Evaluating cognitive disturbances as treatment target and predictor of antidepressant action in major depressive disorder: A NeuroPharm study

Abstract

Cognitive disturbances in major depressive disorder (MDD) constitute a critical treatment target and hold promise as an early predictor of antidepressant treatment response; yet their clinical relevance is not fully established. Therefore, we here investigate if (1) cognitive performance improves over the course of antidepressant treatment and (2) cognitive performance at baseline is predictive of antidepressant treatment response. In the NeuroPharm study (clinical trial id: NCT02869035), 92 antidepressant-free patients with a moderate to severe depressive episode were assessed with a comprehensive cognitive test battery including both cold (emotion-independent) and hot (emotion-dependent) tasks. Patients were tested before and after 12 weeks of standard antidepressant treatment with escitalopram in flexible doses of 10-20 mg. Performance improved across most cognitive domains over the course of antidepressant treatment. Notably, these improvements were independent of improvement in mood symptoms, emphasizing that cognitive disturbances are a distinct symptom and therefore treatment target in MDD. Results did not suggest that performance on any single cognitive measure at baseline was associated with later clinical response to antidepressant treatment. However, a small cluster of patients (N = 28) with globally disturbed cognition at baseline exhibited poorer clinical response after 8 but not 12 weeks of antidepressant treatment, suggesting that severe cognitive disturbances may delay treatment response. Thus, while pretreatment cognitive performance on individual tests may not be useful as clinical markers of treatment response, profiles capturing performance across different cognitive domains may be useful for stratification of patients with MDD and could be helpful in future intervention trials.

Conflict of interest statement

BJS is a co-inventor of the EMOTICOM test battery and consults for Cambridge Cognition, Greenfield BioVentures, and Cassava Sciences. VGF and GMK have received speaker honorarium from Janssen Pharmaceuticals. The remaining authors have nothing to disclose.

© 2022. The Author(s).

Figures

Fig. 1. Change in depressive symptom severity over time for cognitive profile clusters.

Panel I shows Hamilton Depressive Rating Scale 6 (HDRS6) scores for each of the three cognitive profile clusters at baseline, week 4, week 8, and week 12. Panel II shows improvement (i.e., reduction) in HDRS6 scores in percentage for the three cognitive profile clusters at week 8 and week 12 relative to baseline. The graphs show observed group averages and the error bars denote standard deviations while the significance notation in panel II represents model estimates corrected for age and sex. * p < 0.05.

Fig. 2. Changes in cognitive performance from baseline to week 12.

Changes in affective, social, and cold cognitive outcomes before (N = 92) and after 12 weeks (N = 69) of antidepressant treatment. Panel I. Affective cognition: Recognition = affective bias for hit rate in the Emotional Recognition Task calculated as hit rate for happy faces minus hit rate for sad faces; Misattribution = affective bias for false alarm rate in the Emotional Recognition Task calculated as false alarm rate for happy faces minus false alarm rate for sad faces; Detection threshold = affective bias for the Intensity Morphing Task calculated as detection threshold for sad faces minus detection threshold for happy faces; Affective memory = affective bias for the Verbal Affective Memory Task 26 calculated as number of remembered positive words minus number of remembered negative words. Panel II. Social cognition: Guilt = average ratings of guilt in the Moral Emotions task; Shame = average ratings of shame in the Moral Emotions task; Information preference = choice of theory of mind-related information (thoughts and emotions) relative to facts in the Social Information Preference task; Interpretation bias = affective bias in choice of outcome in the Social Information Preference task. Panel III. Cold cognition: Verbal memory = total recall score for the Verbal Affective Memory Task; Working memory = total score in Letter-Number Sequence task; Reaction time = Simple Reaction Time. Note error bars denote standard deviations and individual data points represent observed values while the significance notation represents model estimates corrected for age and sex; p-values were corrected for 11 tests using the Bonferroni-Holm method. * p < 0.05, ** p < 0.01, *** p < 0.001.