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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

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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?



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/.



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.



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

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Davis

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Pat

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ts W

ith

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ssio

n (

%)



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)



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.



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?



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.



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.



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



HTR1A Polymorphism Predisposes Patients to IFN-Induced Depression HTR1A, serotonin receptor gene

– 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?



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



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.



RBV Dose Associated With Depressive Symptom Scores During IFN Treatment


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



↑ 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


*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?



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 (

%)



Depressive Symptoms and Viral Clearance at 24 Weeks

Baseline SDS Depression Score, % HCV RNA Negative at Week 24

< 10 (n = 32) 69

10-19 (n = 41) 59

≥ 20 (n = 29) 34

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)

Raison CL, et al. Brain Behav Immun. 2005;19:23-27.



Depressive Symptoms, Virologic Outcome, and Treatment Adherence

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

CES-D score Baseline Month 1 Month 3

14.68 ± 8.7114.0 ± 6.9115.86 ± 8.43

21.43 ± 13.3125.18 ± 11.9122.87 ± 13.86

0.94 (0.88-1.01)0.88 (0.80-0.97)0.93 (0.86-1.02)

.09.008.13

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



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?



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.



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?



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.



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.



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.


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?



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



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

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.



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

Mild: 2 typical symptoms + 2 additional symptoms

Moderate: 2 typical symptoms + ≥ 3 additional symptoms

Severe: 3 typical symptoms + ≥ 4 additional symptoms

WHO. Available at: http://www.who.int/classifications/icd/en/.



Screening Instruments for Depression: Physician Rating Scales Depression scales can be used before and during

treatment to assess baseline, changes in symptoms

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

Mild depression: ≥ 8-14 Moderate depression: ≥ 15-24 Severe depression: ≥ 25

Mild depression: ≥ 10-13 Moderate depression: ≥ 18-20 Severe depression: ≥ 32



Screening Instruments for Depression: Self-Rating Scales Depression scales can be used before and during

treatment to assess baseline, changes in symptoms

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

Mild depression: ≥ 16-26

Moderate/severe depression: ≥ 27

Mild depression: ≥ 50-59

Moderate depression: ≥ 60-69

Severe depression: ≥ 70

Clinically relevant ≥ 9 Mild depression: ≥ 10-11

Moderate depression: ≥ 17

Severe depression: ≥ 27-30



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



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


How should patients with current and past alcohol or substance abuse and HCV infection be screened

for depression and managed?



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



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?



Managing Psychiatric Issues During HCV Treatment Education, monitoring, and support

– Information and psychoeducation before and during treatment

– Monitoring of patients and psychiatric issues

– Supportive psychotherapy

– Regulation of sleep

Pharmaceutical strategies

– Antidepressant treatment

– Other treatments: antipsychotics, benzodiazepines (mood stabilizers, amphetamines, naltrexone, tryptophan, etc)

– Antiviral therapy dose reduction, discontinuation as needed



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.



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.



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



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?



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.



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.



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.


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?



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.



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.


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?



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

– 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.



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

– RBV-induced anemia: epoetin alfa therapy indicated

– Thyroid dysfunction: treated under care of endocrinologist



Managing Fatigue Not Associated With Depression, Thyroid Dysfunction Nonpharmacologic measures

– Fluid and electrolyte repletion

– Aerobic exercise

– Improved nutritional intake

– Appetite stimulants

Pharmacologic measures

– Epoetin alfa (if anemia is present)

– Tryptophan

– Ondansetron (5-hydroxytriptophan receptor antagonist)


What are the adverse effects of antidepressants? Are there antidepressants that should not be used in the setting of HCV infection? Why?



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.



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

EscitalopramMirtazapine VenlafaxineBupropionDuloxetineModafinilSertraline

MethylphenidateNefazodoneParoxetineFluoxetine

Fluvoxamine

Antidepressants can interact with the cytochrome P450 enzyme in the liver and, therefore, interfere with the metabolism of other medications


What are the differences in SSRI efficacy (kinetics of therapeutic effects) in IFN-induced depression vs

depressive symptoms of different etiology?



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?



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



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


When should HCV therapy be stopped or dose reduced in patients experiencing new or heightened depressive symptoms? When is hospitalization for

depression required?



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



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


How should one balance optimal treatment duration with HCV therapy and depression

management during HCV 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?



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.



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



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

Interactive Case Challenges: review challenging cases and compare your answers to those of your peers

Expert Viewpoints featuring European expert faculty opinions

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clinicaloptions.com/depression

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