hepatitis c is a major public health problem , 170 million people were reported to be affected worldwide ( who 1999 ) , 225 000 in australia ( 2002 ) . the cytokine interferon alpha ( inf- ) is administered in the treatment of hepatitis - c virus infection ( hcv ) for its immuno - protective quality . the hcv is an enveloped rna virus and 50% of infections progress to chronicity and up to 70% of the asymptomatic carriers have chronic active hepatitis and or cirrhosis . hcv produces symptoms of major depression including fatigue , increased sleepiness , irritability , loss of appetite , and cognitive difficulties ( capuron et al 2001 ; wichers and maes 2002 ; wichers et al 2005a ) . it has been hypothesized that major depressive illness in the general population is accompanied by activation of the inflammatory response system . an increased production and levels of pro - inflammatory cytokines by monocytes and th-1 like lymphocytes , for example , interlukin-1 , il-6 , tumour necrosis factor- ( tnf- ) , and inf- ( kronfol 2002 ) , have been found in major depression occurring in the general population . pro - inflammatory cytokines have been found to have significant effects on the tryptophan metabolism through the enzyme indoleamine-2,3-dioxygenase ( ido ) , which is activated . this results in diversion of tryptophan causing an increase in the ratio of neuro - protective kynurenate and neurotoxic  neurodegenerative quinolinate ( myint and kim 2003 ) . this cytokine tryptophan interaction leading to an imbalance between quinolinate and kynnurate in the brain lies at the basis of the neurodegerative hypothesis of depression . in inf--induced depression intervention with selective serotonin reuptake inhibitors ( ssris ) this paper concerns the onset of major depression in a cohort of inf--induced depression in hcv patients and the clinical observation of complete recovery with ssris . we examined the role of ssri antidepressant therapy in inf--induced depression in patients with hcv . the data were collected from the psychiatric liaison liver clinic of a large teaching hospital in canberra . the main reasons for referrals were 1 ) identifying high risk cases to determine the suitability for combination inf- and ribavirin treatment ; 2 ) developing a comprehensive treatment plan with the liver clinic team in selected cases to maximize compliance for completion of therapy ; and 3 ) for early detection and treatment of inf--induced neuropsychiatric complications particularly depression in order to achieve better treatment outcome . a consultant psychiatrist examined the referred patients and the psychiatric diagnoses were based on the dsm - iv criteria . a total of 78 patients were assessed and found eligible for inf- treatment by the gastroenterology team in their hep c clinic . of these the mean age of the cohort was 40 years and males represented 62.8% of the sample . five of these patients developed an aggravation of personality disorder nos ( dsm - iv ) without co - morbid depression . six of the 53 patients developed major depressive illness following the inf- treatment and had no other psychiatric co - morbidity . six patients who developed major depression and 5 who had aggravation of personality disorder were treated with ssri antidepressants and their progress was recorded fortnightly . four of these patients completed the full course of inf and ribavirin treatment for a period of 612 months , 1 patient developed liver cell carcinoma , and 1 dropped out in spite of good remission before completing the antiviral therapy . the five patients who had aggravation of their personality disorder and received the antidepressants showed no improvement in their mental state . the total number of patients observed in this study is small , as is also the case with other similar reports of patients of major depressive illness secondary to inf administration in hcv patients . these studies are not standardized and do not take into account dose and duration of inf treatment . inevitably they also have heterogeneous patient populations , and there is non - uniformity of the diagnostic criteria for depression and the assessment methods employed . in the six patients who developed significant depressive illness , the complete therapeutic response to ssri antidepressant therapy in all of them is striking . other workers have also reported similar high success rates in the treatment of depression following inf- therapy , with turner and blackwell ( 2005 ) reporting effective response in up to 75% and lang et al 78.5% ( 2003 ) . both schramm et al ( 2000 ) and hauser ( 2004 ) also reported almost 100% success in their series . this is in contrast to the treatment outcome in randomized , controlled clinical trials in major depression in the general population where the overall efficacy for most old and new antidepressant treatments is 50%55% ( parker 2005 ; khan et al 2005 ) . we would like to take into account the statistical differences between very small numbers of patients observed in this study with the outcome of much larger clinical studies . nonetheless , differences in the reversibility of inf - induced depression pending its further confirmation from larger standardized studies is a significant clinical observation . this observation warrants further discussion . if the pathophysiology of inf- is significantly reversible then there is cause to believe that this pathophysiology differs from that of major depression occurring in the general population . the role of intrinsic cytokines may incorporate several other and more complex pathways ( wichers and maes 2002 ) in major depressive disorder . for example , intrinsic cytokines are potent modulators of corticotrophin - releasing hormone ( crh ) which produces heightened hypothalamic - pituitary - adrenal ( hpa ) axis activity characterized by an increase in adrenocorticotropic hormone and cortisol , both of which have been reported to be elevated in major depressive illness ( brebner et al 2000 ; dunn 2001 ) . the role of the enzyme ido has been implicated in the pathophysiology of depression induced by inf- in hcv patients ( wichers et al 2005b ) . this enzyme is stimulated by proinflammatory cytokines including inf- ( wichers et al 2005b ) . first , the stimulation of ido activity induces the kynurenine pathway resulting in the production of neurotoxic metabolites ( depressogenic event ) . second , the tryptophan availability to brain is decreased . in a prospective study of 16 patients with hep c who were treated with inf- , wichers et al ( 2005b ) measured the onset and severity of depression , tryptophan , and kynurenine ratio and its metabolic product kynurenic acid ratio . they found that the montgomery asberg depression rating scale was significantly associated over time with the kynurenine and kynurenic acid ratio , reflecting increased ido activity . the wichers et al ( 2005b ) study favours the ido switch pathway rather than the serotonin depletion . we speculate that one possible or an alternative mechanism for the reversibility and complete remission of symptoms in these patients may be explained by the down - regulation / modification of the ido stimulation / activity , with ssri antidepressants resulting in modulation of the kynurenate and the quinolinate ratio . this speculation is further supported by the observation that in our cohort , the patients who received inf- therapy and developed aggravation of their personality disorder , showed no improvement , as they possibly did not have the underlying ido pathophysiology and therefore inf - induced depression . the ssris have therapeutic efficacy in the treatment of inf--induced major depression in hcv patients and may have mechanism and sites of action other than conventionally considered . other implication of our observation are that patients who are receiving treatment with pro - inflammatory cytokines should be routinely screened for depressive symptoms , as these symptoms appear to be fully responsive to therapeutic intervention . future clinical studies of antidepressants should incorporate cellular and biochemical response of the monocytes and lymphocytes in a variously depressed population of patients . a consensus should be developed as how to undertake larger multicenter studies to examine the role of ido , in the pathophysiology of depression .
this paper examines the role of selective serotonin reuptake inhibitors ( ssris ) in the treatment of hepatitis - c virus ( hcv ) patients who have developed interferon- induced depression . 
 a 2-year data analysis of hcv psychiatric liaison clinic has been undertaken . the diagnosis , treatment , and progress of those patients who were treated with interferon- ( inf- ) are reported . 
 53 of the 78 patients enrolled at the hcv clinic and treated with inf- were referred for psychiatric consultation . 
 six patients developed major depressive illness following inf therapy . 
 they were all treated with ssris and they made full recovery . 
 this is a significant observation and is concordant with other studies . 
 its biochemical ramifications are presented . 
 it is concluded that inf - induced depression is fully reversible . 
 a hypothesis is proposed that ssris modulate the neuro - protective neurotoxic ratio by possibly inhibiting the indole-2,3-dioxygenase induction of the kynurenine pathway .