Early changes in emotional processing as a marker of clinical response to SSRI treatment in depression

Abstract

Antidepressant treatment reduces behavioural and neural markers of negative emotional bias early in treatment and has been proposed as a mechanism of antidepressant drug action. Here, we provide a critical test of this hypothesis by assessing whether neural markers of early emotional processing changes predict later clinical response in depression. Thirty-five unmedicated patients with major depression took the selective serotonin re-uptake inhibitor (SSRI), escitalopram (10 mg), over 6 weeks, and were classified as responders (22 patients) versus non-responders (13 patients), based on at least a 50% reduction in symptoms by the end of treatment. The neural response to fearful and happy emotional facial expressions was assessed before and after 7 days of treatment using functional magnetic resonance imaging. Changes in the neural response to these facial cues after 7 days of escitalopram were compared in patients as a function of later clinical response. A sample of healthy controls was also assessed. At baseline, depressed patients showed greater activation to fear versus happy faces than controls in the insula and dorsal anterior cingulate. Depressed patients who went on to respond to the SSRI had a greater reduction in neural activity to fearful versus happy facial expressions after just 7 days of escitalopram across a network of regions including the anterior cingulate, insula, amygdala and thalamus. Mediation analysis confirmed that the direct effect of neural change on symptom response was not mediated by initial changes in depressive symptoms. These results support the hypothesis that early changes in emotional processing with antidepressant treatment are the basis of later clinical improvement. As such, early correction of negative bias may be a key mechanism of antidepressant drug action and a potentially useful predictor of therapeutic response.

The pulvinar nucleus and antidepressant treatment: dynamic modeling of antidepressant response and remission with ultra-high field functional MRI

“…Elevated pretreatment anterior cingulate activity is most often reported in resting state or facial emotion tasks [6]. Furthermore, the time points of measurement might impact results, since early response might underlie a different neuronal activity as late response [42,43]. A sigmoid response indicates that individual patients respond with a moderate decline of HAM-D values in the beginning, followed by at a certain period of faster response and an again flatter decline at the end of observations.…”

Acute change in anterior cingulate cortex GABA, but not glutamine/glutamate, mediates antidepressant response to citalopram

“…We believe our findings provide support for: 1) the theory that an acute enhancement of GABAergic activity is a common mechanistic pathway across diverse antidepressant agents; and 2) further investigation of acute increases in glutamine/glutamate ratios and GABA levels in pgACC as potential early biomarkers of response to SSRI treatment in MDD. Overall, this study adds to the existing functional neuroimaging literature (Di Simplicio et al, 2012; Godlewska et al, 2016; Harmer et al, 2009) demonstrating changes in the brain early in antidepressant treatment that may mediate later clinical response – findings that may ultimately be valuable in developing novel depression treatments and informing clinical decision-making.…”

How do antidepressants work? New perspectives for refining future treatment approaches

“…In a recent study, Godlewska and colleagues 62 found that clinical response to escitalopram after 6 weeks of treatment was associated with early change during affective processing in the amygdala, thalamus, cingulate, and insula. The responder group showed a greater reduction in neural response in these areas during the processing of negative versus positive facial expressions, consistent with the hypothesis that these early changes are important for the expression of later clinical benefit.…”

“…In line with this hypothesis, early change in the perception and neural response to positive facial expressions has been associated with subsequent improvement in depression severity. 50,51,62 A classification-based approach of data from Tranter and colleagues' study 50 suggests that if an early change in positive processing is not seen with antidepressant treatment, patients have little chance of responding to this same treatment later (table 1). A similar effect was seen in older adults in which a group of patients with depression who did not show an improvement in the recognition of happy faces after 1 week of citalopram treatment also did not respond after 8 weeks of treatment.…”