Depression in Hepatitis C Patients and Interferon Treatment

Paul J. Thuluvath, MD, FRCP

The Johns Hopkins University School of Medicine

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

Outline

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

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

Depress PTSD Psychosis Drug Use

HCV (n= 22,341)Controls (n=43,267)

All Vietnam WarEra Veterans

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 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 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 blood-brain barrier)

• Probably related to complex neuro-endocrine alterations: changes in opioid-dopamine, serotonin, nor-epinephrine system reported

NeuropsychiatricSymptoms

Pro-inflammatoryCytokines

Hypothalamic-Pituitary

Axis

Interferon

5-HTSerum tryptophanPlasma kynurenine

Interferon

Indoleamine 2-3-dioxygenase

Tryptophan 2-3-dioxygenase

5-HT transporter m RNA

5-HT receptor changes

HCV

Pre-emptive Treatment of High Dose Interferon Induced Depression

0

1

2

3

4

5

6

7

8

9

Paroxetine (n = 18) Placebo (n= 20)

Depression

Discontinuation of Rxdue to depression

Musselman, DL, et al. NEJM 2001;344:961-6

Pre-emptive Treatment of High Dose Interferon Induced Depression

Musselman, DL, et al. NEJM 2001;344:961-6

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

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