A Novel Target to Improve Outcomes in Late-Life Depression?


A new study sheds light on the neurological basis of late-life depression (LLD) with apathy and often poor response to treatment.

Researchers led by Faith Gunning, Ph.D., of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and post-treatment brain MRIs, as well as functional MRIs (fMRIs) of elderly people with depression who participated in a 12-week open non-randomized study. clinical trials of escitalopram. Participants underwent clinical and cognitive evaluations.

Impaired resting-state functional connectivity (rsFC) between the salience network (SN) and other large networks that support goal-directed behavior, especially in depressed patients who also had signs of apathy.


Even after participants completed escitalopram treatment, apathy-related functional association variability was associated with poor response to antidepressants and persistent cognitive dysfunction.

“This study suggests that in older people with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for new interventions,” the researchers wrote.

The study was published online July 27 in the JAMA Network Open.


Main cause of disability

The authors write that LLD is “a leading cause of disability and morbidity in the elderly”, with one-third to one-half of patients with LLD also suffering from apathy.

Older people with depression and associated apathy have worse outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with people with LLD but without apathy.


Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain mechanisms behind apathy,” the authors note.

A “new hypothesis” points to a role for compromised SN and its large-scale associations between apathy and poor response to treatment in LLD.

The SN (which includes the insula and the dorsal anterior cingulate cortex) “assigns motivational value to the stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and the default mode network (DMN)”.


Preliminary studies of apathy in depressed patients report a decrease in volume in SN structures and suggest disruption of functional connectivity between SN, DMN, and the executive control network; but the mechanisms linking apathy to poor response to antidepressants in LLD are “not well understood.”

“Connectometry” is “a novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways”. It has been used in conjunction with rest imagery but has not been used in the study of apathy.

The researchers investigated the functional connectivity of the SN by hypothesizing that changes in connectivity between key SN nodes and other main circuits that modulate goal-directed behavior (DMN and the executive control network) were associated with depression and apathy.

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They used connectometry to “detect structural connectivity disorders at the pathway level”, suggesting that impairment of the fronto-parietal and fronto-limbic pathways would be associated with apathy in patients with LLD.

They also wanted to know if apathy-related network abnormalities were associated with response to antidepressants after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.

New model

The study included 40 elderly people (65% women; on average [SD] age, 70.0 [6.6] years) with a DSM-IV diagnosis of major depressive disorder (no psychotic features) who were from a single-arm, open-label study of escitalopram treatment.

The Hamilton Depression Rating Scale (HAM-D) was used to assess depression, and the Apathy Rating Scale was used to assess apathy. On the Apathy Rating Scale, a score of >40.5 represents “clinically significant apathy”. Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.

They also underwent a series of neuropsychological tests to assess cognitive function and underwent MRI scans. fMRI was used to map group differences in rsFC SNs, and diffusion connectometry was used to “evaluate disruption of structural connectivity at the pathway level”.

Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or severity of depression at baseline between those who had apathy and those who did not.

Compared to participants with depression but no apathy, participants with depression and comorbid apathy had lower rsFC of the seeds of the significance network (specifically, the dorsolateral prefrontal cortex). [DLPFC]premotor cortex, middle cingulate cortex, and paracentral lobule).

They also had higher rsFC in the lateral temporal cortex and temporal pole (z>2.7; Bonferroni-corrected threshold P<0.0125).

In addition, participants with apathy had lower structural connectivity in the truncus, cingulate gyrus, and frontooccipital fasciculus compared with participants without apathy (t > 2.5; corrected false discovery rate P = 0.02).

Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (HAM-D score <10). Participants with apathy responded worse to escitalopram treatment.

Inferior insular DLPFC/rsFC of the middle cingulate cortex was associated with less improvement in depressive symptoms (percent change in HAM-D, β [df] = 0.588 [26]; P = 0.001), as well as a greater likelihood that the participant will not achieve remission after treatment (odds ratio, 1.041, 95% CI, 1.003-1.081, P = 0.04).

In regression models, the inferior insular DLPFC/rsFC of the middle cingulate cortex was found to mediate the association between baseline apathy and persistence of depression.

SN’s findings were also relevant to cognition. Inferior dorsal anterior cingulate gyrus-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (β [df] = 0.445 [26] and β [df] = 0.384 [26], respectively; for each P = 0.04).

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“These results support a novel model of apathy that suggests that apathy may arise from dysfunctional interactions between the major networks (eg, SN, DMN, and executive control) that support motivated behavior,” the researchers write.

“This can lead to a failure of network integration, leading to difficulty processing salience, planning actions, and initiating behavior, which manifests clinically as apathy,” they conclude.

One of the limitations they note was the lack of long-term follow-up after emergency treatment and “a relatively limited neuropsychological battery”. Therefore, they could not “determine the persistence of treatment differences or the specificity of cognitive associations.”

The researchers add that “novel interventions that modulate the interactions between affected circuits could help improve clinical outcomes in this distinct subset of elderly people with depression, for whom few effective treatments exist.”

Comment for Medscape Medical News, Helen Lavretzi, MD, professor of psychiatry in residence and director of the Program for Research on Mood, Stress, and Health in Late Life and the Clinic for Integrative Psychiatry at the Jane and Terry Semel Institute of Human Neurology and Behavior, David Geffen UCLA School of Medicine in Los Angeles said the results “may be used in future research aimed at understanding apathy and the underlying neural communication mechanisms of the brain.” Lavretsky did not participate in the study.

The study was supported by grants from the National Institute of Mental Health. Gunning reported receiving grants from the National Institute of Mental Health during his research and grants from Akili Interactive. Disclosures by other authors are listed in the original article. Lavretsky reports the absence of relevant financial relations.

The JAMA network is open. Published online July 27, 2022 Full text

Batya Swift Yasgur, Massachusetts, LSW, is a freelance writer with a consulting practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books, as well as Behind the Burqa: Our Life in Afghanistan and How We Fled to Freedom (a memoir of two brave Afghan sisters who told her their story).

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