Discussion:
Manic symptoms were reported during the third cycle of chemotherapy. The emergence of manic symptoms in the later part of chemotherapy regimens is consistent with the findings published earlier on capecitabine challenge hypothesis7,11. It is also noteworthy to know that Capecitabine is a prodrug of 5 FU, therefore the cumulative adverse effects in the form of mania cannot be ruled out after two cycles of chemotherapy 11. The gradual resolution of manic symptoms after discontinuation of Capecitabine by the patient supports the dechallenge hypothesis. Further, rechallenging with the capecitabine coincided with the re-emergence of manic symptoms that were effectively controlled within a week after starting risperidone alone. In addition, the absence of previous mood episodes, absence of symptoms of delirium or encephalopathy during chemotherapy were characteristic findings of our case that were different from the report published earlier 7. The typical age of presentation of mania, presence of a family history of mood disorder favors the diagnosis of primary mania, however, absence of previous mood episode, the challenge-dechallenge-rechallenge hypothesis with capecitabine chemotherapy favors the capecitabine induced ADR in the form of mania. The score of six on the Naranjo Nomogram Adverse Drug Reaction Scale also implied the probable association of capecitabine and mania.
As capecitabine is the first-line treatment for the CA rectum, the CLP team advised to continue it under the cover of oral risperidone, a potent dopamine blocker, useful to alleviate acute manic symptoms as well as exhibiting additional tumor inhibitory activity a focus of future research12,13. Since behavioral symptoms can limit the compliance to medications, we recommend a careful analysis of the need for continuing the chemotherapy agent in liaison with the psychiatry team in such cases.
The exact cause of the evolution of affective symptoms while on a chemotherapy regimen is a less researched area. Involvement of the kynurenine system in the pathophysiology and clinical symptoms of both cancer and bipolar disorder is a possible hypothesis supported by the recent literature 8,9. The role of Pro-inflammatory cytokines such as TNF-α and IFN-γ assist the degradation of tryptophan through activation of alternative kynurenine pathway that results in the formation of Quinolinic acid and its metabolites that may exert neurotoxic effects on the Central Nervous System (CNS)9. The same mechanism is also postulated to be the reason for the promotion of tumor growth in cancer patients,8 which requires further research in cancer research. While the role of risperidone in blocking the dopaminergic and serotonergic receptors as well as TNF alpha requires further exploration in the context of this ADR8.  Further, it is interesting to note that concurrent radiotherapy and initial two cycles of chemotherapy with capecitabine were not associated with behavioral disturbances against isolated chemotherapy cycles in the later period. The possible cumulative toxic effect of capecitabine is postulated hypothesis for such a late occurrence of ADR. An alternative explanation evolves from the weaning effect of radiotherapy-induced anti-tumor immune activation because of the healing tendency of a healthy tissue that results in the resolution of inflammation in the aftermath of radiation exposure14. Activation of the kynurenine pathway in mood disorders is governed by the acute as well as chronic shift in the anti and pro-inflammatory response of the immune system15. This mechanism could support the hypothesis of maintenance of normal behavior during radiotherapy due to the pro-inflammatory response of the immune system which can indirectly shift the balance towards the anti-inflammatory end during the aftermath of radiotherapy resulting in prominent mood symptoms via activation of the kynurenine pathway16,17.
Acknowledgment: Nil
Conflict of interest: Authors declare no conflict of interest.
Funding and sponsorship: This case report is not supported by funding or grants from any agency.