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


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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    • "In task-related fMRI paradigms it was shown that acute neural changes take place in the limbic system and prefrontal circuitry (Bruhl et al., 2010; Del-Ben et al., 2005; Murphy et al., 2009; Outhred et al., 2013). Despite the instant neural changes after administration of an SSRI, improvements in mood and cognition usually begin only after a few weeks (Frazer and Benmansour, 2002; Harmer et al., 2009). One explanation for this apparent discrepancy is the acute effect of SSRIs on emotional bias (Bhagwagar et al., 2004; Browning et al., 2007; Harmer et al., 2003a, b), which could increase positive information processing, thereby slowly contributing to resolution of the depression (Harmer, 2008). "
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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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    • "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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