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Cited by 107Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorAnxiety, Depression, Psychometrics, Treatment, Cognitive Processes

Blue Again: Perturbational Effects of Antidepressants Suggest Monoaminergic Homeostasis in Major Depression

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Andrews, Paul W., Kornstein, Susan G., Halberstadt, Lisa J., Gardner, Charles O., Neale, Michael C.·2011·Frontiers in Psychology
DOI 10.3389/fpsyg.2011.00159PMC PMC3133866
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Abstract

Some evolutionary researchers have argued that current diagnostic criteria for major depressive disorder (MDD) may not accurately distinguish true instances of disorder from a normal, adaptive stress response. According to disorder advocates, neurochemicals like the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are dysregulated in major depression. Monoamines are normally under homeostatic control, so the monoamine disorder hypothesis implies a breakdown in homeostatic mechanisms. In contrast, adaptationist hypotheses propose that homeostatic mechanisms are properly functioning in most patients meeting current criteria for MDD. If the homeostatic mechanisms regulating monoamines are functioning properly in these patients, then oppositional tolerance should develop with prolonged antidepressant medication (ADM) therapy. Oppositional tolerance refers to the forces that develop when a homeostatic mechanism has been subject to prolonged pharmacological perturbation that attempt to bring the system back to equilibrium. When pharmacological intervention is discontinued, the oppositional forces cause monoamine levels to overshoot their equilibrium levels. Since depressive symptoms are under monoaminergic control, this overshoot should cause a resurgence of depressive symptoms that is proportional to the perturbational effect of the ADM. We test this prediction by conducting a meta-analysis of ADM discontinuation studies. We find that the risk of relapse after ADM discontinuation is positively associated with the degree to which ADMs enhance serotonin and norepinephrine in prefrontal cortex, after controlling for covariates. The results are consistent with oppositional tolerance, and provide no evidence of malfunction in the monoaminergic regulatory mechanisms in patients meeting current diagnostic criteria for MDD. We discuss the evolutionary and clinical implications of our findings.

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Crossref · 10.3389/fpsyg.2011.00159

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  • Oppositional tolerance could contribute to increased relapse risks after prolonged treatment and thereby counterbalance protective effects of longer treatment.

    “This could contribute to increased relapse risks after prolonged treatment and thereby counterbalance protective effects of longer treatment.”

    From Predicting relapse after antidepressant withdrawal – a systematic review (2017) · cites this paper as Andrews et al. 2011

    The Introduction proposes that longer antidepressant treatment allows more time for oppositional tolerance, potentially increasing relapse risk after discontinuation. The Discussion (Clinical implications) reports a non-significant trend toward greater relapse risk with longer treatment, but says the study found no protective effect of treatment duration to counterbalance. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Effect size improvements for both psychosocial and biomedical interventions are minimal or absent.

    “effect size improvements for both psychosocial and biomedical interventions are minimal or absent 3”

    From “Third-wave” cognitive and behavioral therapies and the emergence of a process-based approach to intervention in psychiatry (2021) · cites this paper as [3]

    The Discussion’s “Modest efficacy of ADMs during acute therapy” section says antidepressant drugs have limited efficacy during acute treatment. It does not establish minimal or absent effect-size improvements for psychosocial interventions, or for biomedical interventions generally (page not provided in our copy). (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Andrews et al. (2011) found that relapse risk was higher after discontinuing antidepressants with larger effects on the serotonergic or noradrenergic system.

    “First, they found that relapse risk was higher after discontinuing antidepressants with larger effects on the serotonergic or noradrenergic system.”

    From Predicting relapse after antidepressant withdrawal – a systematic review (2017) · cites this paper as Andrews et al. 2011

  • There are indications that tachyphylaxis and even oppositional tolerance may occur.

    “Patients discontinue for a variety of reasons including side effects; and there are indications that tachyphylaxis (Rothschild et al. 2009) and even oppositional tolerance may occur (Andrews et al. 2011; El-Mallakh & Briscoe, 2012).”

    From Predicting relapse after antidepressant withdrawal – a systematic review (2017) · cites this paper as Andrews et al. 2011

  • Biomedical treatments are becoming more generic rather than more specific.

    “biomedical treatments are becoming more generic rather than more specific”

    From “Third-wave” cognitive and behavioral therapies and the emergence of a process-based approach to intervention in psychiatry (2021) · cites this paper as [3]

    The Study Overview and Discussion address antidepressant drugs, treatment resistance, and relapse, not whether biomedical treatments are becoming more generic rather than more specific. Searches for that wording and for treatment specificity found no passage addressing the claimed trend; page numbers were not available in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 2

  1. Spitzer R. L. (2007). Foreword. New York, NY: Oxford University Press
  2. Young A. M. Goudie A. J. (1995). “Adaptive processes regulating tolerance to behavioral effects of drugs,” in Psychopharmacology: 4th Generation of Progress, eds Bloom F. E. Kupfer D. J. (New York, NY: Raven Press), 733– 742

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Authors
Andrews, P. W., Kornstein, S. G., Halberstadt, L. J., Gardner, C. O., & Neale, M. C.
Affiliations
Virginia Commonwealth University (US)
Corresponding author
Andrews, Paul W.
ORCID
Venue
Frontiers in Psychology
Publisher
Frontiers Media SA
Published
2011
Volume
2
Pages
159-159
ISSN
1664-1078 (ISSN-L)
DOI
10.3389/fpsyg.2011.00159
PMC
PMC3133866
OpenAlex
W2108246528
Cited by
107
References
193
Citations by year
2026: 1 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 9 · 2021: 8 · 2020: 12 · 2019: 10 · 2018: 8 · 2017: 9 · 2016: 2 · 2015: 8 · 2014: 4 · 2013: 6 · 2012: 9
FWCI
4.92
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Psychology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • National Institutes of Health
  • National Institute of Mental Health
  • National Institute on Drug Abuse (R01DA018673, R37DA018673)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Keywords
major depressive disorder, antidepressant discontinuation, serotonin, norepinephrine, dopamine, prefrontal cortex, evolutionary psychiatry

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