Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms
Open accessAbstract
Depression is one of the most prevalent and debilitating of the psychiatric disorders. Studies have shown that cognitive therapy is as efficacious as antidepressant medication at treating depression, and it seems to reduce the risk of relapse even after its discontinuation. Cognitive therapy and antidepressant medication probably engage some similar neural mechanisms, as well as mechanisms that are distinctive to each. A precise specification of these mechanisms might one day be used to guide treatment selection and improve outcomes.
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Pharmacological agents used to treat anxiety disorders (benzodiazepines, clonidine, propranolol, SSRIs, and dual serotonin and norepinephrine reuptake inhibitors) are thought to inhibit the amygdala and other limbic structures by acting on alpha, beta, GABA, or serotonin receptors in the amygdala, hypothalamus, or PAG.
“Pharmacological agents used to treat anxiety disorders—benzodiazepines, clonidine, propranolol, selective serotonin reuptake inhibitors, and dual serotonin and norephinephrine reuptake inhibitors—are thought to inhibit the amygdala and other limbic structures by acting on alpha, beta, GABA, or serotonin receptors in the amygdala, hypothalamus, or PAG.159–162”
From Fear and the Defense Cascade (2015) · cites this paper as [160]
In “Effects of treatment on brain circuitry” (page not provided), the paper says SSRIs could inhibit the amygdala and other ventral limbic regions, and discusses possible inhibitory effects of SSRIs and SNRIs. It addresses antidepressant treatment for depression, not the claimed mechanism for anxiety drugs as a group; the supplied passages do not support the claims about benzodiazepines, clonidine, propranolol, or the specified receptors and sites. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDiscontinuation of medication, with removal of limbic inhibition, will potentially leave the individual prone to strong limbic reactivity to new stressors without long-term changes in information processing.
“Subsequent discontinuation of medication—and with it, the removal of limbic inhibition—will potentially leave the individual prone to experiencing strong limbic reactivity to new stressors, without having brought about any long-term changes in information processing.160”
From Fear and the Defense Cascade (2015) · cites this paper as [160]
In “Effects of treatment on brain circuitry” (page unavailable), the paper proposes that stopping antidepressant medication could leave a person vulnerable to strong reactions to new stressors. But “Antidepressant medication” says the long-term cognitive effects have not been examined, and “Conclusions and future directions” allows that medication might eventually increase reliance on prefrontal function. The asserted absence of long-term changes in information processing is therefore not established. (LLM, conf=0.86)
Experimental — accuracy not yet measuredWhen traumatic memories are successfully processed, the physiological markers of arousal decrease.
“When traumatic memories are successfully processed, the physiological markers of arousal likewise decrease.160,182–186”
From Fear and the Defense Cascade (2015) · cites this paper as [160]
The Effects of treatment on brain circuitry section reports decreased amygdala activity in response to emotional information after cognitive therapy for depression and describes normalized activity after successful therapy for specific phobia. It does not establish that processing traumatic memories reduces physiological markers of arousal; both the condition and the measures differ from those in the claim. No page number is available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredPFC function is enhanced during CBT interventions.
“PFC function has been found to be enhanced during CBT interventions.160,182”
From Fear and the Defense Cascade (2015) · cites this paper as [160]
Memories of past trauma can activate the body's arousal systems, resulting in arousal, the precondition of activating the defense cascade.
“Since memories of past trauma can activate the body’s arousal systems—resulting in arousal, the precondition of activating the defense cascade”
From Fear and the Defense Cascade (2015) · cites this paper as [160]
The ‘Increased or sustained amygdala activity’ section links the amygdala to emotional reactions and associations in memory, while ‘Conclusions and future directions’ mentions childhood trauma as a treatment-outcome variable. Neither passage says that memories of trauma activate bodily arousal systems or that arousal is a precondition for a defense cascade; searches for trauma memories, physiological arousal, and defensive responses found no passage addressing that sequence. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Both biological and psychological therapies remove the structural basis for negative bias formation by affecting prefrontal and subcortical circuitry, possibly differing in terms of initial targets.
“both biological and psychological therapies remove the structural basis for negative bias formation, by affecting prefrontal and subcortical circuitry, however, possibly differing in terms of initial targets”
From Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment (2021) · cites this paper as Derubeis et al. 2008
CBT has also been shown to have some bottom-up effect, decreasing excessive reactivity of ventral cortico-limbic structures, similar to antidepressant medications.
“Although this ‘top-down’ direction prevails, CBT has also been shown to have some ‘bottom-up’ effect, and decrease excessive reactivity of ventral cortico-limbic structures, similar to antidepressant medications (DeRubeis et al. 2008, Kalsi et al. 2017, Sankar et al., 2018).”
From Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment (2021) · cites this paper as DeRubeis et al. 2008
Psychological treatments are likely to work through changes in the frontal control systems.
“It has been suggested that psychological treatments, in contrast, are likely to work through changes in the frontal control systems (22,23).”
From Lateral prefrontal cortex mediates the cognitive modification of attentional bias (2010) · cites this paper as [23]
Patients with affective disorders who remit show recovery in the imbalance between prefrontal and limbic systems.
“Patients with affective disorders who remit have been found to show recovery in the imbalance between these two systems (DeRubeis et al., 2008; Etkin et al., 2005; Siegle et al., 2007).”
From Meta-analyses of the neural mechanisms and predictors of response to psychotherapy in depression and anxiety (2018) · cites this paper as DeRubeis et al., 2008
Psychological therapies for depression act to regulate emotional control processes by increasing prefrontal emotional regulation activation, which has a top-down effect on limbic activation.
“DeRubeis et al. proposed that psychological therapies for depression act to regulate emotional control processes by increasing activation in prefrontal emotional regulation systems which in turn have a top-down effect on limbic activation (DeRubeis et al., 2008).”
From Meta-analyses of the neural mechanisms and predictors of response to psychotherapy in depression and anxiety (2018) · cites this paper as DeRubeis et al., 2008
Cognitive behavioural therapy is efficacious in the treatment of depressive disorders.
“Cognitive behavioural therapy (CBT) has been shown to be efficacious in the treatment of depressive disorders [13, 14]”
From Effectiveness and cost-effectiveness of guided Internet- and mobile-based CBT for adolescents and young adults with chronic somatic conditions and comorbid depression and anxiety symptoms (youthCOACHCD): study protocol for a multicentre randomized controlled trial (2020) · cites this paper as [13]
The type of individual therapy may moderate the effects caused by CAT-DB.
“However, it has to be taken into account that TAU was tailored to the participants to consider their specific needs (including, among others, psychopharmacological therapy and individual and group therapy as well as additional appointments if needed) and, therefore, the type of individual therapy may moderate the effects caused by CAT-DB (57).”
From Computer-assisted avatar-based treatment for dysfunctional beliefs in depressive inpatients: A pilot study (2021) · cites this paper as [57]
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“The observed associations between depressive symptoms and DLPFC activation during this task are consistent with meta-analyses that have reliably implicated hypoactivity of the DLPFC in depression (24,27) and have found that various forms of successful treatments remediate this hypoactivity (26,33).”
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- Authors
- DeRubeis, R. J., Siegle, G. J., & Hollon, S. D.
- Affiliations
- University of Pennsylvania (US)
- Vanderbilt University (US)
- Corresponding author
- DeRubeis, Robert J.
- Venue
- Nature Reviews Neuroscience
- Published
- 2008-09-11
- Volume
- 9
- Issue
- 10
- Pages
- 788-796
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- PMC
- PMC2748674
- OpenAlex
- W2066231855
- Cited by
- 690
- References
- 122
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 24 · 2023: 37 · 2022: 37 · 2021: 43 · 2020: 43 · 2019: 45 · 2018: 33 · 2017: 66 · 2016: 45 · 2015: 54 · 2014: 48 · 2013: 39 · 2012: 44
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH082998, MH 55875, K02MH082998, MH 074807, MH60998, R01MH060713, R01MH060998, MH 50129, MH060713, K02MH001697, MH 01697, R10MH055875, R01MH074807)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
- Keywords
- cognitive therapy, antidepressants, depression, relapse prevention, treatment selection
- MeSH terms
- Antidepressive Agents, Brain, Cognition, Depressive Disorder, Humans, Limbic System, Cognitive Behavioral Therapy, Treatment Outcome, Prefrontal Cortex, Secondary Prevention
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