[Impact of interferon alpha immunotherapy on tryptophan metabolism in patients with chronic hepatitis C. Results of a pilot studies on ten patients].
BACKGROUND
The proinflammatory cytokine interferon (IFN) alpha is commonly used in the treatment of patients with hepatitis C but its administration is often responsible for neuropsychiatric side effects (low mood, fatigue, sleep-wake disorders, irritability and weight loss). Various mechanisms have been incriminated to explain the production of depression and anxiety symptoms, among which serotonergic hypothesis is supported by a growing body of evidence. The latter posits that IFN-alpha is responsible for central serotonin (5-HT) depletion by deviating its precursor, tryptophan (TRP), to a catabolic kynurenine (KYN) pathway through induction of indoleamine 2.3 dioxygenase (IDO). The aim of the study was to examine the time variation of 5-HT blood (serum and platelet) levels and serum KYN/TRP ratio along with instauration of IFN-alpha therapy and to correlate these biological variations with mood fluctuations.


METHODS
Patients. Ten patients (mean [S.D.] age 45 years [12.7], range 29-63; three males, seven females) with chronic hepatitis C eligible to receive IFN-alpha (1.5microg/kg/week Viraferon, Schering-Plough, administered subcutaneously) were recruited from the Gastroenterology department of the University hospital of Lille, France. Patients with cirrhosis, HIV or hepatitis B or D co-infection, persistent intravenous addiction, corticoid therapy or any DSM-IV axis 1 psychiatric disorder (diagnosed with MINI interview) were excluded. Patients with chronic active hepatitis C were assessed at baseline and monthly during the first semester of IFN-alpha and ribavirine bi-therapy. Measurements. The Montgomery Asberg Depression Rating Scale (MADRS) and the Hamilton Rating Scale for Anxiety (HAM-A) were used to assess depression and anxiety fluctuations. Serum and platelet serotonin levels were determined by HPLC with coulometric detection. Simultaneous quantification of TRP and KYN was determined by means of HPLC with fluorescence detection (TRP) or UV detection (KYN). Statistics. TRP, KYN concentrations and KYN/TRP ratio as well as MADRS and HAM-A measurements were performed at three time points (day 1, weeks 4 and 12) of IFN-alpha therapy. Analysis of variance used a linear model (with subject as the random factor) and correlation between measurements used an autoregressive model of order 1. For all probabilities, the level of significance was set at P<.05.


RESULTS
Two patients were excluded before the first post-treatment assessment (results not shown). In the eight remaining patients, we observed significant increase of KYN/TRP ratio from baseline to early (week 4) and late (week 12) assessments (respectively, mean [S.D.] 5.57[5.24], 13.52[15.53] and 29.78[14.11], with P=.04). Similarly, significant increase in the MADRS (respectively 7.13[5.2], 12[6.9] and 16.6[8.6], with P=.03) and HAM-A (respectively 9.25[6.27], 15.1[6.95] and 18.7[6.27], with P=.02) mean scores were observed. Serum and platelet serotonin levels showed no significant variation with time.


CONCLUSIONS
The results are consistent with the physiopathological hypothesis of an induction of IDO underlying depressive and anxiety symptoms related to IFN-alpha therapy in patients with chronic active hepatitis C. Nevertheless, this pilot study allows no firm conclusion since sample effective is weak and delay between IFN-alpha weekly injection and psychiatric and biological assessment was not controlled and thus may have biased our findings. However, these encouraging results advocate for further exploration of tryptophan metabolism for a better understanding of individual vulnerability to IFN-alpha-induced psychiatric adverse effects.
Service d'addictologie-clinique CHRU de Lille, 57, boulevard de Metz, 59037 Lille cedex, France. j-vignau@chru-lille.fr
J
J
Vignau
O
O
Costisella
V
V
Canva
M
M
Imbenotte
A
A
Duhamel
M
M
Lhermitte
D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001008:Anxiety Disorders / Q000097:blood / Q000139:chemically induced*; D001792:Blood Platelets / Q000378:metabolism; D003866:Depressive Disorder / Q000097:blood / Q000139:chemically induced*; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects* / Q000627:therapeutic use; D007737:Kynurenine / Q000097:blood; D008297:Male; D008875:Middle Aged; D010555:Personality Inventory; D010865:Pilot Projects; D011092:Polyethylene Glycols / Q000009:adverse effects* / Q000627:therapeutic use; D011994:Recombinant Proteins; D012701:Serotonin / Q000097:blood; D014364:Tryptophan / Q000097:blood*
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012701:Serotonin; D007737:Kynurenine; D011092:Polyethylene Glycols; D014364:Tryptophan; C417083:peginterferon alfa-2b