Potential mechanisms underlying anxiety and depression in Parkinson's disease: consequences of l-DOPA treatment

Though the most recognizable symptoms of Parkinson's disease (PD) are motor-related, many patients also suffer from debilitating affective symptoms that deleteriously influence quality of life. Dopamine (DA) loss is likely involved in the onset of depression and anxiety in PD. However, these symptoms are not reliably improved by DA replacement therapy with l-3,4-dihydroxyphenylalanine (l-DOPA). In fact, preclinical and clinical evidence suggests that l-DOPA treatment may worsen affect. Though the neurobiological mechanisms remain unclear, recent research contends that l-DOPA further perturbs the function of the norepinephrine and serotonin systems, already affected by PD pathology, which have been intimately linked to the development and expression of anxiety and depression. As such, this review provides an overview of the clinical characteristics of affective disorders in PD, examines the utility of animal models for the study of anxiety and depression in PD, and finally, discusses potential mechanisms by which DA loss and subsequent l-DOPA therapy influence monoamine function and concomitant affective symptoms.