Depression in Hepatitis C Patients and Interferon Treatment

1
Depression in Hepatitis C Patients and Interferon
Treatment

• Paul J. Thuluvath, MD, FRCP
• The Johns Hopkins University School of Medicine

2
Outline

• Evidence for increased prevalence of depression
  or associated symptoms (fatigue, reduced quality
  of life) in patients with HCV
• Incidence of depression with interferon treatment
  and its potential impact on successful outcome of
  treatment for HCV
• Pathophysiology of interferon (and HCV) induced
  depression
• Current role of anti-depressants in interferon
  related depression

3
Common Neuropsychiatry Symptoms

• Fatigue
• Impaired quality of life
• Cognitive impairment
• Depression

4
Fatigue

• Common in HCV 20 to 80 (versus 20-30 with
  general population), but similar in HCV positive
  and negative blood donors
• No clear relationship between severity of liver
  disease and depression
• Conflicting data on improvement after HCV
  clearance
• 35 (29 of 83) improvement in responders vs. 22
  (75 of 348) in non-responders
• Cacoub P et al J Hepatol 200237545
• No difference between those who had spontaneous
  clearance vs. chronic carriers
• Coughlan B et al Br J Health Psychology 20027105

5
Quality of Life Studies

• QOL is lower in HCV independent of the severity
  of liver disease (Ware, 1999 Bonkovsky 1999)
• QOL is lower in HCV compared to HBV, and it is
  unrelated to the mode of infection (Foster, 1998)
• QOL improves after viral eradication (Ware, 1999
  Bonkovsky, 1999 McHutchinson, 2001)
• But QOL is better in those who are unaware of HCV
  diagnosis (Rodgers, 1999)
• No difference in QOL in Irish women with HCV RNA
  positive or negative (Coughlan, 2002)

6
Cognitive Impairment

• Impairment of attention, concentration, and
  psychomotor speed in the presence of minimal
  hepatitis (Forton, DM, et al. Hepatology 2002)
• Impairment is similar to other liver disease
  (Hilsabeck, RC, et al. Hepatology 2002)
• Cerebral choline to creatine ratio elevated in
  basal ganglia and white matter on MRS in the
  presence of minimal liver disease (Forton, DM, et
  al. Lancet 2001)
• Mechanism unknown HCV negative strand identified
  in brain immune mediated upregulation of
  neuroinhibitory pathways?

7
Depression

• Depression is common in patients with HCV
• Dwight, MM, et al. J Hepatol 200236401-7
• Forton, DM, et al. Hepatology 200235433-9
• Zdilar, et al. Hepatology 2000311207-11
• El-Serag, HB. Gastroenterology 2002123476-82
• No large case-controlled studies to date
• Suicide probability and depression similar in HCV
  ve and HCV ve intravenous drug users
• Grassi, L, et al. J Affect Disord 200164195-202

8
Confounding Factors

• Anxiety about diagnosis prognosis
• Severity of liver disease
• Influence of treatment (including IFN)
• Ongoing or previous drug or alcohol use
• Underlying personality traits
• Co-infection with HIV

9
Problems with Published Studies

• Different tools to assess depression and QOL
• No controls and results not adjusted for
  comorbid conditions such as drug abuse,
  alcoholism, and other personality traits
• Studies from specialty clinics
• Small studies except one large, retrospective
  study based on ICD codes in VA population

10
Prevalence of Psychiatric Disorders in HCV
Patients

• 33,842 HCV admitted to VA hospitals during 1992-9
• 31 had active disorders defined at
  hospitalization for psychiatric or drug
  detoxification disorders
• 86.4 had past or present psychiatric, drug or
  alcohol use disorder
• El-Serag, HB, et al. Gastroenterology
  2002123476-82

11
Prevalence of psychiatric disorders in HCV
Patients
All Vietnam War Era Veterans
12
Association between HCV and Neuropsychiatric
Symptoms

• There is significant circumstantial evidence, but
  no confirmatory large case-control studies to
  date
• Pre-existing neuropsychiatric symptoms may impact
  the management of HCV

13
Impact of Neuropsychiatric Symptoms on Treatment

• 43 (242/557) did not keep VA clinic appointment
  and 12 (64/557) had active psychiatric or drug
  use disorders
• Cawthorne, CH, et al. Am J Gastroenterol
  200297149
• Cleveland study (n 293) 37 did not adhere to
  evaluation, 34 had medical or psychiatric
  contraindications and 13 had ongoing drug or
  alcohol use
• Falck-Yitter, Y, et al. Ann Intern Med
  2002136288

14
Adherence to Treatment

• Prospective study of 81 patients in an
  inter-disciplinary setting 16 psychiatric
  disorders, 21 methadone use, 21 former drug
  addiction and 23 controls
• Depression (DSM-IV) and sustained response to
  interferon similar in all groups
• More patients in psychiatric group required
  anti-depressants more drop-out (43) from
  methadone group compared to 13-18 in other
  groups

Schaefer, M, et al. Hepatology 200337443
15
Common Neuropsychiatric Side-effects of
Interferon

• Irritability
• Anxiety
• Insomnia
• Fatigue
• Depression
• Confusion Psychosis (rare)
• Suicide (extremely rare)

16
Neuropsychiatric Side-effects of Interferon

• Common probably in more than one-third
  (reported incidence varies from 6 to 70)
• Variability in incidence is due to differences in
  the dose, duration, patient characteristics and
  the tools used to assess symptoms
• Suicidal ideation is uncommon (lt0.2) very few
  cases of suicides while on treatment

17
Interferon and Depression

• 39 patients prospectively evaluated by Beck
  Depression Inventory (BDI)
• 13 (33) developed Major Depressive Disorder
  (MDD) between 6th and 22nd week
• 11 of 13 responded to (citalopram) Celexa (mean
  dose 36 mg, range 20-60 mg)
• Hauser, P, et al. Mol Psychiatry 20027942-7

18
Proposed Mechanisms for Interferon Induced
Depression

• No direct action (IFN does not cross blood-brain
  barrier)
• Probably related to complex neuro-endocrine
  alterations changes in opioid-dopamine,
  serotonin, nor-epinephrine system reported

19
Interferon
Tryptophan 2-3-dioxygenase
Indoleamine 2-3-dioxygenase
5-HT Serum tryptophan Plasma kynurenine
5-HT transporter m RNA
5-HT receptor changes
Neuropsychiatric Symptoms
Hypothalamic- Pituitary Axis
HCV
Pro-inflammatory Cytokines
Interferon
20
Pre-emptive Treatment of High Dose Interferon
Induced Depression
Musselman, DL, et al. NEJM 2001344961-6
21
Pre-emptive Treatment of High Dose Interferon
Induced Depression
Baseline 4 weeks 12 weeks
Hamilton Depression Rating Scale Paroxetine Placebo 5.6 4.7 5.0 4.4 9.1 5.2 11.8 7.6 8.4 5.0 15.2 9.9
Hamilton Anxiety Scale Paroxetine Placebo 5.1 3.3 4.6 4.7 5.7 4.1 9.5 5.6 6.2 4.4 12.3 7.1
Neurotoxicity Rating Scale Paroxetine Placebo 8.8 6.0 11.3 9.7 11.4 8.1 19.5 17.8 11.8 7.8 28.3 23
Musselman, DL, et al. NEJM 2001344961-6
22
Conclusions

• IFN induced depression is common and often
  undiagnosed unless screened (BDI, ZSDS, CES-D) in
  a systematic way
• Patients with depression could be treated safely
  and effectively with IFN provided their
  depression is controlled prior to treatment
• SSRI may be the first line of therapy for those
  who develop depression during treatment
• Multi-disciplinary (psychiatrists, hepatologists
  and nurses) approach is critical for successful
  management of HCV