Escitalopram ameliorates differences in neural activity between healthy comparison and major depressive disorder groups on an fMRI Emotional conflict task: A CAN-BIND-1 study

Highlights

• 16 MDD 8-Week remitters, 12 MDD 16-week remitters and 14 MDD non-remitters, and 30 healthy controls underwent fMRI during the performance of an emotional conflict task.

• MDD participants were scanned at baseline, prior to treatment initiation and after 8 weeks treatment with the SSRI escitalopram. HC were scanned in the same intervals.

• All groups demonstrated an emotional Stroop effect in reaction time, at Baseline and Week 8.

• All MDD groups showed lower task related activation compared to HC at Baseline.

• By Week 8, task-related activation was not significantly different between MDD groups and HC.

• Findings suggest that escitalopram ameliorates differences in neural activity between HC and MDD groups, while differences in degree of mood symptom alleviation across MDD groups remain.

Abstract

Background

Identifying objective biomarkers can assist in predicting remission/non-remission to treatment, improving remission rates, and reducing illness burden in major depressive disorder (MDD).

Methods

Sixteen MDD 8-week remitters (MDD-8), twelve 16-week remitters (MDD-16), 14 non-remitters (MDD-NR) and 30 healthy comparison participants (HC) completed a functional magnetic resonance imaging emotional conflict task at baseline, prior to treatment with escitalopram, and 8 weeks after treatment initiation. Patients were followed 16 weeks to assess remitter status.

Results

All groups demonstrated emotional Stroop in reaction time (RT) at baseline and Week 8. There were no baseline differences between HC and MDD-8, MDD-16, or MDD-NR in RT or accuracy. By Week 8, MDD-8 demonstrated poorer accuracy compared to HC. Compared to HC, the baseline blood-oxygen level dependent (BOLD) signal was decreased in MDD-8 in brain-stem and thalamus; in MDD-16 in lateral occipital cortex, middle temporal gyrus, and cuneal cortex; in MDD-NR in lingual and occipital fusiform gyri, thalamus, putamen, caudate, cingulate gyrus, insula, cuneal cortex, and middle temporal gyrus. By Week 8, there were no BOLD activity differences between MDD groups and HC.

Limitations

The Emotional Conflict Task lacks a neutral (non-emotional) condition, restricting interpretation of how mood may influence perception of non-emotionally valenced stimuli.

Conclusions

The Emotional Conflict Task is not an objective biomarker for remission trajectory in patients with MDD receiving escitalopram treatment. Escitalopram may have influenced emotion recognition in MDD groups in terms of augmented accuracy and BOLD signal in response to an Emotional Conflict Task, following 8 weeks of escitalopram treatment.

Introduction

Major depressive disorder (MDD) is projected to be the leading source of global burden of disease across both sexes by 2030 (World Health Organization, 2008). Presently, there is no reliable method of predicting who will achieve remission or response to a specific antidepressant (Kudlow et al., 2012). A current research priority is to identify objective biomarkers that may subtype individuals with MDD based on likelihood of achieving remission/non-remission to a given treatment. Such biomarkers could ultimately reduce the treatment steps required to reach remission, while improving remission rates, reducing the burden of MDD on patients, caregivers, and the healthcare system.

From the patient point of view, remission provides a greater opportunity to enhance functioning (Kennedy, 2002). Patients achieving only partial remission are more likely to experience significant difficulties in occupational and social functioning (Romera et al., 2010), and have a greater risk of recurrence or relapse (Paykel, 2008; Paykel et al., 1995), compared to patients who achieve complete remission.

The ability to correctly perceive and understand emotional information is essential for healthy social functioning (Blair, 2003; Darwin, 1872). Impaired ability to interpret facial expressions has been associated with poorer relationships and increased feelings of depression (Carton et al., 1999). Many studies report evidence of a mood-congruent bias in emotional information processing in MDD, with heightened attenuation or decreased responsivity for positive emotional stimuli and a negative potentiation or increased responsivity to negative stimuli (Bouhuys et al., 1999; Bourke et al., 2010; Gotlib et al., 2011; Stuhrmann et al., 2011). Some reports indicate patients with MDD express an overall attenuated response to a range of emotional stimuli, irrespective of valence (Bylsma et al., 2008; Imbault and Kuperman, 2018; Rottenberg et al., 2005) or patients with MDD have difficulty inhibiting responses to negatively valenced information or disengaging from it (Gotlib and Joormann, 2010), even when in remission (Vanderhasselt et al., 2012).

Our goal was to examine whether differences in emotional information processing predict different remission rates in patients with MDD. Following baseline measurements, patients with MDD began treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram. A subset of patients that did not reach a ≥ 50% reduction in their Montgomery-Åsberg Depression Rating Scale (MADRS) (Montgomery and Åsberg, 1979) score by their 8th week of treatment, received adjunctive treatment with the atypical antipsychotic aripiprazole for an additional 8 weeks (Lam et al., 2016). To assess difference in emotional information processing, we employed an Emotional Conflict Task (Etkin et al., 2006). This task is constructed from images of fearful or happy faces with a congruent or incongruent emotional word label superimposed across the face. The task requires participants to ignore emotional task-irrelevant information (the printed name of an emotion) and identify, emotional task-relevant information (the affect expressed on the face). Slower reaction time (RT) on incongruent compared to congruent trials is recognized as the emotional Stroop effect (Hill and Knowles, 1991), and studies measuring accuracy have reported decreased accuracy on incongruent compared to congruent trials (Etkin et al., 2006; Favre et al., 2015; Fournier et al., 2017; Rey et al., 2014; Torres-Quesada et al., 2014).

To evaluate baseline task-based differences between HC and 8-week remitters (MDD-8), 16-week remitters (MDD-16) and non-remitters (MDD-NR) in processing congruent and incongruent emotional information, we compared groups on the Emotional Conflict Task. We expected all groups to demonstrate the emotional Stroop effect in both RT and accuracy, given the robust nature of the task. We also expected overall accuracy rates to be lower in MDD groups compared to HC, based on impaired emotion recognition in MDD (Dalili et al., 2015; Rubinow and Post, 1992). Furthermore, we expected slower RT in the MDD-NR compared to HC, based on previous work identifying psychomotor slowing as a predictor of treatment non-response to SSRI fluoxetine (Taylor et al., 2006). Decreased accuracy has also been shown in a Non-Responder group on both incongruent and congruent trials in a color word Stroop task (Xue et al., 2017). Thus, we expected lower accuracy in the MDD-NR group on both congruent and incongruent trials, compared to HC. Comparing patterns of neural response, we hypothesized that response differences on congruent, incongruent, and incongruent > congruent trials, would distinguish between HC, and MDD-8, MDD-16 and MDD-NR groups at baseline. Previous findings of rostral cingulate hypometabolism in MDD treatment non-responders and hypermetabolism in treatment responders in a positron emission tomography study (Mayberg et al., 1997), predicted there would be similar differences in blood-oxygen dependent (BOLD) cingulate activity between HC and MDD-8/−16 and MDD-NR groups, respectively.

A secondary objective was to examine within-group changes in behavioural responding and BOLD activity induced by escitalopram at Week 8. Within each group, we expected to observe a preserved emotional Stroop effects across time. In MDD groups, we expected changes in observed BOLD activity in response to escitalopram, due to the early positive effects of an SSRI on emotional information processing (Harmer and Cowen, 2013). Between groups, we expected MDD-8 neural activity would more closely approximate that of HC by Week 8, while neural and behavioural responses in MDD-16 and MDD-NR would not.

Finally, to identify differences in participants responding to escitalopram after 8 weeks of treatment, compared to participants that would respond with the later addition of aripiprazole we compared MDD-8 and MDD-16 at Week 8.