The studies in this dissertation are designed to address whether antidepressant-mediated neuroplasticity can benefit Parkinson’s disease (PD). The first aim investigates whether antidepressants are neuroprotective to dopamine (DA) neurons in the 6-OHDA rat model of PD. The second aim examines whether antidepressant therapy can increase neurotrophic factors relevant to DA neuron survival in the intact and degenerating nigrostriatal system. The final aim extends the scope of the previous two aims to determine whether antidepressants have disease-modifying effects in a population of early PD patients. Findings from these studies show the tricyclic antidepressant (TCA) amitripyline (AMI) partially protects DA neurons of the injured nigrostriatal system. Furthermore, results show divergent regulation of brain derivedneurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) occurs within the nigrostriatal system in response to AMI treatment before and after 6-hydroxydopamine lesion. Taken together, these results suggest that AMI treatment elicits significant trophic changes important to DA neuron survival within both the intact and injured nigrostriatal system. Additionally, results from our patient-level meta-analysis indicate TCAs have disease-modifying effects in an early population of PD. Further, they suggest that untreated mild depression is associated with a higher probability to begin therapy compared to subjects taking antidepressants or non-depressed subjects. Interestingly, there was no impact on annualized UPDRS scores for antidepressant treatment or depression severity. These results suggest tricyclic therapy may provide additional therapeutic benefit for PD patients beyond the treatment of depressive symptoms. Additionally, they highlight the importance of treating depression in PD. Overall, the studies in this dissertation show that antidepressants mediate neuroplastic changes that extend beyond the mesolimbic system, which may have important consequences in PD. They also point to a need for more widespread therapies that address both the motor and non-motor symptoms that contribute to the overall disability experienced by PD patients.