Hepatitis is common in Pakistan and so the psychiatric morbidity. How to manage it.

3. Hepatitis and Depression
Dr. M. Nasar Sayeed Khan
Associate Professor and Head Department of Psychiatry,
SIMS and SHL.
nasarsayeed@yahoo.com

5. Outline
Epidemiology
Pathophysiology / Co morbidity
Diagnosis of Depression
Treatment Guidelines for management

6. World Health Organization. Available at:
http://www.who.int/mediacentre/factsheets/fs164/en/.
Epidemiology of HCV Infection
 No. of HCV affected persons:
 Approx. 180 million persons (>2.5% of world population)
 No. of new cases :
 Approx. 3-4 millions / year
 80% of new cases become chronic
 HCV infection
 Constitute up to 76% of all HCC cases
 Responsible for 65% of liver transplantations in developed world
 Lead to Cirrhosis develops in 20% to 30% over 20-30 years

7. 1- Lang CA, et al. J Pain Sym Manage. 2006;31:335-344. 2-. World Health Organization. http://www.who.int/mediacentre/factsheets/fs265/en/.
Depression More Common in HCV Patients
vs General Population
Prevalence
rate of MDD
Depression in
General
population%
Depression in
HCV infected
patients %
Worldwide1,2 6% -10% 24% - 70%
Pakistan 30- 35% 60% - 70%3

8. Overlap of Common Adverse Effects of
HCV Infection and Depression symptoms
Adverse Event, % Estimated Proportion of
Patients
Physical fatigue 86
Irritability 74
Depression 70
Mental fatigue 70
Abdominal discomfort 68
Poor memory 65
Sleep problems 65
Joint discomfort 64
Trouble concentrating 62
Generalized pain 57
Headache 56
Muscular discomfort 54
Nausea 52
Lang CA, et al. J Pain Sym Manage. 2006;31:335-344.

9. Epidemiology of Depression in
HCV-Infected Patients
Lang CA, et al. J Pain Sym Manage. 2006;31:335-344.
86
74 70 70 68
0
20
40
60
80
100
Physical
tiredness
Irritability Depression Mental
tiredness
Abdominal
pain
Prevalence of Symptoms in HCV-Infected Patients
Patients(%)

10. 1
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.

11. 1
Time Course of Mood Changes in Patients
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
MeanMADRSScore
Schaefer M, et al. Hepatology. 2007; 46:991-998.

12. 1
Etiology 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?

13. 1
Factors Possibly Influencing Depressive
Symptoms in HCV
Viral Factors
Viral load?
HCV genotype?
CNS involvement
Other Factors
Therapy options
Nonresponse
Social support
Host Factors
Sex
Time since diagnosis
Comorbidities
Age
Viral Factors
HCV RNA?
HCV genotype?
CNS involvement
Kraus MR, et al. Psychosomatics. 2000;41:377-384. Loftis JM, et al. Drugs.
2006;2:155-178. McDonald EM, et al. Lancet. 1987;2:1175-1178.

14. 1
Putative Mechanisms of Depression in HCV
Infection
 Chronic HCV leads to high degree of psychological
distress (stigmatisation ↑, anxiety ↑, quality of life ↓)
 Reduced quality-of-life measures may account to
some extent for the increase in depressive symptoms
observed
 HCV-linked depression as “reactive depression”
Angelino A, et al. Int Rev Psychiatry. 2005;17:471-476.

15. 1
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.

16. 1
Review of CNS Cytokines and Possible
Modulators of Inflammation
Proinflammatory
 Interleukin (IL)-1
 IL-1 receptor agonist
 IL-6
 IL-8
 Tumor necrosis factor
(TNF)
 Prostaglandin (PG)E2
 Interferon gamma
Antiinflammatory
 IL-4
 IL-10
 IL-13

17. 1
Major Depression and Cytokines
 Major depression has been associated with many
abnormalities in cytokines
 Including elevated PGE2, IL-1, soluble IL-1 receptor
antagonist, IL-2, IL-6, and IFN gamma
 IL-1, IL-6, and TNF can directly stimulate the
hypothalamic-pituitary-adrenal axis
 Resulting in the release of corticotropin-releasing factor,
with associated physiologic changes found to be relevant to
the pathophysiology of depression
Musselman DL, et al. Am J Psychiatry. 2001;158:1252-1257. Lieb J, et al.
Prostaglandins Leukot Med. 1983;10:361-367. Basterzi AD, et al. Hum
Psychopharmacol. 2005;20:473-476. Seidel A, et al. Clin Immunol Immunopathol.
1996;67:72-74.

18. 1
Neuropsychiatric
Symptoms
Pro-inflammatory
Cytokines
Hypothalamic-
Pituitary
Axis
Interferon
5-HT
Serum tryptophan
Plasma kynurenine
Interferon
Indoleamine 2-3-dioxygenase
Tryptophan 2-3-dioxygenase
5-HT transporter m RNA
5-HT receptor changes
HCV

19. 1
From: Immune System Contributions to the Pathophysiology of Depression
Focus. 2008;6(1):36-45.
Mechanisms by which Innate Immune Cytokines Can Contribute to Depression
Note: Through influences on the neuroendocrine system, monoamine
metabolism, and synaptic plasticity, innate immune cytokines and their
signaling pathways (e.g., NF-κB and MAPK) can influence molecules that are
believed to play a role in depression including CRH, the GR, serotonin (5HT),
Figure Legend:

20. 2

21. 2
Screening and Identification
of Depression
1-Suspect Depression
2-Screen depression
3-Diagnose depression

22. 2
When to suspect Depression in
Non-Psychiatric setting
 Patient speaks with monotonous
voice
 Look sad
 Sits with slumped posture in chair
 Speaks abnormally slow
 Somatic complaints with no obvious
cause
Ref: David Goldberg , Prescribing anti-depressants in primary care and hospital practice ;
Depression in medical secularities ; WPA Bulletin on Depression “ Facing, understanding and managing
Depression Vol.7 No 26 ,2003
Patient with physical illness can be depressed
& it may be exacerbating their symptoms & further spoiling their QOL.

23. 2
Screening Depression in Suspected cases
 Use following 2 screening questions
in suspected case
1. How they have been feeling , or what their
moods has been like in past couple of
week.
2. Have they lost interest or pleasure in their
routine activity during couple of weeks
Ref: David Goldberg , Prescribing anti-depressants in primary care and hospital practice ;
Depression in medical secularities ; WPA Bulletin on Depression “ Facing, understanding and managing
Depression Vol.7 No 26 ,2003
If whether of these is present , then ask additional questions

24. 2
Question to confirm Depression in
Patient +ve on screening
 Has their appetite changed
 Have they felt unable to concentrate
 Have they lost confidence in themselves
 Have they felt like ending their life
 Have they felt pessimistic .hopeless about
the future
 Have they felt low libido( Sex drive)
 Have there been either agitation or slowing of
their movements
 Have they felt guilt or self-blame
 Disturbed sleep
Ref: David Goldberg , Prescribing anti-depressants in primary care and hospital practice ;
Depression in medical secularities ; WPA Bulletin on Depression “ Facing, understanding and managing
Depression Vol.7 No 26 ,2003
If there are 4 or more of these symptoms , then they satisfy
international criteria for depression

25. 2
Diagnostic Instruments:
ICD-10 Criteria for Depression
Typical Symptoms Additional Symptoms
1. Depressed mood
2. Loss of interest and enjoyment
3. Reduced energy leading to
increased fatigability and
diminished activity
1. Reduced concentration and attention
2. Reduced self-esteem and self-
confidence
3. Ideas of guilt and unworthiness
4. Bleak and pessimistic views of the
future
5. Ideas or acts of self-harm or suicide
6. Disturbed sleep
7. 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/.

26. 2
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)

27. 2

28. 2
Current Options for Management,
Treatment,
and Prevention of Depression
in Patients Receiving
HCV Therapy

29. 2
Approach to 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
stabilisers, amphetamines, naltrexone, tryptophan, etc)
 Antiviral therapy dose reduction, discontinuation

30. 3
Treatment for Depression Associated With
HCV Therapy
SSRIs
Type Class Features
Escitalopram
Citalopram
Paroxetine
Sertraline
Good tolerability
No hepatic toxicity
Low influence on cytochrome P450 system
(low drug-drug interactions)
Others
Type Class Features
Mirtazapine Good tolerability
Good sedation and induction of sleep
Venlafaxine  Few drug-drug interactions
Amitriptyline, doxepin Good sedation, induction of sleep
Anticholinergic adverse effects
Some delirium, increase of liver enzymes,
and cardiac adverse effects
Raison C, et al. CNS Drugs. 2005;19:105-123.

31. 3
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
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.

32. 3
Selecting an Antidepressant:
Potential for Drug-Drug Interactions
Crewe HK, et al. Br J Clin Pharmacol. 1992;34:262-265. Nemeroff CB, et al. Am J Psychiatry.
1996;153:311-320. von Moltke LL, et al. J Clin Psychopharmacol. 1994;14:1-4. von Motkle LL,
et al. Clin Pharmacokinet. 1995;20(suppl 1):33.
Potent P450 Blockers:
Potential for strong impact on
metabolism of other drugs
Weak P450 Blockers:
Likely to have little impact on
metabolism of other drugs Citalopram
Escitalopram
Mirtazapine
Venlafaxine
Bupropion
Duloxetine
Modafinil
Sertraline
Methylphenidate
Nefazodone
Paroxetine
Fluoxetine
Fluvoxamine
Antidepressants can interact with the cytochrome P450 enzyme in the liver and, therefore,
interfere with the metabolism of other medications

33. Escitalopram for the Prevention of Peginterferon-α2a–Associated Depression in
Hepatitis C Virus–Infected Patients Without Previous Psychiatric Disease: A
Randomized Trial
Ann Intern Med. 2012;157(2):94-103. doi:10.7326/0003-4819-157-2-201207170-00006
Montgomery–Asberg Depression Rating Scale scores during hepatitis C virus therapy.
Significant group differences were seen at weeks 12 (P = 0.004), 24 (P =
0.002), and 48 (P = 0.001, genotypes 1 and 4).
* Only genotypes 1 and 4.
Figure Legend:

34. 3
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.

35. 3
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.

36. 3
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
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; 46:991-998.
Guidance based on clinical data and experience; consensus guidelines not available

37. 3
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 required
Guidance based on clinical data and experience; consensus guidelines not available

38. 3
Management of HCV Patients With
Psychiatric Disorders: Review
HCV-infected
patient
Screen for
substance abuse,
psychiatric disorders
Psychiatric disorder
present
Referral to
psychiatric
specialist
Consultation
with
HCV treater
YE
S
NO
HCV treatment
decision
Loftis J, et al. Drugs. 2006;66:155-174.

39. 3
Written Handout for patients
starting anti-depressants
1. Single daily dose, likely to be taken for about 4 months
2. Anti-depressant are not addictive- no dependency
3. Inform them of side effects & risks
4. Stress the imp. Of taking them regularly until advised
5. Not a “pick me up”, so there must be taken even when not feeling depressed
6. Advisable to continue treatment for some weeks after improvement has
occurred
7. Importance of “ tapering off” the dose because of discontinuation symptoms
8. Involve carers for assistance with tablets or suicidal patients ( Prefer drug
safe in overdose).Ref: David Goldberg , Prescribing anti-depressants in primary care and hospital practice ;
Depression in medical secularities ; WPA Bulletin on Depression “ Facing, understanding and managing
Depression Vol.7 No 26 ,2003

40. 4
Conclusions
 Acute antidepressant treatment in patients with depressive
symptoms during HCV treatment is highly effective
 Prophylactic use of antidepressants should be offered
 At least to patients with preexisting depressive syndromes
 Also in patients with a history of treatment-associated depression
during previous HCV therapy
 Antidepressant treatment should be continued for at least 3
months after the end of antiviral treatment
 Most psychiatric adverse effects can be managed without dose
reduction or discontinuation of antiviral therapy

41. 4
41
Mujtaba Nasar

42. 4
Thanks