Research report
Neural response to emotional stimuli associated with successful antidepressant treatment and behavioral activation

https://doi.org/10.1016/j.jad.2013.06.050Get rights and content

Abstract

Background

Major Depressive Disorder (MDD) is a leading cause of disability globally. Currently available treatments have limited efficacy and combination strategies are frequently used. Several lines of research have demonstrated that MDD patients experience impairments in various components of affective processing, including regulation of affective states.

Aim

To identify baseline and 1-week neuroimaging predictors of response to a 6-week trial of fluoxetine/olanzapine combination treatment during an affective processing task.

Methods

Twenty-one MDD patients and 18 healthy controls were enrolled in the study. MDD patients were treated for 6 weeks with fluoxetine (40–60 mg/day) and olanzapine (5–12.5 mg/day). All participants viewed images from the International Affective Picture Rating System during a functional magnetic resonance (fMRI) scan at baseline and 1 week.

Results

There was a 57% response rate (defined as a 50% decrease in Hamilton Rating Scale for Depression-17 item) at 6 weeks. At baseline, responders had increased premotor activity while viewing negative images compared to non-responders and healthy controls. Higher baseline premotor activity was also predictive of greater percent change on the HAMD-17 and improvement in negative disposition and behavioral drive. Non-responders exhibited increased insular activity at baseline compared to responders. Higher activity in the posterior cingulate cortex was also predictive of greater percent change on the HAMD-17. Change from baseline to 1 week did not produce any significant predictive findings.

Conclusions

Treatment with fluoxetine/olanzapine demonstrated similar biomarkers of response to monotherapeutic strategies. In particular, posterior cingulate cortex, anterior insula, and premotor cortex may show predictive differences in their response to affective images prior to treatment. Further research needs to be conducted to determine the utility of early changes in emotion circuitry in predicting antidepressant response.

Introduction

Major depressive disorder (MDD) is a common, often severe, and chronic illness with high rates of non-recovery (Collins et al., 2011, Warden et al., 2007). Suboptimal outcomes with conventional antidepressants provide the impetus for identifying phenotypic and/or biological markers that would inform treatment decisions to improve likelihood of response. Towards this aim, functional magnetic resonance imaging (fMRI) investigations provide an opportunity to assess the direct effects of different treatments on brain circuits that subserve the phenomenology of MDD. In particular, fMRI studies have been used to define the brain networks associated with different emotions (Fu et al., 2004, Fu et al., 2007, Hariri et al., 2002, Kalin et al., 1997, McCabe et al., 2009, Northoff et al., 2000, Phillips et al., 2001, Siegle et al., 2002, Wang et al., 2012). Evaluating antidepressant effects on emotion processing neurocircuitry can provide important insights into illness states, as well as potential biomarkers of response, all of which can contribute to improving selection of current therapies and development of future targeted therapeutics.

A replicated outcome when employing emotional provocation techniques evaluated with fMRI in depressed states is overactivity in the subgenual cingulate, amygdala, insula, and prefrontal cortex (Anand et al., 2005, Harmer et al., 2009, Keedwell et al., 2009, Kalin et al., 1997, Sheline et al., 2001). These abnormalities are noted to normalize following successful treatment with selective serotonin reuptake inhibitors (SSRI) or serotonin and norepinephrine reuptake inhibitors (SNRIs) (Rosenblau et al., 2012; Davidson et al., 2003). However, it is not clear when these changes begin to occur in the course of antidepressant therapy and whether they are specific to treatment strategy (e.g. monotherapy with an SSRI, SNRI, combination therapy).

The imaging studies of emotional processing conducted thus far have all utilized monotherapeutic approaches primarily with an SSRI or SNRI (Davidson et al., 2003, Fu et al., 2004, Kalin et al., 1997, Rosenblau et al., 2012). However, combination strategies are commonly used and are included in clinical guidelines (Lam et al., 2009). In particular, there has been a steady increase in the use of atypical antipsychotics to treat depression either as a monotherapy (e.g. quietiapine) or as an augmentation strategy (e.g. olanzapine, risperidone, aripiprazole) (Alexander et al., 2011, Blier et al., 2010, Papakostas, 2009, Chen et al., 2011, Nelson et al., 2012). The combination of fluoxetine and olanzapine has demonstrated efficacy in depression and it is the first medication approved for treatment resistant depression by the FDA (Bobo and Shelton, 2010, Croxtall and Scott, 2010).

Anhedonia is a core deficit in MDD, which is inherently related to emotional processing. In addition to being a core abnormality in MDD, aberrations in reward-based phenomenology may be a baseline predictor of treatment outcome with antidepressants. For example, low scores on the interest-activity item on the Hamilton Rating Scale for Depression-17 item (HAMD-17; Hamilton, 1960), which reflects reward responsiveness and drive, predicted poor outcome in a post-hoc analysis of data from the Sequenced Treatment Alternatives to Relieve Depression (STARD) study (Uher et al., 2012) and was a unique negative predictor of time to remission in SSRI resistant adolescents (McMakin et al., 2012). Furthermore evidence also suggests that low reward seeking may be a vulnerability factor for incident MDD and may separately predict functional domain outcomes (Rawal et al., 2013). Neuroimaging studies and quantitative meta-analyses have identified a consistent pattern of abnormal activity in MDD in a corticostriatal “reward circuit” encompassing the ventromedial prefrontal cortex, ventral striatum, and ventral tegmental area (Tremblay et al., 2005, Diekhof et al., 2007, Diekhof et al., 2012). Reward function might thus be expected to act as a mediator of antidepressant response, both at the behavioral and at the neural level.

The primary aim of the current study was to determine whether brain activation in response to negative and positive images at baseline and 1 week would predict treatment outcome in a 6-week trial of fluoxetine and olanzapine in patients with MDD. The extent to which behavioral activation (reward responsiveness, drive, and fun seeking) correlates with emotion processing circuitry and is a mediator of antidepressant response was also explored. We hypothesized the following: (1) Differences between responders and non-responders to treatment will be evident at baseline and these changes will predict antidepressant outcome; (2) MDD patients will demonstrate changes in neural activity in response to viewing positive and negative images by 1 week, and these changes will predict antidepressant outcome at 6 weeks; (3) Baseline and changes in behavioral activation in MDD patients will correlate with treatment outcome and brain activity in response to positive and negative images, and (4) MDD patients will exhibit increased pre-treatment activity in limbic and cortical regions compared to healthy controls in response to negative pictures, and successful treatment will normalize this activation pattern.

Section snippets

Participants

Patients with MDD (n=21) were recruited from the Mood Disorders Psychopharmacology Unit (MDPU) at the University Health Network. Age- and sex-matched healthy controls (n=18) were also recruited from the community through local advertisements. All participants provided written informed consent. The study was approved by the University Health Network Research Ethics Board.

All participants were required to be 18–55 years old, and right-handed. Exclusion criteria for both MDD and healthy controls

Clinical data

Statistical significance between responders vs. non-responders and MDD vs. healthy controls was assessed using the student's t-test in instances where the data met criteria for normality and Mann–Whitney U tests when normality was not met. Similarly, Spearman's Rho was used to assess the correlation and prediction between non-normal continuous measures and Pearson correlation coefficients for normal variables. A repeated measures analysis of variance was employed to evaluate the effect of time

Participants

A total of 21 MDD patients and 18 healthy controls were enrolled in the trial. At 6 weeks, 17 patients had completed the antidepressant trial and had repeat fMRI scans at 1 week and 6 weeks, while 11 healthy controls had repeat fMRI scans. Due to high levels of movement, scans from 2 of the MDD patients were not included in the imaging analyses.

The healthy control and MDD group were similar in age and percentage of females (Table 1). Responders and non-responders also did not differ on these

Discussion

To our knowledge, this is the first study to assess fMRI biomarkers of response at baseline and 1 week during an antidepressant combination (i.e. olanzapine/fluoxetine) treatment trial. We demonstrated that high baseline response to positive images in the posterior cingulate cortex and to negative images in the premotor cortex predicted change in depression scores from baseline to 6 weeks. High baseline premotor activity also correlated with greater increases in drive and decreases in negative

Role of funding source

Eli Lilly provided fellowship support for Dr. Jakub Konarski to complete this trial. Eli Lilly did not have a role in the design or conduct of the study. They also did not have a role in data analysis or manuscript preparation. No other funding was received for this study, and study costs were contributed by Dr. Sidney H. Kennedy through internal research funds.

Conflict of interest

SJR has received conference travel funding from St. Jude Medical and Eli Lilly Canada. TVS has no conflicts to report. JZK has received a fellowship from Eli Lilly Canada for the purposes of conducting this trial. JD has received a travel stipend from Lundbeck. PG has received honoraria or grant funding from AstraZeneca, Eli Lilly and St. Jude Medical. RSM has received honoraria or funding from Astra Zeneca, Bristol-Myers Squibb, CME Outfitters, Eli Lilly, Forest, Janssen-Ortho, Lundbeck, Merck

Acknowledgments

The authors would like to thank Deborah Mancini and Kari Fulton for research support. The analysis of this data was conducted in connection with the CAN-BIND study, for which the authors would like to thank OBI and Lundbeck A/S for their unrestricted contributions.

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