Comparison of Functional and Structural Neural Network Features in Older Adults With Depression With vs Without Apathy and Association With Response to Escitalopram

Abstract

IMPORTANCEApathy is prevalent among individuals with late-life depression and is associated with poor response to pharmacotherapy, including chronicity and disability. Elucidating brain networks associated with apathy and poor treatment outcomes can inform intervention development. OBJECTIVES To assess the brain network features of apathy among individuals with late-life depression and identify brain network abnormalities associated with poor antidepressant response. DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of a single-group, open-label nonrandomized clinical trial of escitalopram conducted at an outpatient geriatric psychiatry clinic enrolled 40 adults aged 59 to 85 years with major depressive disorder from July 1, 2012, to July 31, 2019. INTERVENTIONS After a 2-week washout period, participants received escitalopram titrated to a target of 20 mg/d for 12 weeks. MAIN OUTCOMES AND MEASURES Baseline and posttreatment magnetic resonance imaging (MRI), clinical, and cognitive assessments were conducted. Functional MRI was used to map group differences in resting state functional connectivity (rsFC) of the salience network, and diffusion MRI connectometry was performed to evaluate pathway-level disruptions in structural connectivity. The Apathy Evaluation Scale was used to quantify apathy, and the Hamilton Depression Rating Scale (HAM-D) was used to quantify the primary outcome of depression severity. RESULTS Forty participants (26 women [65%]; mean [SD] age, 70.0 [6.6] years [range, 59-85 years]) with depression were included; 20 participants (50%) also had apathy. Relative to nonapathetic participants with depression, those with depression and apathy had lower rsFC of salience network seeds with the dorsolateral prefrontal cortex (DLPFC), premotor cortex, midcingulate cortex, and paracentral lobule and greater rsFC with the lateral temporal cortex and temporal pole (z score >2.7; Bonferroni-corrected threshold of P < .0125). Compared with participants without apathy, those with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus (t score >2.5; false discovery rate-corrected P = .02). Twenty-seven participants completed escitalopram treatment; 16 (59%) achieved remission (HAM-D score <10). Lower insula-DLPFC/midcingulate cortex rsFC was associated with less symptomatic improvement (HAM-D % change) (β [df] = 0.588 [26]; P = .001) and a higher likelihood of nonremission (odds ratio, 1.041 [95% CI, 1.003-1.081]; P = .04) after treatment and, in regression models, was a mediator of the association between baseline apathy and persistence of depression.(continued) Key Points Question What are the brain network features of apathy in late-life depression, and how are they associated with treatment outcomes? Findings In this secondary analysis of a 12-week nonrandomized single-group trial of escitalopram titrated to 20 mg/d, compared with 20 older adults with depression without apathy, 20 older adults with depression and apathy showed distinct alterations in ne...

Connectivity patterns of the core resting-state networks associated with apathy in late-life depression

“… 46 While we identified very similar ROIs associated with apathy to previous results on the topic, the directions of the associations we observed were different from those reported in the studies using seed-based approaches. 9 , 47 , 48 These differences might be related to the use of few seeds in previous studies omitting the variability between ROI connectivity within a same RSN. Our findings suggest that the AES might provide a more consistent measure of modified intranetwork connectivity in the DMN in individuals with apathy.…”

“… 7 Apathy was also correlated with higher rsFC between the anterior insula and the right DLPFC, mid-cingulate and premotor cortices, and reduced rsFC with the bilateral parietal posterior regions. 8 , 9 This hyperconnectivity between the insula and the DLPFC has been associated with treatment nonresponse in individuals with apathy and LLD, 9 while hypoconnectivity between the dACC and DLPFC has been correlated with poorer executive functions 10 and apathy during effortful emotion recognition 11 in individuals with LLD. Taken together, these results suggest that apathy in LLD and its traits are underpinned by an altered intrinsic rsFC of the executive network as well as a dysconnectivity of the anterior insula to recruit goal-oriented cognitive and motor processes.…”

“…Taken together, these results suggest that apathy in LLD and its traits are underpinned by an altered intrinsic rsFC of the executive network as well as a dysconnectivity of the anterior insula to recruit goal-oriented cognitive and motor processes. 9 , 12 …”

Post-stroke apathy biotypes and their relation to the effort-based reward decision network: a resting-state fMRI study

“…For example, some studies have found that antidepressant treatments may exacerbate symptoms of apathy 20 . And Lauren et al found in elderly depressed patients that apathy may contribute to antidepressant side effects 21 . In our study, biotypes 1, 2, and 4 have similar symptoms but different or even completely opposite neurobiological bases.…”

The neurobiology of apathy in depression and neurocognitive impairment in older adults: a review of epidemiological, clinical, neuropsychological and biological research

“… Yuen, et al, [ 139 ] rsfMRI ROI-to-voxel FC right anterior insula, rAI as ROIs AES HC ( n = 10), LLD with apathy ( n = 7) LLD without apathy ( n = 9) LLD with apathy had lower FC within salience network (rAI-dACC) and higher rAI-dlPFC and rAI-PCC FC. Oberlin, et al, [ 140 ] rsfMRI, dMRI ROI-to-Voxel functional connectivity and structrual connectivity AES LLD with apathy ( n = 20) LLD without apathy (n = 20) Among the 40 LLD, 12-week nonrandomized single-group trial of escitalopram, 27 remitted Relative to nonapathetic depression, those depression with apathy had lower FC of SN seeds with the dlPFC, premotor cortex, mid CC, and paracentral lobule and greater FC of SN with the lateral temporal cortex and temporal pole. Compared with depression without apathy, those with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus.…”