Transcript Depression in Hepatitis C Patients and Interferon Treatment

Depression in Hepatitis C
Patients and Interferon Treatment
Paul J. Thuluvath, MD, FRCP
The Johns Hopkins University School
of Medicine
Outline
1. Evidence for increased prevalence of
depression or associated symptoms
(fatigue, reduced quality of life) in
patients with HCV
2. Incidence of depression with interferon
treatment and its potential impact on
successful outcome of treatment for HCV
3. Pathophysiology of interferon (and HCV)
induced depression
4. Current role of anti-depressants in
interferon related depression
Common Neuropsychiatry
Symptoms
Fatigue
Impaired quality of life
Cognitive impairment
Depression
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 2002;37:545
– No difference between those who had spontaneous
clearance vs. chronic carriers
» Coughlan B et al Br J Health Psychology 2002;7:105
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)
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?
Depression
• Depression is common in patients with HCV
–
–
–
–
Dwight, MM, et al. J Hepatol 2002;36:401-7
Forton, DM, et al. Hepatology 2002;35:433-9
Zdilar, et al. Hepatology 2000;31:1207-11
El-Serag, HB. Gastroenterology 2002;123:476-82
• 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 2001;64:195-202
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
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
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 2002;123:476-82
Prevalence of psychiatric
disorders in HCV Patients
70.00%
All Vietnam War
Era Veterans
60.00%
50.00%
40.00%
HCV (n= 22,341)
Controls (n=43,267)
30.00%
20.00%
10.00%
0.00%
Depress
PTSD
Psychosis Drug Use
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
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 2002;97:149
• 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 2002;136:288
Adherence to Treatment
• Prospective study of 81 patients in an interdisciplinary 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 antidepressants; more drop-out (43%) from
methadone group compared to 13%-18% in other
groups
Schaefer, M, et al. Hepatology 2003;37:443
Common Neuropsychiatric
Side-effects of Interferon
Irritability
Anxiety
Insomnia
Fatigue
Depression
Confusion & Psychosis (rare)
Suicide (extremely rare)
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 (<0.2%);
very few cases of suicides while on
treatment
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 2002;7:942-7
Proposed Mechanisms for
Interferon Induced Depression
• No direct action (IFN does not cross bloodbrain barrier)
• Probably related to complex neuroendocrine alterations: changes in opioiddopamine, serotonin, nor-epinephrine
system reported
Interferon
5-HT
Serum tryptophan
Plasma kynurenine
Neuropsychiatric
Symptoms
HCV
Pro-inflammatory
Cytokines
Interferon
HypothalamicPituitary
Axis
Pre-emptive Treatment of High Dose
Interferon Induced Depression
9
8
7
6
5
Depression
4
Discontinuation of Rx
due to depression
3
2
1
0
Paroxetine (n = 18)
Placebo (n= 20)
Musselman, DL, et al. NEJM 2001;344:961-6
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 11.4 + 8.1 11.8 + 7.8
11.3 + 9.7 19.5 + 17.8 28.3 + 23
Musselman, DL, et al. NEJM 2001;344:961-6
Conclusions
• IFN induced depression is common and often
undiagnosed unless screened (BDI, ZSDS, CESD) 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