Elsevier

Journal of Affective Disorders

Volume 166, September 2014, Pages 179-186
Journal of Affective Disorders

Research Report
Neuroanatomical correlates of apathy in late-life depression and antidepressant treatment response

https://doi.org/10.1016/j.jad.2014.05.008Get rights and content

Abstract

Background

Apathy is a prominent feature of geriatric depression that predicts poor clinical outcomes and hinders depression treatment. Yet little is known about the neurobiology and treatment of apathy in late-life depression. This study examined apathy prevalence in a clinical sample of depressed elderly, response of apathy to selective serotonin reuptake inhibitor (SSRI) treatment, and neuroanatomical correlates that distinguished responders from non-responders and healthy controls.

Methods

Participants included 45 non-demented, elderly with major depression and 43 elderly comparison individuals. After a 2-week single-blind placebo period, depressed participants received escitalopram 10 mg daily for 12 weeks. The Apathy Evaluation Scale (AES) and 24-item Hamilton Depression Rating Scale (HDRS) were administered at baseline and 12 weeks. MRI scans were acquired at baseline for concurrent structural and diffusion tensor imaging of anterior cingulate gray matter and associated white matter tracts.

Results

35.5% of depressed patients suffered from apathy. This declined to 15.6% (p<0.1) following treatment, but 43% of initial sufferers continued to report significant apathy. Improvement of apathy with SSRI was independent of change in depression but correlated with larger left posterior subgenual cingulate volumes and greater fractional anisotropy of left uncinate fasciculi.

Limitations

Modest sample size, no placebo control, post-hoc secondary analysis, use of 1.5T MRI scanner

Conclusions

While prevalent in geriatric depression, apathy is separable from depression with regards to medication response. Structural abnormalities of the posterior subgenual cingulate and uncinate fasciculus may perpetuate apathetic states by interfering with prefrontal cortical recruitment of limbic activity essential to motivated behavior.

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.

References (76)

  • H. Lavretsky et al.

    Neuroanatomical characteristics of geriatric apathy and depression: a magnetic resonance imaging study

    Am. J. Geriatr. Psychiatry: Off. J. Am. Assoc. Geriatr. Psychiatry

    (2007)
  • H. Lavretsky et al.

    Clinical and neuroradiologic features associated with chronicity in late-life depression

    Am. J. Geriatr. Psychiatry: Off. J. Am. Assoc. Geriatr. Psychiatry

    (1999)
  • Y. Levkovitz et al.

    Differential effects of deep TMS of the prefrontal cortex on apathy and depression

    Brain Stimul.

    (2011)
  • R.S. Marin et al.

    Reliability and validity of the Apathy Evaluation Scale

    Psychiatry Res.

    (1991)
  • R.S. Marin et al.

    The sources of convergence between measures of apathy and depression

    J. Affect. Disord.

    (1993)
  • H.S. Mayberg et al.

    Deep brain stimulation for treatment-resistant depression

    Neuron

    (2005)
  • K. Mikami et al.

    Prevention of poststroke apathy using escitalopram or problem-solving therapy

    Am. J. Geriatr. Psychiatry: Off. J. Am. Assoc. Geriatr. Psychiatry

    (2013)
  • T. Murakami et al.

    Neuroanatomic pathways associated with poststroke affective and apathetic depression

    Am. J. Geriatr. Psychiatry: Off. J. Am. Assoc. Geriatr. Psychiatry

    (2013)
  • C.U. Onyike et al.

    Epidemiology of apathy in older adults: the Cache County Study

    Am. J. Geriatr. Psychiatry: Off. J. Am. Assoc. Geriatr. Psychiatry

    (2007)
  • J. Raskin et al.

    Apathy in currently nondepressed patients treated with a SSRI for a major depressive episode: outcomes following randomized switch to either duloxetine or escitalopram

    J. Psychiatr. Res.

    (2012)
  • M. Thiebaut de Schotten et al.

    Monkey to human comparative anatomy of the frontal lobe association tracts

    Cortex: J. Devoted Study Nerv. Syst. Behav.

    (2012)
  • G.S. Alexopoulos et al.

    Anterior cingulate dysfunction in geriatric depression

    Int. J. Geriatr. Psychiatry

    (2008)
  • G.S. Alexopoulos et al.

    Frontal white matter microstructure and treatment response of late-life depression: a preliminary study

    Am. J. Psychiatry

    (2002)
  • G.S. Alexopoulos et al.

    ‘Vascular depression’ hypothesis

    Arch. Gen. Psychiatry

    (1997)
  • G.S. Alexopoulos et al.

    Microstructural white matter abnormalities and remission of geriatric depression

    Am. J. Psychiatry

    (2008)
  • G.S. Alves et al.

    Clinical characteristics in subcortical ischemic white matter disease

    Arquivos Neuro-Psiquiatria

    (2009)
  • L.G. Apostolova et al.

    Structural correlates of apathy in Alzheimer׳s disease

    Dement. Geriatr. Cogn. Disord.

    (2007)
  • M.Y. Bolling et al.

    Reasons for quitting serotonin reuptake inhibitor therapy: paradoxical psychological side effects and patient satisfaction

    Psychother. Psychosom.

    (2004)
  • J. Brandt et al.

    The Hopkins Verbal Learning Test—Revised

    (2001)
  • P.D. Bruen et al.

    Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer׳s disease

    Brain: J. Neurol.

    (2008)
  • C.S. Carter et al.

    Anterior cingulate cortex, error detection, and the online monitoring of performance

    Science

    (1998)
  • C.S. Carter et al.

    Anterior cingulate cortex and conflict detection: an update of theory and data

    Cogn. Affect. Behav. Neurosci.

    (2007)
  • R.A. Charlton et al.

    White-matter tract integrity in late-life depression: associations with severity and cognition

    Psychol. Med.

    (2013)
  • T.N. Chase

    Apathy in neuropsychiatric disease: diagnosis, pathophysiology, and treatment

    Neurotox. Res.

    (2011)
  • S.K. Chaturvedi et al.

    Prediction of outcome in depression by negative symptoms

    Acta Psychiatr. Scand.

    (1986)
  • D.E. Clarke et al.

    Apathy in dementia: an examination of the psychometric properties of the apathy evaluation scale

    J. Neuropsychiatry Clin. Neurosci.

    (2007)
  • O. Devinsky et al.

    Contributions of anterior cingulate cortex to behaviour

    Brain: J. Neurol.

    (1995)
  • W.C. Drevets et al.

    The subgenual anterior cingulate cortex in mood disorders

    CNS Spectr.

    (2008)
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