Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action
Open accessAbstract
Background: The neuropharmacological actions of antidepressants are well characterised but our understanding of how these changes translate into improved mood are still emerging. Aims: To investigate whether actions of antidepressant drugs on emotional processing are a mediating factor in the effects of these drugs in depression. Method: We examined key published findings that explored the effects of antidepressants on behavioural and functional magnetic resonance imaging (fMRI) measures of emotional processing. Results: 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. Conclusions: 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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Studies on MDD have found that SSRI intervention often normalises abnormal neural processing, which in turn improves cognitive functioning and at a later time point, mood.
“Studies on MDD have found that SSRI intervention often normalises abnormal neural processing [49–52], which in turn improves cognitive functioning and at a later time point, mood [52].”
From Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study (2023) · cites this paper as [52]
The ‘Studies in patients with depression or anxiety’ section reports that SSRI treatment normalised some abnormal neural responses in patients with depression. The Conclusions propose that changes in emotional processing could free resources for cognitive tasks and later improve mood, but do not establish that this sequence of improvements in cognitive functioning and mood was found in MDD studies. Page numbers are not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBiased patterns of information processing might constitute a final pathway to negative affect and self-reported symptomatology via their chronic and cumulative influence on the individual's day-to-day perceptions and experiences.
“Biased patterns of information processing might then constitute a final pathway to negative affect and self-reported symptomatology (discussed further below), via their chronic and cumulative influence on the individual's day-to-day perceptions and experiences 82,106-109 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [109]
Amygdala reactivity to negative affective stimuli is a marker of negative affective bias in depression.
“Amygdala reac vity to nega ve informa on is a marker of nega ve affec ve processes in depression that is reduced by an depressant medica on.”
From Amygdala Reactivity, Antidepressant Discontinuation, and Relapse (2024) · cites this paper as [17]
The direct effect of effective antidepressant treatment is to modify biases in emotional processing.
“The key hypothesis underlying this work has been that the direct effect of antidepressant treatment is to modify emotional processing.10-12”
From The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment (2015) · cites this paper as [10]
Changes in the cognitive processing of emotional stimuli are linked to the direct pharmacological action of antidepressant treatment but are dissociated in time from mood changes, which appear some weeks later.
“These changes in the cognitive processing of emotional stimuli are linked to the direct pharmacological action of the treatment, but they are dissociated in time from changes in mood which appear some weeks later in treatment.”
From The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment (2015) · cites this paper as [10]
Healthy volunteer models of emotional processing can be employed as an assay for putative novel treatments.
“A clear implication of this model of antidepressant drug action is that it should be possible to employ healthy volunteer models of emotional processing as an assay for putative novel treatments.10”
From The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment (2015) · cites this paper as [10]
A clear prediction of the cognitive neuropsychological model is that early, direct effects of treatment underlie subsequent mood improvement.
“A clear prediction of the model is that early, direct effects of treatment underlie subsequent mood improvement.10”
From The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment (2015) · cites this paper as [10]
The modification of emotional bias may be the final common pathway by which all antidepressant drug treatments exert their positive effects on mood.
“It has been suggested that the modification of emotional bias may be the final common pathway by which all antidepressant drug treatments exert their positive effects on mood,10-12 and we have reviewed evidence from drugs with diverse pharmacological actions to support this.”
From The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment (2015) · cites this paper as [10]
It might take time to generalize a newly acquired information processing style to daily life and the experience of stressful life events, so emotional effects might only become apparent at a later time point.
“As it might take time to generalize a newly acquired information processing style to daily life and the experience of stressful life events, emotional effects might only become apparent at a later time point (cf.Harmer, Goodwin, & Cowen, 2009).”
From Online attentional bias modification training targeting anxiety and depression in unselected adolescents: short- and long-term effects of a randomized controlled trial (2016) · cites this paper as Harmer, Goodwin, & Cowen, 2009
Long-term emotional effects might be observed, as newly acquired information processing styles could be applied in situations encountered after the training period.
“Also, longterm emotional effects might be observed, as newly acquired information processing styles could be applied in situations encountered after the training period (Harmer et al., 2009).”
From Online attentional bias modification training targeting anxiety and depression in unselected adolescents: short- and long-term effects of a randomized controlled trial (2016) · cites this paper as Harmer et al., 2009
The clinically therapeutic effects of antidepressants are usually only reported 2-6 weeks into treatment.
“Harmer, Goodwin, and Cowen (2009) have suggested that their clinically therapeutic effects, usually only reported 2 -6 weeks into treatment, may be explained by acute but very subtle changes in emotional processing that accumulate over time.”
From Mood Disorders in Everyday Life: A Systematic Review of Experience Sampling and Ecological Momentary Assessment Studies (2012) · cites this paper as Harmer, Goodwin, and Cowen (2009)
Acute but very subtle changes in emotional processing that accumulate over time may explain the delayed therapeutic effects of antidepressants.
“Harmer, Goodwin, and Cowen (2009) have suggested that their clinically therapeutic effects, usually only reported 2 -6 weeks into treatment, may be explained by acute but very subtle changes in emotional processing that accumulate over time.”
From Mood Disorders in Everyday Life: A Systematic Review of Experience Sampling and Ecological Momentary Assessment Studies (2012) · cites this paper as Harmer, Goodwin, and Cowen (2009)
Most currently available antidepressants have a delayed onset of action.
“Indeed, another opportunity for ESM/EMA in the context of mood disorders research is created in the context of the delayed onset of action of most currently available antidepressants.”
From Mood Disorders in Everyday Life: A Systematic Review of Experience Sampling and Ecological Momentary Assessment Studies (2012) · cites this paper as Harmer, Goodwin, and Cowen (2009)
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Amygdala Reactivity, Antidepressant Discontinuation, and Relapse
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- Authors
- Harmer, C. J., Goodwin, G. M., & Cowen, P. J.
- Affiliations
- Warneford Hospital (GB)
- Corresponding author
- Harmer, Catherine J.
- Venue
- British Journal of Psychiatry
- Publisher
- Royal College of Psychiatrists
- Published
- 2009-08
- Volume
- 195
- Issue
- 2
- Pages
- 102-108
- ISSN
- 0007-1250 (ISSN-L)
- 1472-1465
- OpenAlex
- W2105190393
- Cited by
- 542
- References
- 47
- Citations by year
- 2026: 20 · 2025: 30 · 2024: 35 · 2023: 27 · 2022: 27 · 2021: 30 · 2020: 25 · 2019: 29 · 2018: 32 · 2017: 35 · 2016: 42 · 2015: 48 · 2014: 32 · 2013: 44 · 2012: 37
- FWCI
- 20.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The British Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- antidepressants, antidepressant mechanism, depression, emotional processing, cognitive theories of depression, limbic system, prefrontal cortex, mood improvement
- MeSH terms
- Affect, Antidepressive Agents, Cognition, Depressive Disorder, Emotions, Facial Expression, Humans, Limbic System, Magnetic Resonance Imaging, Models, Neurological, Models, Psychological, Negativism, Time Factors
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