Anemia is prominently involved, but certainly not the only factor in the pathogenesis of cancerrelated fatigue. Fatigue and also reduced physical performance are among other symptoms frequently encountered in BYL719 PI3K inhibitor patients with depression. Interestingly, associations between immune-mediated tryptophan breakdown and fatigue were only significant in patients without antidepressant medication, which fits well with results of an earlier study in HIV-infected patients. In that study, correlations between immune activation and Becks depression score as well as QoL Score MQoL-HIV were encountered only in patients without antidepressant treatment. Our data thus indirectly indicate that immune activation and tryptophan breakdown might be related with the development of fatigue. Antidepressant treatment appeared to influence the relationship between fatigue feeling and the biochemical pathways we investigated in our population of lung cancer patients: Patients under antidepressant treatment had lower tryptophan and higher CRP levels than those without this medication, also indicating indirectly that enhanced tryptophan breakdown might be involved in the development of depression. However, this finding may be biased by the fact that we had only 50 patients and a high percentage of patients with antidepressant medication. Tryptophan is the precursor of neurotransmitter serotonin, and thus, increased tryptophan breakdown might lead to decreased serotonin formation or trigger depressive-like behaviour by the accumulation of neurotoxic metabolites of kynurenine: Elevated concentrations of neurotoxins quinolinic acid and 3-hydroxykynurenine have been shown in the CSF and also brains of patients with inflammatory neurological diseases. Quinolinic acid interferes with the NMDA receptor and alleviates NMDAmediated induction of apoptosis of primary neuronal cell cultures, while 3-hydroxy-kynurenine generates free radicals, which can cause oxidative stress and lipid peroxidation. Kynurenic acid on the other hand is an endogenous neuroprotect, the formation of which is increased in patients with inflammatory neurological diseases, but in fact, the balance between neurotoxic and neuroprotective kynurenine metabolites seems to be shifted towards neurotoxins in patients with chronic immune activation and also in patients with major psychiatric disorders. Also a recent study in mice points to a crucial role of IDO in the development of depressive-like behaviour: Chronic infection with BCG induced depressive-like behaviour in normal mice, while IDO-deficient mice were resistant to BCG-induced depressive-like behaviour. Interestingly, IDO-deficient mice showed a normal induction of pro-inflammatory cytokines in response to BCG infection. However, there is also the possibility that tryptophan catabolism can be stressinduced when hepatic tryptophan 2,3-dioxygenase is upregulated. In fact, IDO expression in cells or tissues was not examined in our cancer patients, but the significant relationship found between neopterin and Kyn/Trp supports a role of IDO in the cytokine-induced tryptophan metabolic changes observed in our patients. Recent data by Capuron and coworkers are in line with this hypothesis, in fact increased tryptophan catabolism was associated with the depressive symptoms of lassitude, reduced motivation, anorexia, and pessimism, while disturbed phenylalanine/tyrosine/dopamine metabolism was shown to be related with neurovegetative symptoms.