An option currently being explored for the treatment of COVID-19 is the use of interferons (INFs), either alone or in combination with other antiviral agents. INFs are known to shift the metabolism of tryptophan (TRP) away from its role as a precursor of serotonin. For some patients, reduction in TRP levels may either expose an underlying vulnerability to depression or trigger a de novo episode of depression. This Commentary discusses the pathway involved and recommends in-hospital augmentation with foods or supplements that increase TRP levels for COVID-19 patients treated with INFs. Selective serotonin reuptake inhibitors may also be tried if the depressive symptomatology is not short-lived.