The relationship between change in apathy and changes in cognition and functional outcomes in currently non-depressed SSRI-treated patients with major depressive disorder

doi:10.1016/j.comppsych.2013.08.008

Comprehensive Psychiatry

Volume 55, Issue 1, January 2014, Pages 1-10

https://doi.org/10.1016/j.comppsych.2013.08.008 Get rights and content

Abstract

Aims

Apathy in the context of treated major depressive disorder (MDD) is a frequently observed phenomenon in clinical practice. This study aimed to assess the validity of the Rothschild Scale for Antidepressant Tachyphylaxis® (RSAT) and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) for measuring apathy, and to assess the relationship between apathy and possible contributing factors, in patients with MDD and residual apathy in the absence of depressed mood.

Methods

The underlying structure and validity of the RSAT and CPFQ were assessed via factor analysis and correlation with the Apathy Evaluation Scale—Clinician rated version (AES-C) in 483 patients who had previously responded to treatment with a selective serotonin reuptake inhibitor. The relationship between apathy and contributing variables was investigated via structural equation modeling. Correlation and regression analyses were conducted to examine the relationship between the Sheehan Disability Scale (SDS) and the RSAT, CPFQ, and AES-C.

Results

The RSAT and CPFQ were validated with the AES-C with respect to energy and motivation. The latent variable “Energy and Interest”, based on the energy, motivation, and interest items (RSAT and CPFQ), was a major contributing factor to apathy. Improvements in function (SDS) were significantly correlated with, and predicted by, improvements in apathy and cognitive and physical functioning (assessed by the RSAT, CPFQ, and AES-C).

Conclusions

These analyses provide further information on apathy and its assessment in the context of treated MDD. A better understanding of apathy will aid further investigation of this phenomenon and, ultimately, determination of the most appropriate approach for its clinical management.

Introduction

Apathy has been defined as lack of motivation not attributable to diminished level of consciousness, cognitive impairment, or emotional distress [1]. Many patients who meet the criteria for remission following treatment for major depressive disorder (MDD) experience clinically significant residual symptoms, including apathy [2], [3], [4]. Apathy in patients treated for MDD may also arise as a treatment-emergent symptom of antidepressant treatment, in particular, selective serotonin reuptake inhibitor (SSRI) treatment [5], [6].

Apathy has been associated with decreased gray matter volume in the right anterior cingulate gray matter [7] and reduced activity of the noradrenergic system [8], [9]. Increasing noradrenergic activity by switching from an SSRI to a serotonin–norepinephrine reuptake inhibitor (SNRI) is therefore hypothesized to result in a greater improvement in apathy compared with switching to another SSRI. To test this, we conducted a multicenter, double-blind, randomized study (described by Raskin et al. [10]) comparing apathy, depression, and functional outcomes associated with switching to a SNRI (duloxetine) or remaining on an SSRI (escitalopram) in 483 patients who had previously responded to treatment with an SSRI (citalopram, escitalopram, paroxetine, sertraline) for MDD and who had residual apathy in the absence of depressed mood. This study showed statistically and clinically significant improvements from baseline in the Apathy Evaluation Scale—Clinician rated version (AES-C) total score and in the secondary apathy, depression, and functional outcomes in both the duloxetine (244 patients) and escitalopram (239 patients) treatment groups following 8 weeks of treatment. However, there were no significant differences between the two treatment groups in any of these measures in this study. A better understanding of apathy in the context of treated MDD is therefore required to guide appropriate clinical approaches for its management.

In the current paper, we describe additional analyses undertaken in the study population described by Raskin et al. [10] to provide further information on apathy and its assessment in the context of treated MDD. The AES-C, which was the primary measure of apathy in this study, assesses behavioral, cognitive, emotional, and other symptoms of apathy [1]. Two other scales that were used to assess symptoms of apathy in the study were the Rothschild Scale for Antidepressant Tachyphylaxis® (RSAT), which assesses symptoms of apathy or decreased motivation among depressed patients who have achieved symptomatic remission with antidepressant treatment [11], and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), a self-rating scale which evaluates cognitive and physical symptoms and well-being [12]. The analyses presented here were conducted to (i) assess the validity of the RSAT and the CPFQ for measuring apathy and (ii) assess the relationship between apathy and possible contributing factors, in patients with MDD and residual apathy in the absence of depressed mood.

Section snippets

Study design

Full details of the study design have been published elsewhere [10]. Briefly, eligible study participants were male or female outpatients aged ≥18 years who had: a historical diagnosis of MDD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV); received treatment with an SSRI (escitalopram, sertraline, paroxetine, or citalopram) for at least 3 months for MDD; an AES-C total score >30 at the start and end of the Screening Period; and a Montgomery–Åsberg

Patient characteristics

There were 483 patients who met the eligibility criteria and were randomized in the study (duloxetine: 244 patients; escitalopram: 239 patients) [10]. The median (range) age of the patients was 45.0 (18.7, 78.0) years and approximately three-quarters of the patients (366/483 patients, 75.8%) were female (Table 1). There was clinically significant apathy in the study population at baseline, with a mean AES-C total score (standard deviation [SD]) of 46.3 (7.97) (Table 1). Patients were

Discussion

Apathy, while common in MDD, needs to be assessed across multiple domains in order to ascertain its cause. In addition, the definition of apathy needs to be refined so that clinicians can more readily recognize it and researchers can more readily design studies to ascertain how to address it. A better understanding of apathy in MDD will contribute to improved strategies for its clinical management. To our knowledge, this is the largest population of patients with nonsyndromic MDD to be formally

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After 8 weeks of vortioxetine treatment, mean (standard deviation) change in MEI total score from baseline was 33.0 (27.3) points. At week 8, mean change in MEI total score from baseline was 37.5 (27.8) points in patients no longer reporting emotional blunting and 28.3 (26.2) points in those still experiencing emotional blunting. In patients considered minimally improved (i.e. Clinical Global Impression–Improvement [CGI-I] score of 3 after 8 weeks of vortioxetine), mean change in MEI total score from baseline was 14.7 (19.1) points. In patients defined as responders (CGI-I score of 2 at 8 weeks), mean change in MEI total score was 33.0 (24.7) points.
Short study duration.
These results provide further validation of the clinical utility of the MEI for assessing treatment response in patients with MDD. The suggested MCID for MEI total score is 15 points.
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Evidence indicates that some of these effects of cytokines are due to actions on brain mechanisms, including mesotelencephalic dopamine systems (Dantzer et al., 2008, 2012; Miller, 2009; Felger and Miller, 2012; Treadway et al., 2019). Historically, serotonin transport (SERT) inhibitors have been the most commonly prescribed drugs for treating MDD patients, but SERT blockers are relatively ineffective at improving anergia or fatigue-related aspects of motivation (Cooper et al., 2014; Fava et al., 2014; Rothschild et al., 2014). In contrast, evidence indicates that the catecholamine uptake inhibitor bupropion (Pae et al., 2007; Papakostas et al., 2006; Cooper et al., 2014), and drugs that inhibit the dopamine (DA) transporter (DAT) such as d-amphetamine and methylphenidate (Stotz et al., 1999; Hanna et al., 2006), can partially alleviate these symptoms in depressed patients.
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Apathy and depression have each been associated with an increased risk of conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD).These symptoms often co-occur and the contribution of each to risk of AD is not clear.
National Alzheimer's Coordinating Center participants diagnosed with MCI at baseline and followed until development of AD or loss to follow-up (n = 4,932) were included. The risks of developing AD in MCI patients with neuropsychiatric symptoms (NPS) (apathy only, depression only, or both) were compared to that in those without NPS in a multivariate Cox regression survival analysis adjusting for baseline cognitive impairment, years of smoking, antidepressant use, and AD medication use.
Thirty-seven percent (N = 1713) of MCI patients developed AD (median follow-up 23 months). MCI patients with both apathy and depression had the greatest risk (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.17–1.61; p < 0.0001; Wald χ² = 14.70; df = 1). Those with apathy only also had a greater risk (HR = 1.24; 95% CI: 1.05–1.47; p = 0.01; Wald χ² = 6.22; df = 1), but not those with depression only (HR = 1.08; 95% CI: 0.95–1.22; p=0.25; Wald χ² = 1.30; df = 1). Post-hoc analyses suggested depression may exacerbate cognitive decline in MCI patients with apathy (odds ratio = 0.70; 95% CI 0.52–0.95; p = 0.02; Wald χ² = 5.28; df = 1), compared to those without apathy.
MCI patients with apathy alone or both apathy and depression are at a greater risk of developing AD compared to those with no NPS. Interventions targeting apathy and depression may reduce risk of AD.
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2023, Acta Neuropsychiatrica

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: Funding Support. This study (F1J-CR-HMGM) was sponsored by Eli Lilly and Company, manufacturer/licensee of duloxetine (Cymbalta®). In compliance with the Uniform Requirements for Manuscripts, established by the International Committee of Medical Journal Editors, the sponsor of this study did not impose any impediment, directly or indirectly, on the publication of the study's results. Medical writing assistance was provided by Justine Southby, PhD, and Serina Stretton, PhD, CMPP, of ProScribe Medical Communications and was funded by Eli Lilly Australia. ProScribe's services complied with international guidelines for Good Publication Practice (GPP2).

: Role of the Sponsor. Eli Lilly was involved in the study design, data collection, data analysis, and preparation of the manuscript.

: Role of Contributors. All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. LM and JR were involved in the study design.

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The relationship between change in apathy and changes in cognition and functional outcomes in currently non-depressed SSRI-treated patients with major depressive disorder

Abstract

Aims

Methods

Results

Conclusions

Introduction

Section snippets

Study design

Patient characteristics

Discussion

Psychiatry Res

Am J Geriatr Psychiatry

J Psychiatr Res

Compr Psychiatry

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

Psychother Psychosom

A cross-sectional study of the prevalence of cognitive and physical symptoms during long-term antidepressant treatment

J Clin Psychiatry

Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication

J Clin Psychopharmacol

Olanzapine in the treatment of apathy in previously depressed participants maintained with selective serotonin reuptake inhibitors: an open-label, flexible-dose study

J Clin Psychiatry