Peg IFN proved to have depressive symptoms in chronic HCV patients by altering levels of tryptophan and phenylalanine. Also, our study proved that direct-acting antiviral (sofosbuvir) has the same side effects, as the two therapies having the same mechanism.
This study showed that increasing phenylalanine among treated cases at a cutoff of 2.13 μg/ml phenylalanine had 96.9% sensitivity, 62.5% specificity, and area under the curve of 0.848 with significant p value (0.003) to predict severe depression. Also, decreasing tryptophan levels among treated cases at a cutoff of 8.53 ng/ml had 81.2% sensitivity, 75% specificity, and area under the curve of 0.812 with significant p value of 0.007 to predict severe depression. Yang et al. found that with a bad prognosis of liver cirrhosis in HCV patients to hepatocellular carcinoma, the IDO level increases and converts tryptophan to kynurenine, so decreasing tryptophan level according to the fibrotic degree without the antiviral therapy, which is in contrast with our results (Yang et al. 2018).
Also Mehraj and Routy reported that in a chronic viral infection that was not cleared during acute infection highjacks the host immune response to create a state of disease tolerance via kynurenine catabolites via IDO-mediated pathway of tryptophan, so that confirming the hypothesis that kynurenine causing immunosuppression to the host (Mehraj and Routy 2015). Another result is done by Murakami et al. that agree with our result that reported IDO gene deletion in mice leading to increasing destruction of tryptophan (↓level) and that resulting in (↑) kynurenine and low serotonin level leading to high degree of depression (Murakami et al. 2016).
Also, the previous results confirmed that result which is done by Zoller.et al. who reported that viral IL28B polymorphism with C/C genotype in chronic HCV patients showed that highest rate of tryptophan destruction with kynurenine production (high KYN/TRP ratio) leading to immunosuppression, and T/T genotype showed the lowest rate (Zoller et al. 2015).
As our result proved that lowering tryptophan and increasing phenylalanine causing different depression degrees by using HDRS that study agreed with result done by Comai et al. who confirmed that increased IDO-mediated TRP metabolism along kynurenine pathway leading to TRP depletion and a decline of serotonin pathway leading to development of depressive symptoms observed in HCV patients undergoing IFN-α therapy, concluding that the antiviral therapy causing depressive symptoms via a long pathway starting with tryptophan amino acid as a precursor (Comai et al. 2011).
Also, our result agrees with the result done by Oxenkrug et al., who reported that the elevated tryptophan level may reflect the impairment of tryptophan conversion into serotonin in agreement with the suggested link between serotonin deficiency and depression. So, upregulation of IDO might be an additional risk factor of IFN-α-associated depression. This study confirms that antiviral therapy (IFN-α) causes depression by increasing IDO level that destructs TRP and lowers serotonin (Oxenkrug et al. 2014).
That result can be confirmed again by Loftis et al., results who reported that baseline serotonin level, in combination with other variables such as liver fibrosis degree, may be clinically useful for identifying patients in whom HCV can be cleared by antiviral therapy (Loftis et al. 2010), and that also can be explained by Messaoud et al., who reported that the reduced availability of TRP for serotonin synthesis and increased activation of KYN pathway and cortisol correlate with depression and suicide, so low tryptophan levels may be a biomarker of major depressive disorder (MDD) and suicide in MDD (Messaoud et al. 2018).
Also, Saleem et al.’s results agree with our study reporting that increasing TRP and brain serotonin metabolism change diet-restriction-induced behaviors such as depression, anxiety, and anorexia nervosa (AN). So, they conclude that diet-restriction-induced behavioral changes might be reverted back with the administration of TRP and helpful to improve psychological problems in AN (Saleem et al. 2018).
Also, Zignego et al.’s results agree with our result stating that HCV patients have reduced (− 28%)TRP levels and confirming that they frequently suffer from anxiety and depression-related symptoms (Zignego et al. 2007).