Managing epilepsy-associated depression: Serotonin enhancers or serotonin producers?

Depression is one of the major psychiatric comorbidities having a major impact on the quality of life in people with epilepsy (PWE). Selective serotonin reuptake inhibitors (SSRIs) are considered as safest therapy for the treatment of depression in PWE. Although administration of SSRIs increases the synaptic serotonin levels, it decreases the overall serotonin synthesis in the brain. Long-term therapy with SSRIs has been reported to decrease serotonin synthesis, which may be the possible reason for lessening of their antidepressant effect over time as well as elevated seizure outcomes observed in PWE. Thus the present scenario warrants streamlined studies to explore the safety and efficacy of SSRIs as well as approaches beyond SSRIs for treatment of depression in epilepsy. In this review, we outline the approaches which may restore serotonin levels rather than a pseudo enhancement of serotonin with SSRIs. The potential of various anti-inflammatory approaches such as selective cyclooxygenase-2 inhibitors, inflammatory cytokine inhibitors, and indoleamine 2,3-dioxygenase inhibitors pertaining to their serotonin restoring effects is discussed as possible therapy for treatment of depression in epilepsy.