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
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Michael R. Kraus, MD, PhDAssociate Professor of MedicineDepartment of Gastroenterology and HepatologyMedizinische Klinik IIKreiskliniken Altötting – BurghausenBurghausen, Germany
Answering the Questions: Depression Related to HCV and Its Treatment
This program is supported by an educational grant from
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Answering the Questions: Depression Related to HCV and Its Treatment
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We are grateful to Michael R. Kraus, Medizinische Klinik II, Kreiskliniken Altötting – Burghausen, Burghausen, Germany, who aided in the content creation of these slides
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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?
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Answering the Questions: Depression Related to HCV and Its Treatment
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. http://www.who.int/mediacentre/factsheets/fs265/en/.
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Answering the Questions: Depression Related to HCV and Its Treatment
HCV May Lead to Changes in Brain Metabolism 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. 7. Tanaka H, et al. Clin Exp Med. 2006;6:124-128.
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Answering the Questions: Depression Related to HCV and Its Treatment
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
Schafer A, et al. Int J Methods Psychiatr Res. 2007;16:186-201.
0
16 17 17 20 20 23 24 24 2633 34 35 36 37 41 44
82
0
20
40
60
80
100
Muld
er 2
000
Davis
199
8
Renau
lt 19
87
Scalo
ri 20
05
Hunt 199
7
Parie
nte 1
999
Horikaw
a 20
03
Scalo
ri 20
00
Caste
ra 2
002
Schaf
er 2
003
Hause
r 200
2
Bernst
ein 2
002
Kraus
2003
McH
utchin
son 1
998
Kraus
2005
Bonacco
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002
Miy
aoka
199
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Reich
enber
g 200
5
Pat
ien
ts W
ith
D
epre
ssio
n (
%)
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Answering the Questions: Depression Related to HCV and Its Treatment
Worsened Depression and Fatigue Scores Following HCV Treatment 32 HCV-infected patients
randomized to no treatment or pegIFN alfa-2a/2b + RBV
Depression and fatigue evaluated at baseline and at ~ 12 weeks
HCV treatment associated with development of depressive symptoms, fatigue
P < .01
-10
-5
0
5
10
15
20
Depression (MADRS)
Fatigue (MFI)
Mea
n C
han
ge
at F
ollo
w-u
p
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)
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Answering the Questions: Depression Related to HCV and Its Treatment
De Novo Depression in Patients Treated With PegIFN + RBV
Type of Depressive Disorder, % Patients
Any depression or anxiety 37
Major depression 6
Major or minor depression 35
Anxiety with/without depression 11
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
Martin-Santos R, et al. Alimen Pharmacol Ther. 2008;27:257-265.
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Answering the Questions: Depression Related to HCV and Its Treatment
HPA Axis Response to Interferon in Nondepressed Patients ACTH, cortisol, IL-6 levels evaluated in malignant
melanoma patients following IFN administration (N = 14)
– Immediately before, and 1, 2, and 3 hours after IFN administration
– Presence of major depression evaluated throughout therapy
ACTH and cortisol levels following IFN injection higher in those who eventually developed MDD vs those who did not (P < .01)
– No differences in IL-6 responses
HPA axis response indicates a vulnerability to IFN-induced depression
Capuron L, et al. Am J Psychiatry. 2003;160:1342-1345.
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
Factors Possibly Influencing Depressive Symptoms in HCV
Viral Factors
Viral load?HCV genotype?
CNS involvement
Other FactorsTherapy options
NonresponseSocial support
Host FactorsSex
Time since diagnosisComorbidities
Age
Viral FactorsHCV 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.
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Answering the Questions: Depression Related to HCV and Its Treatment
Patient-Related Risk Factors for Depression During IFN-Based Therapy Key risk factor for depression during HCV therapy is presence
of depressive symptoms right before antiviral treatment
Other factors that may be associated
– History of drug abuse
– HIV coinfection
– Older age
– Organic brain impairment
– Genetic polymorphisms in the serotonergic system
Patient 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. 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.
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Answering the Questions: Depression Related to HCV and Its Treatment
Depression History Associated With Depression at Baseline, on Treatment Patients with past history of depression had higher risk of
– Becoming depressed during pegIFN/RBV therapy – Having a higher depression score at baseline
Raison CL, et al. J Clin Psychiatry. 2005;66:41-48.
0
20
40
60
80
100
Past History of DepressionYes No
Pat
ien
ts W
ith
SD
S
Ind
ex ≥
60
on
Tre
atm
ent
(%)
Chi Square = 10.6, df = 1P < .005
YesPast History of Depression
30
40
50
60
Mea
n D
epre
ssio
n S
core
at
Bas
elin
e (S
DS
Ind
ex)
No
t = 4.5, P < .0001
64.5
32.8
48.7
40.3
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Answering the Questions: Depression Related to HCV and Its Treatment
– C1019G polymorphism linked with IFN-induced depression
HTR1A
Max
(Δ
HA
DS
)
P = .011
C/C C/G G/G0
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.
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
Rates of Depression With Standard vs PegIFN alfa-2b + Weight-Based RBV
Little information on depression in patients receiving novel HCV treatments 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)
Pat
ien
ts (
%)
Evaluation Time Points
Baseline Week 4 Months3-4
Months6-8
Week 4Posttreatment
0
20
40
60
80
100
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Answering the Questions: Depression Related to HCV and Its Treatment
Depression Among Patients Receiving 48 vs 72 Weeks of PegIFN + RBV 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
Duration of Therapy (Weeks)
1219
0
20
40
Pat
ien
ts (
%)
60
80
100
48 72
Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451-460.
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Answering the Questions: Depression Related to HCV and Its Treatment
RBV Dose Associated With Depressive Symptom Scores During IFN Treatment
Raison CL, et al. J Clin Psychiatry. 2005;66:41-48.
Mea
n (
± S
E)
SD
S I
nd
ex P < .01
Weight-Based RBV(800-1400 mg/day)
Fixed-Dose RBV(800 mg/day)
46.8
0
20
40
6051.5
n = 86 n = 76
80
100
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Answering the Questions: Depression Related to HCV and Its Treatment
↑ Risk of Moderate/Severe Depressive Symptoms With Weight-Based RBV
Risk of Moderate or Severe Depression According to RBV Dosage
Risk Factor: RBV DosageWeight-Based vs Fixed-Dose RBV
OddsRatio
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
Raison CL, et al. J Clin Psychiatry. 2005;66:41-48.
*P < .05†P < .01
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
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)
Schaefer M, et al. Hepatology. 2007; 46:991-998.
6472
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
5459
9
28
156
Pat
ien
ts (
%)
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Answering the Questions: Depression Related to HCV and Its Treatment
Depressive Symptoms and Viral Clearance at 24 Weeks
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
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Answering the Questions: Depression Related to HCV and Its Treatment
Conflicting Results on Impact of IFN-Induced Depression on SVR Rates
28.5% of 39 patients developing major depression on IFN-based therapy attained SVR vs only 11.5% of patients without depression[1]
– Possible caveat: high rate of antidepressant use in group of patients with major depression
Depression did not predict response in the 64% of 29 pegIFN-treated patients who achieved SVR[2]
– Depression may adversely effect SVR rates due to need for dose reductions or discontinuations
– Conversely, high HCV RNA due to nonresponse possibly associated with inflammation and cytokine release, which induces fatigue and depression[3]
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
Epidemiology and Mechanisms Is depression occurrence during HCV therapy
dependent on IFN dose received?
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Answering the Questions: Depression Related to HCV and Its Treatment
IFN Dose May Increase Incidence of Depression, Further Data Needed Evidence suggests higher IFN doses increase risk of
cytokine-induced depression
– Both dosage and duration (cumulative dose) increase risk of depression
– Linear relationship: higher IFN dose generally correlates with more severe depression
Association remains to be confirmed by future prospective studies
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.
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Answering the Questions: Depression Related to HCV and Its Treatment
IDEAL: Depression With Standard IFN vs Standard- vs High-Dose PegIFN
Week 72
Tx-naive genotype 1
HCV–infectedpatients
(N = 3070)
PegIFN alfa-2b 1.5 µg/kg/week
+ RBV800-1400 mg/day
(n = 1019)
PegIFN alfa-2b 1.0 µg/kg/week
+ RBV800-1400 mg/day
(n = 1016)
PegIFN alfa-2a 180 µg/week
+ RBV1000-1200 mg/day
(n = 1035)
Week 48
24-WeekFollow-up
Incidence of Depression*
26
19 21
0
20
40
Pat
ien
ts (
%)
60
80
100
Sulkowski M, et al. EASL 2008. Abstract 919. *P value not reported.
Screening and Identification of Depression
What is the typical time course of HCV treatment adverse effects, including
psychiatric adverse effects?
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Answering the Questions: Depression Related to HCV and Its Treatment
Months
Inci
den
ce/S
ever
ity
Depression
Fatigue
Influenza-like symptoms
Time Course of Treatment-Associated Psychiatric Adverse Effects
1 2 3 400
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.
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Answering the Questions: Depression Related to HCV and Its Treatment
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 1-3 months of HCV therapy
*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
Mea
n M
AD
RS
Sco
re
Schaefer M, et al. Hepatology. 2007; 46:991-998.
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Answering the Questions: Depression Related to HCV and Its Treatment
Persistence of Psychiatric Symptoms After Discontinuation of HCV Therapy
Symptoms often reversible
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.
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
Diagnostic Instruments: DSM-IV Criteria for Major Depression Presence of ≥ 1 of the elements below for ≥ 2 weeks
It is sufficient to have only 1 of these plus
– ≥ 4 additional symptoms listed in the next slide over a 2-week period
APA. Diagnostic and statistical manual of mental disorders revision IV-TR, 4th ed. 2000.
orDepressed mood Anhedonia
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Answering the Questions: Depression Related to HCV and Its Treatment
Diagnostic Instruments: DSM IV Criteria for Major Depression (cont’d)1. Feelings of overwhelming sadness
and/or fear or emptiness
2. Decrease in the amount of interest or pleasure in all, or most, daily activities
3. Changing appetite and marked weight gain or loss
4. Disturbed sleep patterns
5. Psychomotor agitation or retardation nearly every day
6. Fatigue, mental or physical; also loss of energy
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.
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Answering the Questions: Depression Related to HCV and Its Treatment
Diagnostic Instruments: ICD-10 Criteria for Depression
Typical Symptoms Additional Symptoms
1. Depressed mood2. Loss of interest and enjoyment3. Reduced energy leading to
increased fatigability and diminished activity
1. Reduced concentration and attention2. Reduced self-esteem and self-
confidence3. Ideas of guilt and unworthiness4. Bleak and pessimistic views of the
future5. Ideas or acts of self-harm or suicide6. Disturbed sleep7. Diminished appetite
Answering the Questions: Depression Related to HCV and Its Treatment
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.
How to Use Diagnostic Scales
Depression rating scales
– 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
– ICD-10
– Or using the SCID as a diagnostic interview
To diagnose major depression–specific symptoms, they must be present over a period of ≥ 14 days
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Answering the Questions: Depression Related to HCV and Its Treatment
When to Assess Depression in Patients Beginning HCV Therapy Initial evaluation
– Immediately prior to start of IFN treatment
On-treatment screening
– At least every 8 weeks (preferably every 4 weeks) throughout the whole period of antiviral treatment
In the case of depressive events or the onset of antidepressant treatment
– More frequently evaluations indicated
– At least weekly in the initial phase
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
1. Anand BS, et al. Gastroenterology. 2006;130:1607-1616.
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
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Answering the Questions: Depression Related to HCV and Its Treatment
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. 7. Schaefer M, et al. J Hepatol. 2005;42:793-798.
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
Managing Psychiatric Issues During HCV Treatment Education, monitoring, and support
– Information and psychoeducation before and during treatment
– Antiviral therapy dose reduction, discontinuation as needed
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Answering the Questions: Depression Related to HCV and Its Treatment
Prophylactic Antidepressant Therapy Should Be Considered in Subset of Pts Prophylactic treatment for depression indicated in
– Patients with previous IFN-associated depression[1]
– Patients with increased depression scores immediately prior to initiation of IFN therapy[2,3]
– Potentially also those with a demonstrated genetic risk for developing treatment-associated mood disorders or depression[4]
Prophylactic treatment for patients starting HCV treatment generally not recommended
– Patients not developing IFN-induced depression (vast majority) would be unnecessarily exposed to SSRIs and their potential additional adverse effects
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.
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Answering the Questions: Depression Related to HCV and Its Treatment
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
– 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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Answering the Questions: Depression Related to HCV and Its Treatment
Prophylactic Treatment Reduced Depression Symptom Severity Prospective, double-blind trial compared paroxetine vs placebo for 2 weeks before IFN
+ RBV therapy (N = 61) No difference in rates of MDD with paroxetine vs placebo (13% vs 21%; P = .71) Depression symptom severity reduced with use of paroxetine among patients with
elevated baseline depressive symptoms
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
921
07
Pat
ien
ts (
%)
Rates of Mild, Moderate, Severe, Depression During IFN/RBV Therapy
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Answering the Questions: Depression Related to HCV and Its Treatment
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)
– Reduced depressive symptoms severity with retreatment (P = .036)
Kraus MR, et al. J Viral Hepatitis. 2005;12:96-100.
0
24
6
8
1012
14
t1 t2 t3 t4 t5Time Point of Examination
HA
DS
Dep
ress
ion
S
core
First therapyRetreatment with SSRI
Antidepressant Use During HCV Therapy
What are the preferred treatments for depression and why? What are the dosing schedules? How should
psychotherapy be incorporated?
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Answering the Questions: Depression Related to HCV and Its Treatment
SSRIs Most Effective for IFN-Induced Depression
Reference N Treatment Definition of Response Response, %
Gleason[1] 18 Escitalopram10-20 mg/day
≥ 50% reduction inHAMD-17 score
88.2
Schaefer[2] 14 Citalopram 20 mg/day*
≥ 40% reduction inMADRS score after 3 weeks
86.0
Hauser[3] 39 Citalopram20-60 mg/day
≥ 50% reduction inBDI score
85.0
Kraus[4] 14 Paroxetine 20 mg/day
Able to completeHCV therapy
78.6
Efficacy with SSRIs across multiple studies
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.
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Answering the Questions: Depression Related to HCV and Its Treatment
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
HA
DS
Dep
ress
ion
Sco
re
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 = .025P = .016
Kraus MR, et al. Gut. 2008;57:531-536.
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Answering the Questions: Depression Related to HCV and Its Treatment
Patients With Psychiatric Problems: During 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
Loftis J, et al. Drugs. 2006;66:155-174. Raison C, et al. CNS Drugs. 2005;19:105-123.
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
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 8-14 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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Answering the Questions: Depression Related to HCV and Its Treatment
Patients With Psychiatric Problems: Management After HCV Therapy 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.
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
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
– Referral to psychiatric, consideration of hospitaliztion
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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Answering the Questions: Depression Related to HCV and Its Treatment
Management of Neuropsychiatric Adverse Effects Other Than Depression Sleep disorders associated with depression
– Antidepressant with noradrenergic properties, such as reboxetine
– Mirtazapine may be first choice, although amitriptyline or trimipramine can also be considered
– Citalopram and escitalopram cause less insomnia than paroxetine and sertraline
Sleep disorders not associated with depression
– Benzodiazepine-like drugs or sedative antidepressants preferred
– Caution in patients with history of drug addiction
What are the adverse effects of antidepressants? Are there antidepressants that should not be used in the setting of HCV infection? Why?
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Answering the Questions: Depression Related to HCV and Its Treatment
Adverse Effects of Antidepressants
Type Features
SSRIs Sexual dysfunction, headache, dizziness, GI adverse effects, tremors, anxiety
TCAs Potential for lethal overdose Alpha-adrenergic effects Delirium risk from anticholinergic/antihistamine adverse effects Cardiac conduction prolongation
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
Hansen RA, et al. Ann Intern Med. 2005;143:415-426. Hanje A, et al. Clin Gastroenterol Hepatol. 2006;4:912-917.
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Answering the Questions: Depression Related to HCV and Its Treatment
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
Antidepressants can interact with the cytochrome P450 enzyme in the liver and, therefore, interfere with the metabolism of other medications
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
SSRI Efficacy in IFN-induced vs Non-Substance–Induced Depression Evidence of more rapid response to SSRIs in patients with
IFN-induced depression vs depression not substance induced
– Response in patients with IFN-induced depression typically seen within 1-2 weeks
– Response in patients with depression not substance induced typically seen in > 4 weeks
SSRI response rates higher in patients with IFN-induced depression vs depression not substance induced
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.
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
Multifactorial Care of HCV-Infected Patients With Psychiatric Issues Team of experts recommended for HCV-infected patients
with psychiatric issues
– Hepatologist (or infectious diseases doctor with expertise in viral hepatitis and its treatment)
– Psychiatrist familiar with management of drug abuse, including alcohol detoxification and methadone substitution strategies
– Nurses, nurse practitioners, or physician assistants with psychological expertise may be supportive and helpful for managing troubles in the family and job environment
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Answering the Questions: Depression Related to HCV and Its Treatment
Michigan Quality Improvement Consortium. Management of adults with major depression. 2006.
When to Refer the Patient to a Psychiatrist Identified or suspected risk of suicide
Alcohol or substance abuse Primary physician not comfortable managing patient’s
depression Diagnosis is uncertain or complicated by other psychiatric
factors Complex social situation Management is complex, response to medication is not optimal,
or considering prescribing multiple agents Psychotherapeutic treatment is requiredGuidance based on clinical data and experience; consensus guidelines not available
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
HCV Therapy Alterations in Presence of Depression Changes in treatment schedule not usually required for
mild/moderate depression without psychotic symptoms or suicidal ideation
– Can typically be managed with supportive psychotherapy, counseling, and/or antidepressants
PegIFN dosing should be promptly modified or withdrawn in presence of severe depression
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Answering the Questions: Depression Related to HCV and Its Treatment
When Might Hospitalization Be Required? High risk of suicide
Lack of response to appropriate therapy
Any psychotic symptoms significantly affecting patient’s thinking and behavior
– Psychotic depression, paranoid psychosis, etc
Disorientation
Delirious symptoms
Michigan Quality Improvement Consortium. Management of adults with major depression. 2006.
Guidance based on clinical data and experience; consensus guidelines not available
Other Strategies for Managing Depression During HCV Therapy
How should one balance optimal treatment duration with HCV therapy and depression
management during HCV treatment?
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Answering the Questions: Depression Related to HCV and Its Treatment
Balancing Optimal Duration of HCV Therapy With Depressive Symptoms Genotypes 2/3
– Recommended duration: 24 weeks
– Treatment may be stopped at 14-16 weeks in patients who develop depressive symptoms if RVR achieved and no advanced fibrosis
Genotype 1/4
– Recommended duration: 48 weeks
– Treatment may be stopped at 24 weeks in patients who develop depressive symptoms if RVR achieved and low baseline HCV RNA
– Treatment may be stopped at 38-40 weeks in patients who develop depressive symptoms if complete virologic response achieved
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.
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?
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Answering the Questions: Depression Related to HCV and Its Treatment
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 useDieperink E, et al. Gen Hosp Psychiatry. 2004;26:237-240.
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Answering the Questions: Depression Related to HCV and Its Treatment
How to Screen for Suicide Risk
Assess risk of suicide by direct questioning about suicidal thoughts
If present
– Suicide planning
– Identify potential means
– Personal/family history of suicide attempts
Guidance based on clinical data and experience; consensus guidelines not available
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Answering the Questions: Depression Related to HCV and Its Treatment
Guidance for Preventing Suicide During IFN/RBV TherapyThe following is based on clinical experience and expert opinion Ask all patients about suicidal ideation and plan, obtaining as
much specific information as possible Treat underlying depressive and anxiety symptoms aggressively
– Such as use of benzodiazepines short term to suppress agitation/anxiety Prior to treatment, obtain permission to communicate with
significant others– Enlist their aid in monitoring patient and reducing danger in environment
(eg, removing firearms) Encourage patients to concentrate on reasons for living Hospitalize patients who are at high risk for suicide (based on
self-report or severe symptoms such as agitation, anxiety, panic)
CME-certified modules and slidesets exploring the relationships among HCV infection, HCV therapy, and depression
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