[Impact of interferon alpha immunotherapy on tryptophan metabolism in patients with chronic hepatitis C. Results of a pilot studies on ten patients]. / Impact du traitement par interféron alpha sur le métabolisme du tryptophane chez des patients porteurs d'hépatite C chronique Résultats de la phase d'étude pilote sur dix patients.

INTRODUCTION: 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. METHOD: 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. CONCLUSION: 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.

[Hepatitis C, interferon a and depression: main physiopathologic hypothesis]. / Hépatite C, Interféron alpha et dépression: principales hypothèses physiopathologiques.

UNLABELLED: Imputability of thymic disorders caused by IFNalpha during the chronic Hepatitis C treatment -- hepatitis C and depression -- the infection by the hepatitis C virus (HCV) is a major public health concern since it affects 1.2% in the French population. Eighty percent of those contaminated by HCV keep bearing the virus chronically although they remain asymptomatic during many years. HCV infection is associated with psychiatric symptoms like depression. Together with other factors (eg the severity of hepatic condition), depression may induce significant impairment in quality of life. Conversely, some psychiatric conditions may increase the risk of HCV infection. In drug-addicted subjects using intravenous route, HCV contamination rate ranges from 74 to 100%. Compared with general population, a higher HCV contamination rate has also been noticed in some other subgroups of subjects (patients with alcohol abuse or dependence, with alcohol-induced hepatic disease and psychiatric inpatients). However, no valid explanation to this phenomenon has been established. Interferon alpha and depression - Interferons are a variety of cytokines naturally produced by human tissues and have also been synthesized for therapeutic purposes (treatment of a variety of cancers and viral infections). Many psychobehavioural symptoms are observed under IFNalpha treatment. Among them, mood disorders are known to occur early after entry into treatment and to be within the reach of preventive measures. The reported frequency of depression during IFNalpha treatment ranges from 0 to 37%. This variation reflects either methodological biases (eg differences in psychiatric assessment) or the heterogeneity of the population of patients accepted in therapeutic protocols. Note that the adjunction of ribavirine to IFNalpha in therapeutic protocols has not brought any changes in the depression frequency. The causal relationship between IFNalpha administration and the occurrence of mood disorders has been tackled by various recent research works focusing on the importance of the immune system in the pathophysiology of depression. Miscellaneous pathophysiological hypotheses -- nature of the psychobehavioural symptomatology -- in addition to depressive symptoms, IFNalpha treatment also induces various cognitive impairments and disruptions in EEG patterns. These symptoms are consistent with a mild subcortical dementia. Data resulting from pharmacological trials in humans and in animals are controversial (eg IFNalpha-induced symptoms being alleviated by both immune and antidepressant therapies). However, the debate about the nature of the psychobehavioural disorders observed under IFNalpha treatment might be no longer relevant in the light of recent theories which regard depression as a maladaptive response to a particular form of stress, namely a deep and diffuse feeling of sickness ("malaise"). These theoretical views ascribe the production of depressive symptoms to a disruption in the immune function, mediated by the variety of cytokines. The therapeutic effects of anti-depressive drugs are thus attributed to their analgesic properties, reducing the "malaise" feeling underlying depressive symptoms. Necessity of a second messanger -- accordingly to current pathophysiological theories, depression results from disorders of various CNS functions, mainly limbic, monaminergic and neuroendocrinal systems. Though, exogenous IFNalpha does not cross the blood-brain barrier when unscathed and an intermediary mechanism is necessary. First to be addressed is the cytokines system itself since it is composed of numerous different molecules interacting in an infinite number of possible combinations. Some of these cytokines (eg some interleukins) both are activated by IFNalpha and can reach CNS; they are good candidates for the role of second messenger mediating the induction of psychobehavioural disorders. Second, keeping in mind that serotonin is a monoaminergic neurotransmitter classically involved in depression pathophysiology, other works have demonstrated that IFNalpha modulates the peripheral activity of indolamine-dioxygenase -- a regulating enzyme of serotonin metabolism -- possibly through lymphocyte T CD4 activation. Third, other authors have postulated an immune-induced vagal mechanism to explain depression caused by IFNalpha. Action of IFNalpha on the neuroendocrine and on neuromodulating functions: monoaminergic hypothesis -- cytokines could have an influence on the mood through their modulating role on the serotoninergic system. IFNalpha treatment is reported to produce: 1) a decrease in tryptophan availability for serotonin synthesis, 2) a decrease in the 5-HIAA level in the LCR, and 3) a modification of the central serotoninergic receptors. Moreover, selective inhibitors of serotonin transporters are effective to treat or prevent depression caused by IFNalpha. Many studies support the serotonin-transporter hypothesis: in vitro, both IFNalpha and interleukine 4 (IL-4) increases the expression of serotonin transporter gene, IFNalpha increases in the production of IL-4 by mononucleus cells (not found in vivo). Serotoninergic system can also be altered by a peripheral action of IFNalpha on trytophan catabolism by activating a concurrent pathway (known as "kynurenine pathway") to serotonin synthesis. Finally, serotonin-mediated vulnerability to the psychobehavioural effects of IFNalpha could be underlain by a polymorphism of serotonin transporter gene. Concerning the other monoaminergic systems, IFNalpha seems to have an amphetamine-like effect at its first administration, followed by a decrease in dopaminergic tone with chronic administration. Dopaminergic depletion, subsequent to psychostimulant abuse for instance, results in severe depressive syndromes. Interactions between IFNalpha and noradrenergic system have also been reported. Neuroendocrinian hypothesis -- when administered through central or peripheral way, IFNalpha simulates/inhibits the corticotrope axis and alters endorphin system as shown by the induction of analgesia, catatonia and behavioural slowdown that can be suppressed by opioid antagonists. IFNalpha neurotoxic effects are successfully treated by naltrexone. Lastly, IFNalpha is known to cause disorders in thyroid function that are likely to contribute to the production or aggravation of mood disorders. CONCLUSION: A better understanding of pathophysiologic mechanisms underlying psychiatric side-effects of IFNalpha is essential to extend access to treatment to some categories of patients that remain excluded from the protocols. A better management of those psychiatric side effects should help the clinician not to draw aside patients at risk, ie patients with depression, drug and alcohol addiction. Treating them in a pragmatic and careful way is a major issue, since this population represents a high percentage of the potential candidates for interferon therapy.