Harmer CJ, Goodwin GM, Cowen PJ. Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action. Br J Psychiatry 195: 102-108

University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK.
The British journal of psychiatry: the journal of mental science (Impact Factor: 7.99). 09/2009; 195(2):102-8. DOI: 10.1192/bjp.bp.108.051193
Source: PubMed

ABSTRACT The neuropharmacological actions of antidepressants are well characterised but our understanding of how these changes translate into improved mood are still emerging.
To investigate whether actions of antidepressant drugs on emotional processing are a mediating factor in the effects of these drugs in depression.
We examined key published findings that explored the effects of antidepressants on behavioural and functional magnetic resonance imaging (fMRI) measures of emotional processing.
Negative emotional bias has been reliably associated with depression. Converging results suggest that antidepressants modulate emotional processing and increase positive emotional processing much earlier than effects on mood. These changes in emotional processing are associated with neural modulation in limbic and prefrontal circuitry.
Antidepressants may work in a manner consistent with cognitive theories of depression. Antidepressants do not act as direct mood enhancers but rather change the relative balance of positive to negative emotional processing, providing a platform for subsequent cognitive and psychological reconsolidation.

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    • "Changes in emotional processing have frequently been studied using an 'emotional test battery' comprising tests of verbal memory for positive and negative valenced words, a facial expression recognition test (FERT) and an emotional dot probe task. This emotional test battery has now been used in a large number of studies of the effects of various psychotropic medication (Arnone, Horder, Cowen, & Harmer, 2009; Harmer, Heinzen, O'Sullivan, Ayres, & Cowen, 2008, 2011). "
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    ABSTRACT: Little is known of the retest reliability of emotional cognitive tasks or the impact of using different tasks employing similar emotional stimuli within a battery. We investigated this in healthy subjects. We found improved overall performance in an emotional attentional blink task (EABT) with repeat testing at one hour and one week compared to baseline, but the impact of an emotional stimulus on performance was unchanged. Similarly, performance on a facial expression recognition task (FERT) was better one week after a baseline test, though the relative effect of specific emotions was unaltered. There was no effect of repeat testing on an emotional word categorising, recall and recognition task. We found no difference in performance in the FERT and EABT irrespective of task order. We concluded that it is possible to use emotional cognitive tasks in longitudinal studies and combine tasks using emotional facial stimuli in a single battery.
    Cognition and Emotion 07/2015; DOI:10.1080/02699931.2015.1055713 · 2.52 Impact Factor
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    • "This could be explained by the asymmetrical effects of medication on depressive symptoms. For instance, antidepressants may primarily elevate mood, with improvement of other symptoms as a secondary consequence (Harmer et al., 2009). As a result, a patient may report improvement on milder symptoms but less so on severe symptoms, which respond slower to Fig. 2. Differences in symptom profiles between the atypical, middle and prototypical group. "
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    ABSTRACT: Atypical response behavior on depression questionnaires may invalidate depression severity measurements. This study aimed to identify and investigate atypical profiles of depressive symptoms using a data-driven approach based on the item response theory (IRT). A large cohort of participants completed the Inventory of Depressive Symptomatology self-report (IDS-SR) at baseline (n=2329) and two-year follow-up (n=1971). Person-fit statistics were used to quantify how strongly each patient׳s observed symptom profile deviated from the expected profile given the group-based IRT model. Identified atypical profiles were investigated in terms of reported symptoms, external correlates and temporal consistency. Compared to others, atypical responders (6.8%) showed different symptom profiles, with higher 'mood reactivity' and 'suicidal ideation' and lower levels of mild symptoms like 'sad mood'. Atypical responding was associated with more medication use (especially tricyclic antidepressants: OR=1.5), less somatization (OR=0.8), anxiety severity (OR=0.8) and anxiety diagnoses (OR=0.8-0.9), and was shown relatively stable (29.0%) over time. This is a methodological proof-of-principal based on the IDS-SR in outpatients. Implementation studies are needed. Person-fit statistics can be used to identify patients who report atypical patterns of depressive symptoms. In research and clinical practice, the extra diagnostic information provided by person-fit statistics could help determine if respondents׳ depression severity scores are interpretable or should be augmented with additional information. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 07/2015; 180:36-34. DOI:10.1016/j.jad.2015.03.043 · 3.38 Impact Factor
    • "In doing so, we suggest that antidepressants not only impact emotion processing, but its regulation at the acute stage of treatment. Drawing on previously proposed models (Harmer et al., 2009; Outhred et al., 2014b), we posit an extended cognitive neuropsychological model of antidepressant action (see Fig. 2). Our study has a number of methodological strengths including a within-subjects design and extensive manipulation checks (see Supplement), along with recruitment of a homogenous, wellcharacterized sample. "
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    ABSTRACT: Acute antidepressant administration modulates neural activity consistent with decreases in negative emotion processing bias. However, studies are yet to examine whether treatment facilitates neural activity during reappraisal, an adaptive emotion regulation strategy associated with behavioral treatment response. Here we examine the impact of acute administration on reappraisal of negative stimuli using pharmaco-fMRI. Thirty-six healthy female participants completed two sessions of fMRI scanning, separated by a one-week washout period. A single dose of the selective serotonin reuptake inhibitor, escitalopram (20mg) was administered to participants using a double-blind, randomized, placebo-controlled crossover design. When participants were administered escitalopram (relative to a placebo) and asked to reappraise negative emotional stimuli, left amygdala activation was decreased and right inferior frontal gyrus (R IFG) activation was increased. Also observed was a greater negative left amygdala-R IFG functional connectivity when participants were administered escitalopram relative to placebo, and this change in connectivity was associated with reductions in subjective ratings of valence and arousal of negative stimuli. Further analysis revealed connectivity modulation across multiple frontal regions. Results suggest that the acute effect of a commonly prescribed antidepressant may include facilitating the regulation of negative emotional stimuli, providing new important leads for models of antidepressant action. Copyright © 2015. Published by Elsevier Ireland Ltd.
    07/2015; 233(3). DOI:10.1016/j.pscychresns.2015.07.018
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