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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    • "Based on the reduced FC in the CO network and increased FC in the DM network, our results reinforce that a deficient salience network might be associated to the inability to reallocate resources to externallyoriented mental activity in unipolar patients [Menon, 2011], which would predispose and/or sustain internallyoriented ruminative thoughts associated to the negative biases in information processing. A platform for cognitive and psychological reconsolidation [Harmer et al., 2009] might dependent on the restoration of the FC between the hippocampus and the medial prefrontal cortex [Genzel et al., 2015]. Although we could not evaluate it prospectively , the retrospective collection of the clinical features has given us an important insight into the implication of these dysconnectivities. "
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    • "It is widely accepted that most mental disorders may be the result of combinations of several different factors and individual susceptibility. Although their pathophysiology is still incompletely understood, various psychiatric diseases might share common mechanisms (Graeff and Zangrossi, Jr., 2010; Harmer et al., 2009). Purines and purinergic neurotransmission and neuromodulation in the brain have attracted increasing therapeutic interest in the field of psychiatry. "
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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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