Research ReportNeuroanatomical correlates of apathy in late-life depression and antidepressant treatment response
Introduction
Apathy is a common feature of late-life depression (Chase, 2011, Krishnan et al., 1995, Mehta et al., 2008). It afflicts 19–88% of those suffering from major depression, and is most prevalent in depressed older adults (Forsell et al., 1993, Lampe and Heeren, 2004, Mehta et al., 2008). The syndrome of apathy is defined as a primary motivational impairment that in depression results in diminished goal-oriented behavior, lack of intellectual interest, and indifference or flattening of affect (Marin, 1990). These clinical signs often translate into apathetic, depressed patients being poorly engaged in treatment, posing a greater burden to caregivers, and having increased risk of future functional and cognitive impairment(Holtta et al., 2012). Further, apathy is a predictor of poor response to antidepressants(Chaturvedi and Sarmukaddam, 1986, Levkovitz et al., 2011), and chronicity of depression (Lavretsky et al., 1999).
While selective serotonin reuptake inhibitors (SSRIs) are prescribed first-line for depression, apathy response to SSRIs is variable. Several case reports and case-control studies argue that SSRIs may actually cause or exacerbate apathy when used in the treatment of depression (Bolling and Kohlenberg, 2004, Fava, 2006, Hoehn-Saric et al., 1990, Kodela and Venkata, 2010, Padala et al., 2012, Sato and Asada, 2011, Wongpakaran et al., 2007). It is unclear to what extent apathy represents an SSRI side effect, a residual symptom not adequately treated by SSRIs alone, or both. To date, we lack an understanding of the neurobiology of apathy in depression and lack a consensus on its optimal treatment. As such, this study sought to investigate differences in neuroanatomical correlates that might explain the variable response of apathy to SSRI treatment in the context of depression.
Convergent findings from structural MRI, functional MRI, and neuropsychological studies implicate altered function of frontolimbic networks in late-life depression (Alexopoulos et al., 2012, Alexopoulos et al., 1997, Gunning-Dixon et al., 2009, Gunning-Dixon et al., 2008, Raz et al., 1997). Among the frontolimbic networks implicated in geriatric depression, the anterior cingulate cortex (ACC) plays a key role (Alexopoulos et al., 2008a). Based on cytoarchitecture and functional connectivity, the ACC is divided into dorsal (BA 24b′–c′ and 32′) and perigenual ACC (rostral BA 24a–c and 32 and subgenual BA 25 and 33) regions, which govern cognitive and emotional processes, respectively (Bush et al., 2000, Devinsky et al., 1995, Drevets et al., 2008, Vogt et al., 1992). While the dorsal ACC controls aspects of executive function (conflict detection, cognitive inhibition, and conflict resolution) (Carter et al., 1998, Carter and van Veen, 2007, Posner and DiGirolamo, 1998), the perigenual ACC assesses the salience of emotional input and regulates emotional responses (Devinsky et al., 1995, Etkin et al., 2006). In a previous analysis, our group described a pattern wherein smaller dorsal and rostral ACC volumes and decreased frontosubcortical white matter integrity predicted failure of depression to remit with SSRI treatment (Alexopoulos et al., 2010, Alexopoulos et al., 2002, Alexopoulos et al., 2008b, Gunning et al., 2009).
Given the association of apathy with poor depression response to antidepressants, we performed a post-hoc, secondary analysis to explore a potential relationship between structural characteristics of ACC and adjacent white matter tracts and apathy in late-life depression. Several clinical observations and neuroimaging studies support the notion that apathy may emerge from frontosubcortical network dysfunction and ACC abnormality. Apathy is common in elderly individuals with prominent vascular white matter lesions (Alves et al., 2009, Lavretsky et al., 2007) and focal frontal lobe and basal ganglia lesions (Chase, 2011, Levy and Dubois, 2006). Among various neurodegenerative diseases, apathy develops early and prominently in dementias with greater frontosubcortical pathology (Huntington׳s, Lewy Body, Parkinson׳s and HIV dementia) (Chase, 2011, Quaranta et al., 2012, Starkstein et al., 2006), and, in the case of Alzheimer׳s disease, apathy correlates with neurofibrillary tangle density in the ACC (Marshall et al., 2006) and reduced gray matter volume and metabolic activity of the ACC (Apostolova et al., 2007, Bruen et al., 2008, Marshall et al., 2007, Starkstein et al., 2009). In a prior study of late-life major depression, apathy was associated with reduced right ACC gray matter volumes (Lavretsky et al., 2007). Further dissecting the neural correlates of apathy in depression would afford an understanding of the brain circuitry underlying motivational states and thus inform future treatment approaches for apathetic depression.
The objectives of this study were to examine the prevalence and severity of apathy in a clinical sample of patients with late-life depression, to analyze the response of apathy to SSRI treatment, and to identify the neuroanatomical correlates that might explain the maintenance of an apathetic state. We included a non-depressed comparison group to examine the relative specificity of such neuroanatomical findings to apathetic versus depressed states. Guided by the above literature, this study focused on the role of ACC subregions and white matter tracts in the apathy of late-life depression. It hypothesized that depressed elders who suffer from persistent apathy despite SSRI treatment were more likely to possess structural abnormalities in perigenual, as opposed to dorsal, ACC and in white matter tracts connecting the perigenual ACC to structures related to mood regulation, such as the amygdala and ventral striatum.
Section snippets
Participants
We studied 45 non-demented, elderly (>60 years) patients with non-psychotic major depression and 43 elderly, psychiatrically healthy participants. Subjects were recruited through radio and print advertisement in community radio stations and newspapers. Participants signed written informed consent approved by the Institutional Review Boards of Weill-Cornell Medical College and of the Nathan Kline Institute.
The depressed group met DSM-IV-TR criteria for unipolar major depression and had a score
Depressed versus non-depressed subjects
A total of 84 depressed elderly participants fulfilled selection criteria, signed consent and entered the study. After the 2-week drug washout and single-blind placebo lead-in period, 63 continued to meet DSM-IV criteria for major depression, had a HDRS score equal to or greater than 18, and entered the escitalopram treatment phase. Of these participants, 53 had baseline apathy data and MRI scans collected, and 45 participants completed the 12-week treatment trial. Eight participants failed to
Discussion
The principal finding of this study is that depressed elderly patients who continued to suffer from apathy after treatment with escitalopram had greater white matter abnormalities of the uncinate fasciculus and smaller volumes of the posterior subgenual cingulate cortex than depressed patients whose apathy improved. This is the first study, to our knowledge, to identify a relationship between the persistence of apathy after SSRI treatment with frontolimbic white and gray matter abnormalities.
Role of funding source
Personnel and imaging cost of this work was supported by NIMH Grants R01 MH065653, R01 MH079414, P30 MH085943, T32 MH019132 (GSA), K23 MH74818 (FMG) and the Sanchez Foundation. Escitalopram and placebo were provided free of cost by Forest Pharmaceuticals, Inc.
Conflict of interest
Dr. Alexopoulos received Grant support from Forest Pharmaceuticals and has been a member of speakers׳ Bureaus of Astra Zeneca, Avanir, Forest, Merck, and Lundbeck. He holds equity of Johnson and Johnson. No other authors report biomedical financial interests or potential conflicts of interest.
Acknowledgments
The authors thank Raj Sangoi RT (R) MR for his work as chief MR technologist.
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2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Beyond remission of the depressive episode, it has been reported that residual negative self-referential thinking after a 12-week treatment of escitalopram was associated with lower FA in the dorsal ACC and uncinate fasciculus in LLD (Victoria et al., 2019). A good response to a 12-week treatment of escitalopram for apathy in patients with LLD was associated with greater FA in the left uncinate fasciculus (Yuen et al., 2014). Aforementioned evidence on the association between antidepressant response and the decreased structural connectivity of the brain network via WMH or impaired white matter integrity in LLD may support a vascular depression hypothesis or the conceptualization of LLD as a disconnecting syndrome (Smagula and Aizenstein, 2016).