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.