with BDI and SCID throughout treatment for
development of major depression
 SVR attained by 38.5% of patients who developed major
depression vs only 11.5% of patients without depression
 All patients who developed depression initiated
antidepressants
Ongoing prospective CIPPAD trial of 100 patients pretreated with antidepressants
vs 100 patients receiving placebo should offer more definitive conclusions regarding
interrelationships of depression, antidepressant use, and virologic outcomes
Loftis JM, et al. Neurosci Lett. 2004;365:87-91.
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Pretreatment Assessment and
Pharmacologic Treatment for
HCV Treatment–Related
Depression
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Approach to Managing Psychiatric
Issues During HCV Treatment
 Education, monitoring, and support
– Information and psychoeducation before and during treatment
– Monitoring of patients and past and current psychiatric issues
– Assessment of current or previous substance abuse
– Supportive psychotherapy and counseling
– Regulation of sleep
 Pharmaceutical strategies
– Antidepressant treatment
– Other treatments: antipsychotics, benzodiazepines (mood stabilizers,
amphetamines, naltrexone, tryptophan, etc)
– Antiviral therapy dose reduction, discontinuation if needed
Schaefer M, et al. Current Drug Abuse Reviews. 2008;1:177-187.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Depression Rating Scales
 Depression scales can be used before and during
treatment to assess baseline, changes in symptoms
 Self-rating scales
– BDI (Becks Depression Inventory)
– Z-SDS (Zung Self-Rating Depression Scale)
– HADS (Hospital Anxiety and Depression Scale)
 Rating scales
– HAMD (Hamilton Depression Scale)
– MADRS (Montgomery-Åsberg Depression Scale)
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
How to Use Diagnostic Scales
 BDI, Z-SDS, HADS, HAMD, or MADRS
– Show changes in depressive symptoms over time
– Try to quantify the severity of depressive symptoms
 Diagnosis of a “major depression” must be confirmed by
diagnostic criteria
– DSM-IV
– Or using the SCID as a diagnostic interview
 To diagnose major depression–specific symptoms, they must
be present over a period of ≥ 14 days
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.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
When to Use Diagnostic Depression
Scales During HCV Treatment
 Early diagnosis
– Required symptom duration of 14 days for MD diagnosis
should not prevent initiation of clinical management of
HCV-associated or treatment-associated depression
 Early intervention
– When depressive symptoms appear or a significant increase
in depression scores occurs over several days
– May prevent development of severe depressive symptoms
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Use of Antidepressants for
IFN-Induced Depression
 Initiate antidepressants at lowered doses to reduce adverse
events and increase adherence
 Therapeutically relevant antidepressive effect can be expected
at Day 8 to 14 of treatment
 Adverse effects generally appear in first 8 days
 In case of nonresponse
– Assess adherence
– Monitor serum levels to determine if dose escalation is needed
– Switch or add if current drug found to be ineffective
– Combination of 2 antidepressants with a different profile can be considered
(eg, citalopram and mirtazapine)
Raison C, et al. CNS Drugs. 2005;19:105-123. 61.
Schaefer M, et al. Neuropsychobiology. 2000;42(suppl 1):43-45.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Treatment for Depression Associated
With HCV Therapy
 Open trials/case series/case reports
– Fluoxetine[1]
– Nortriptyline[2]
– Trimipramine/nefazodone[3]
– Sertraline[4]
– Paroxetine[5-7]
– Citalopram[8,9]
 Prospective controlled trial for acute treatment
– Citalopram[10]
1. Levenson JL, et al. Am J Gastroenterol. 1993;88:760-761. 2. Valentine AD, et al. Psychosomatics.
1995;36:418-419. 3. Schafer M, et al. Neuropsychobiology. 2000;42(suppl 1):43-45. 4. Schramm TM, et al.
Med J Aust. 2000;173:359-361. 5. Kraus MR, et al. Aliment Pharmacol Ther. 2002;16:1091-1099. 6. Kraus
MR, et al. N Engl J Med. 2001;345:375-376. 7. Capuron L, et al. Neuropsychopharmacology. 2002;26:643652. 8. Gleason OC, et al. J Clin Psychiatry. 2002;63:194-198. 9. Schaefer M, et al. J Hepatol.
2005;42:793-798. 10. Kraus MR, et al. Gut. 2008;57:531-536.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Antidepressant Efficacy in Patients
Receiving HCV Treatment
 Efficacy with SSRIs across multiple studies
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
*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.
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.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Improved Depression Scores With
Citalopram During HCV Treatment

First prospective, controlled trial of citalopram 20 mg/day vs placebo for
depression during HCV treatment with pegIFN + RBV
Citalopram (n = 14)
HADS Depression Score
14
12
Placebo (n = 14)
P = NS
P = .025
1 wk f/u
2 wks f/u
P = .016
10
8
6
4
2
Baseline
Depression
diagnosis
Kraus MR, et al. Gut. 2008;57:531-536.
4 wks f/u
Citalopram Treatment Period
After IFN
therapy
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Safety Considerations When
Prescribing Antidepressants
Type
Features
SSRIs
 Sexual dysfunction, headache, dizziness, GI adverse effects, tremors,
anxiety
TCAs




Venlafaxine
 Minimal protein binding
 Blood pressure risk
Mirtazapine
 Risk of decreased WBC count
 Risk of weight gain, sedation
Nefazodone
 Risk of hepatic failure
Bupropion
 May increase risk of IFN-associated seizures
Duloxetine
 Risk of liver toxicity
Potential for lethal overdose
Alpha-adrenergic effects
Delirium risk from anticholinergic/antihistamine adverse effects
Cardiac conduction prolongation
Hansen RA, et al. Ann Intern Med. 2005;143:415-426. Stahl SM, et al. CNS Spectr. 2005;10:732-747.
Hanje AJ, et al. Clin Gastroenterol Hepatol. 2006;4:912-917. Montgomery SA, et al. Int J Clin Pract.
2005;59:1435-1440. Edwards IR, et al. Lancet. 2003;361:1240.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Selecting an Antidepressant:
Potential for Drug-Drug Interactions
Antidepressants can interact with the cytochrome P450 enzyme in the liver and, therefore,
interfere with the metabolism of other medications
Weak P450 Blockers:
Likely to have little impact on
metabolism of other drugs
Potent P450 Blockers:
Potential for strong impact
on metabolism of other drugs
Citalopram
Escitalopram
Mirtazapine
Venlafaxine
Bupropion
Duloxetine
Modafinil
Sertraline
Methylphenidate
Nefazodone
Paroxetine
Fluoxetine
Fluvoxamine
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,
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et al. Clin Pharmacokinet. 1995;20(suppl 1):33.
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Special Safety Considerations With
SSRIs
 SSRIs considered safe in patients without liver cirrhosis,
thrombocytopenia, or other contraindications
 No differences in serum levels or adverse effects in HCVinfected patients without cirrhosis treated with citalopram
vs non-HCV–infected individuals
 SSRIs associated with risk of GI bleeding in setting of
hepatitis C
– Potential for bleeding should be noted in particular for
cirrhotic patients
Gleason OC, et al. J Clin Psychiatry. 2002; 63:194-198. Gleason OC, et al. Prim Care Companion J Clin
Psychiatry. 2005; 7:225-230. Schaefer M, et al. Hepatology. 2003; 37:443-451. Schaefer M, et al. J
Hepatol. 2005; 42:793-798. Weinrieb RM, et al. J Clin Psychiatry. 2003; 64:1502-1510. clinicaloptions.com/hep
Antidepressant Treatment
Before HCV Therapy
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Early Studies: Benefit of Prophylactic
Treatment for IFN-Induced Depression
 40 malignant melanoma patients received paroxetine or
placebo starting 2 weeks before IFN therapy and
continuing throughout treatment
– Reduced incidence of depression (P = .04), fewer cases of
depression requiring HCV treatment discontinuation
(P = .03) with paroxetine
– Pretreatment with paroxetine associated with lower
incidence of fear, cognitive impairment, and pain
– Paroxetine did not reduce or prevent symptoms such as
fatigue, sleeping disturbances, anhedonia, or irritability
Musselman DL, et al. N Engl J Med. 2001;344:961-966.
Capuron L, et al. Neuropsychopharmacology. 2002;26:643-652.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Prophylactic Treatment Reduced
Depression Symptom Severity

Prospective, double-blind trial of 61 HCV-infected patients randomized to paroxetine vs placebo for
2 weeks before IFN + RBV therapy

No difference in rates of major depression with paroxetine (13%) vs placebo (21%); P = .71

Depression symptom severity reduced during treatment with use of paroxetine among patients with
elevated baseline depressive symptoms
100
Rates of Mild, Moderate, Severe, Depression
During IFN/RBV Therapy
Patients (%)
80
60
Paroxetine* (n = 28)
57
55
40
20
Placebo (n = 33)
35
21
17
7
9
0
0
*P = .02
Normal
(MADRS < 15)
Mild
(MADRS ≥ 15)
Moderate
(MADRS ≥ 25)
Raison CL, et al. Aliment Pharmacol Ther. 2007;25:1163-1174.
Severe
(MADRS ≥ 31)
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
No Reduction in IFN-Induced
Depression With Pretreatment
 33 HCV-infected patients
randomized to paroxetine vs
placebo before HCV
treatment[1]
– 35.7% vs 31.6% of the
paroxetine and placebo groups
developed depression
– In rescue arm of study, 10 of
11 patients receiving
paroxetine experienced
reductions in depressive
symptoms
1. Morasco BJ, et al. J Affect Disord. 2007;103:83-90.
2. Diez-Quevedo C, et al. 2007 AASLD. Abstract 347.
 133 patients received either
escitalopram or placebo
before pegIFN alfa-2a +
RBV[2]
– 2% vs 8% of patients in
placebo and escitalopram
arms developed depression
during first 12 weeks of
treatment
– Patients with previous
psychiatric risk factors or
preexisting depression
excluded
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Use of SSRI Pretreatment in Patients
Receiving HCV Retreatment

Patients experiencing major depression during first course of HCV treatment
received SSRI pretreatment when retreated for HCV (N = 8)
HADS Depression
Score
– Reduced depressive symptoms severity with retreatment
14
12
10
8
6
4
2
0
P = .036
t1
t2
t3
t4
Time Point of Examination
Kraus MR, et al. J Viral Hepatitis. 2005;12:96-100.
First therapy
Retreatment with SSRI
t5
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Patients With Psychiatric Problems:
During and After HCV Therapy
 Psychiatric visits
– Every 2-4 weeks for first 3 months
– Then every 4-8 weeks
 Encourage patient and confidant (relative, friend, etc) to look for
psychiatric changes and in self-rating scores
 Continue antidepressant treatment ≥ 3 months after the end of
HCV treatment
– Reduce the dosage of antidepressant slowly
 Attend to mental changes ≥ 6 months after end of HCV
treatment
Loftis J, et al. Drugs. 2006;66:155-174. Raison C, et al. CNS Drugs. 2005;19:105-123. clinicaloptions.com/hep
Cognitive Function, HCV,
and HCV Therapy
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Cognitive Disturbances in HCV
Infection
 Cognitive disturbances associated with both HCV infection
and IFN-based therapy
 Psychomotor slowing, poor concentration and memory
may occur independently or as part of depressive mood
changes
 Cognitive changes compared in HCV-infected patients
with minimal liver disease (n = 37) vs uninfected controls
(n = 46)
– HCV group showed marginally poorer learning efficiency
Valentine AD, et al. Semin Oncol. 1998;25(1 suppl 1):39-47. McAndrews MP, et al. Hepatology.
2005;41:801-808. Weissenborn K, et al. J Hepatol. 2004;41:845-851.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Cognitive Disturbances in HCV
Infection (cont’d)
 HCV-infected patients with normal liver function, mild
fatigue (n = 15) vs HCV-infected patients with normal liver
function, moderate-to-severe fatigue (n = 15) vs healthy
matched volunteers (n = 15)
– Greater cognitive impairment in HCV-infected patients
vs controls
– Poorer attention levels, higher executive functions, higher levels of
anxiety and depression, impaired quality of life
– Deficits more marked in patients with moderate vs
mild fatigue
Valentine AD, et al. Semin Oncol. 1998;25(1 suppl 1):39-47. McAndrews MP, et al. Hepatology.
2005;41:801-808. Weissenborn K, et al. J Hepatol. 2004;41:845-851.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Conflicting Results: Cognitive
Impairment During HCV Therapy
 Fontana and colleagues’ HALT-C subanalysis
– IFN nonresponders retreated with pegIFN alfa-2a + RBV for
24 weeks (n = 177) or 48 weeks (n = 57)
– Cognitive impairment: 32% at baseline vs 34% through
Week 24 (P = .64)
– No increase in overall cognitive impairment in patients
receiving 48 weeks of treatment (P = .48)
– Significant increases in difficulty concentrating, emotional
distress, and symptoms of depression (BDI) in patients
receiving 48 weeks of treatment
Fontana RJ, et al. Hepatology. 2007;45:1154-1163.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Conflicting Results: Cognitive
Impairment During HCV Therapy (cont’d)
 Kraus and colleagues
– 70 patients received IFN alfa-2b or pegIFN alfa-2b + RBV
– Poorer reaction times (P < .001), alertness (P < .001), divided attention
(P < .001), vigilance (P < .001) after 3 months of HCV therapy vs baseline
– Performance returned to pretreatment levels after treatment cessation
 Lieb and colleagues
– 38 HBV- or HCV-infected patients treated for 12 weeks with low-dose IFN
– Decreased immediate recall (P = .015) and reduction in words recited
(P = .034)
– Cognitive impairment not correlated with depressive symptoms or anxiety
– May be caused by disturbances in prefrontal cortex, hippocampus
Kraus MR, et al. Clin Pharmacol Ther. 2005;77:90-100.
Lieb K, et al. Eur Psychiatry. 2006;21:204-210.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Cognitive Disturbances May Appear
Late in Therapy, Persist After
 50 patients receiving pegIFN/RBV treatment assessed at
baseline,14 times during a 48-week course of treatment,
and 4 times during 24 weeks of follow-up
– 30% of patients experienced cognitive problems during
therapy
– 37% of patients who complained of cognitive disturbances
during treatment still suffered from cognitive disturbances
8 weeks after treatment end
– 3 patients first reported cognitive disturbances after the end
of IFN treatment
– Highest incidence of cognitive symptoms between
Weeks 12-20 of treatment
Reichenberg A, et al. AIDS. 2005;(19 suppl 3):S174-S178.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
How Does HCV Impair Cognitive
Function?
 HCV infection leads to changes in brain metabolism and in
the serotonin-dopamine transporter[1-5]
– Significant decrease in N-acetyl-aspartate/creatinine ratio[5]
– Increased choline and decreased N-acetyl-aspartate levels[3]
– Hypometabolism in the prefrontal cortex[6]
– Significant reduction of regional cerebral blood flow in areas
associated with memory and language function[7]
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.
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7. Tanaka H, et al. Clin Exp Med. 2006;6:124-128.
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Risk Factors for Cognitive Impairment
During HCV Therapy
 Neurocognitive problems may occur independently from dose
and duration of HCV treatment
 Risk factors
– Pretreatment with neurotoxic medication
– Diabetes, vascular disease, older age, early vegetative symptoms
– Fatigue, severe depression, history of severe psychiatric adverse effects
with IFN
– Abuse of benzodiazepines or alcohol; methadone treatment
– Concomitant cirrhosis, hepatic encephalopathy, or depression
Fattovich G, et al. J Hepatol. 1996;24:38-47. Jaubert D, et al. Presse Med. 1991;20:221-222. Reichenberg
A, et al. AIDS. 2005;(19 suppl 3):S174-S178. 96. Wichers MC, et al. Psychol Med. 2005;35:433-441.
Wichers MC, et al. Mol Psychiatry. 2005;10:538-544. Weissenborn K, et al. J Hepatol. 2004;41:845-851.
Weissenborn K, et al. Metab Brain Dis. 2000;15:173-178.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Other Symptoms During IFN Treatment
 Sleep disturbances
– Administration of sleep
medications (eg,
benzodiazepines) or sedative
antidepressants (eg,
mirtazapine) may be indicated
 Irritability
– Antidepressants, mood
stabilizers, or antipsychotics
may be indicated depending on
etiology
 Fatigue
– Thyroid dysfunction and
anemia must be ruled out
– SSRIs may be indicated
 Psychotic symptoms
– Psychiatric monitoring indicated
 Suicidal symptoms
– Dose reductions or treatment
interruptions may be indicated
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.
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HCV Patients With Psychiatric
Disorders in the Setting of
Drug Addiction
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
HCV Prevalence by Selected Groups,
United States: High Rates in IDUs
87.0
Hemophilia
79.0
Injection Drug Users
10.0
Hemodialysis
STD Clients
6.0
Gen Population, Adults
3.5
Surgeons, PSWs
2.0
Pregnant Women
1.0
Military Personnel
0.3
0
10
20 30
40 50
60 70
80
Mean Percentage Anti-HCV Positive
Prevalence of hepatitis C in patients with psychiatric disorders: 6% to 9%
90
100
Centers for Disease Control and Prevention. Available at:
http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/101/101_hcv.ppt. Dinwiddie SH, et
al. Am J Psychiatry. 2003;160:172-174. Chang TT, et al. J Med Virol. 1993;40:170-173.
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Cividini A, et al. J Hepatol. 1997;27:455-463.
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Duration of Injection Drug Use and
Prevalence of Blood-Borne Viruses
Estimated Seroprevalence (%)
100
80
HCV
60
HBV
HIV
40
HTLV
20
0
0-4
5-8
9-12
13-24 25-36 37-48 49-60 61-72
Duration of Injection Drug Use (Months)
Garfein RS, et al. Am J Public Health. 1996;86:655-661.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Psychiatric, Drug, Alcohol Disorders
Often Coexist in HCV Patients
 33,824 HCV-infected patients admitted to VA hospitals during
1992-1999
– 31% had “active disorders” defined as hospitalization for psychiatric or
drug detoxification disorders
– 86% had past or present psychiatric, drug, or alcohol use disorder
Patients (%)
100
HCV (n = 22,341)
Controls (n = 43,267)
80
P < .0001 for all between-arm comparisons
60
40
50
39
41
34
25
20
0
69
Depression
PTSD
24 21
Psychosis
El-Serag HB, et al. Gastroenterology. 2002;123:476-482.
33
31
16 13
Bipolar
Anxiety
Drug Use
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Prevalence of Psychiatric Disorders
and Substance Abuse in HCV
 Medical records review of past and present DSM-IV–based
psychiatric disorders (N = 306)
Prevalence (%)
100
86
80
60
40
20
38
30
28
19
9
17
0
Yovtcheva SP, et al. Psychosomatics. 2001;42:411-415.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Management of Hepatitis C:
NIH Consensus Conference Statement
 All patients with chronic
hepatitis C are potential
candidates for antiviral
therapy
 Treatment is recommended
for patients with an
increased risk of developing
cirrhosis
HCV therapy has been successful even when the patients have
not abstained from continued drug or alcohol use . . . .
Thus, it is recommended that treatment of active injection drug use be
considered on a case-by-case basis and that active injection
drug use in and of itself not be used to exclude such
patients from antiviral therapy.
NIH Management of Hepatitis C Consensus Conference Statement. Available at:
http://consensus.nih.gov/2002/2002HepatitisC2002116html.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
NIH Recommendations on Treating
Injection Drug Users
 Management of HCV is enhanced by linking to drugtreatment programs
 Methadone is not a contraindication to HCV treatment
 HCV treatment of active injection drug users should be
considered on a case-by-case basis
 Active injection drug use in and of itself should not exclude
such patients from antiviral therapy
NIH Management of Hepatitis C Consensus Conference Statement. Available at:
http://consensus.nih.gov/2002/2002HepatitisC2002116html.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
HCV Treatment in Patients With
Preexisting Psychiatric Problems
 Patients with preexisting psychiatric disorders can be treated for
chronic hepatitis C
 In general, psychiatric patients
– Do not have increased early antiviral treatment discontinuation
– Do not have lower compliance
– Do not have lower SVR rates
– Do not have higher risk of developing depression during treatment
– Do not have higher mean increase of depression scores
Guidance based on clinical data and experience; consensus guidelines not available
Pariante CM, et al. Lancet. 1999;354:131-132. Pariante CM, et al. Biol Psychiatry. 2001;49:391-404. Van
Thiel DH, et al. Hepatogastroenterology. 1995;42:900-906. Van Thiel DH, et al. Am J Gastroenterol.
2003;98:2281-2288. Schaefer M, et al. Hepatology. 2003;37:443-451. Schaefer M, et al. Hepatology. 2007;
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46:991-998.
Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Very Low Rate of HCV Reinfection
Among Active Injection Drug Users
 Treatment of HCV-infected patients with active drug
addiction controversial because of hypothetical increased
risk of HCV reinfection
– However, available data do not support withholding
treatment in this group
– Dalgard and colleagues: reinfection in only 1 of 27 patients
with active injection drug use 5 years after HCV treatment
– Backmund and colleagues: reinfection rate of 4.1 cases per
100 person-years after 48 months of antiviral treatment
– Currie and colleagues: reinfection rate of 1.75 cases per
100 person-years in injection-drug users
Dalgard O, et al. Eur Addict Res. 2002;8:45-49. Backmund M, et al. Clin Infect Dis.
2004;39:1540-1543. Currie SL, et al. Drug Alcohol Depend. 2008;93:148-154.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Treatment Outcomes Are Similar in
Injection Drug Users vs Other Groups
100
P = .01
76
Patients (%)
80
60
P = .16
50
56
42
40
Patients on
methadone
maintenance
20
0
Controls
(no history
of injection
drug use for
 5 years)
n=
50
50
50
50
ETR
SVR
Response Outcomes
Mauss S, et al. Hepatology. 2004;40:120-124.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
EOT, SVR, and Dropout Rates Similar
Between Controls and Psychiatric Pts

70 HCV-infected patients prospectively evaluated for response to HCV
therapy based on presence of psychiatric disease or drug addiction
– PegIFN alfa-2b + RBV administered for 24 weeks (genotypes 2/3) or 48 weeks
(genotypes 1/4)
Psychiatric (n = 22)
Patients (%)
100
80
60
Methadone (n = 18)
64
77
72
54
Former drug abuse (n = 13)
72
50
54
59
Control (n = 17)
40
28
20
0
9
EOT
Schaefer M, et al. Hepatology. 2007; 46:991-998.
SVR
15
6
Dropout
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Active Alcohol Use Should Be
Moderated If Possible
 Current guidelines strongly recommend complete abstinence
from alcohol during therapy
– Consider screening: CAGE, AUDIT
– Patients with history of alcohol use should not be excluded from HCV
therapy
 Recent alcohol use associated with higher rates of treatment
discontinuation and lower SVR rates[1]
– Patients who use alcohol and complete treatment may have comparable
SVR rates to nondrinkers
 Engage problem alcohol users during care to maximize their
ability to complete treatment
– Treatment programs
– Disulfiram—watch for hepatotoxicity
– Acamprosate
1. Anand BS, et al. Gastroenterology. 2006;130:1607-1616.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Patients With Psychiatric Risk Factors
Require Interdisciplinary Treatment
 Drug abuse disorders
– Methadone treatment improves adherence and
compliance[1-2]
– Recent studies suggest that buprenorphine[3-5] and
naltrexone[6] improve adherence and response rates
 Psychiatric disorders
– Pretreatment with citalopram or mirtazapine reduces
depressive episodes during treatment[7]
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.
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Clinical Data and Best Practices for Managing Depression in HCV-Infected Patients
Summary
 HCV-infected patients receiving antiviral treatment at increased
risk of developing depressive symptoms
– Depression typically occurs within 12 weeks of beginning therapy
– Early diagnosis of depression is imperative to improve adherence to
HCV therapy
– SSRIs effective at reducing depressive symptoms
 Prophylactic antidepressive therapy thus far recommended only
for patients with preexisting depression
– Therapy should be continued throughout treatment and for 6 months after
treatment cessation
 Limited information available on psychiatric adverse events
after 24 weeks of HCV therapy
– Patients should be monitored closely for such events
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