Individuals with Late Life Depression (LLD) often have cognitive deficits, particularly executive dysfunction (ED), which is associated with antidepressant non-response. Our group and others have shown that decreased processing speed is the central cause of functional impairment in patients with LLD. Similarly, decreased gait speed is associated with depression and carries additional risk for falls, hospitalization, an death. Available evidence suggests that declining functionality of the nigrostriatal dopamine system contributes to age-related cognitive and motor slowing. The central hypothesis of this R61/R33 Phased Innovation Award is that by enhancing striatal dopamine neurotransmission and improving cognitive and motor slowing, administration of carbidopa/levodopa (L-DOPA) will improve depressive symptoms in older adults. In the R61 Phase, 60 adults aged > 60 years with (1) a DSM 5 depressive disorder, (2) significant depressive symptoms (CES-D > 10), (3) decreased processing speed (? 1 SD below age-adjusted norms), and (4) decreased gait speed (average walking speed over 15' < 1m/s) will be randomized to receive 3 weeks of treatment with L-DOPA 100mg or 300mg. We will test each dose for engagement of our molecular and functional targets by determining whether L-DOPA increases synaptic dopamine (measured by displacement of [11C]-raclopride on pre-post L-DOPA positron emission tomography [PET]) and increases processing and gait speed. Additional baseline PET and magnetic resonance imaging (MRI) will compare subjects with 15 healthy controls (HCs) on measures of endogenous dopamine functioning, structural and morphologic brain indices, and neural activation patterns underlying processing speed. If L-DOPA increases dopamine release and improves slowing at our proposed thresholds, we will proceed to compare the best-tolerated dose of L-DOPA exhibiting target engagement to placebo in the R33 Phase. 90 additional subjects meeting the above criteria will be randomized to L-DOPA or placebo in order to determine whether L-DOPA improves depressive symptoms and examine how changes in processing and gait speed influence depressive symptoms. Our target for the R33 Phase is depressive symptomatology as measured by the Hamilton Rating Scale for Depression (HRSD). Data collected in the proposed studies may help identify a novel therapeutic approach to LLD, which could have large public health ramifications given the prevalence, frequent treatment resistance, and chronicity characteristic of LLD. This project also will elucidate the neurobiology of slowing at molecular, structural, and functional levels of analysis, increasing our understanding of the interplay between these aging-associated processes and the pathophysiologic changes underlying late life neuropsychiatric disorders. Exploring patient-level moderators of response to L-DOPA may provide useful information to guide differential therapeutics and develop personalized medicine for LLD.
Late Life Depression, a prevalent disorder causing substantial disability in older patients, does not respond well to first-line antidepressant medications. This application seeks to develop a new treatment intervention for Late Life Depression by targeting the cognitive and motor slowing that is frequently observed in older depressed patients.