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Cited by 77Treatment of Major DepressionPsychological Treatments and DisordersAnxiety, Depression, Psychometrics, Treatment, Cognitive Processes

Major Depressive Disorder: Understanding the Significance of Residual Symptoms and Balancing Efficacy with Tolerability

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Culpepper, Larry, Muskin, Philip R., Stahl, Stephen M.·2015·The American Journal of Medicine
DOI 10.1016/j.amjmed.2015.07.001
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Abstract

Introduction Major depressive disorder is a complex and frequent psychiatric condition that poses significant challenges to both the patients who experience it and the physicians who treat them. The goal of therapy is for patients to achieve remission, which requires identifying and measuring symptoms at the outset and throughout treatment to document both response and resistance to treatment. A number of validated instruments are available both for diagnosis of and response to treatment. Many factors affect a patient's ability to achieve remission, but although many patients do achieve remission, a significant number continue to have residual symptoms that cause functional impairment.Methods Review of the literature for treatment of major depression, including mechanisms of action, individualized treatment optimization, residual symptom reduction, and minimization of side effects.Results For sustained remission, all symptoms must be treated until they are undetectable. Patients who do not achieve remission after adequate treatment trials should be evaluated for adherence to treatment, as well as comorbid psychiatric and medical disorders. In these cases, consideration should be given to changing therapy by switching, combining, or augmenting initial therapy, as well as referring some patients to a psychiatrist for treatment with specialized modalities. Linking symptoms with malfunctioning brain circuits and neurotransmitters provides a targeted approach for achieving sustained remission. Neurobiology also provides a rational basis for combination therapy in patients with treatment-resistant depression, because it can aid selection of different drugs with different mechanisms of action or of multifunctional/multimodal antidepressant drugs that target more than 1 molecular mechanism.Discussion Recent advances and better understanding of neurobiology provide a rational basis for individualizing treatment of patients with major depression.

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  • Ketamine produces swift mood elevation, while iTBS supplies a modifiable scaffold whose effects often persist longer than infusion benefits.

    “Ketamine produces swift mood elevation, while iTBS supplies a modifiable scaffold whose effects often persist longer than infusion benefits”

    From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [354]

    The Nonpharmacologic Interventions section (page unavailable) reports short-term benefit from repetitive transcranial magnetic stimulation, but does not address iTBS specifically or the duration of its effects. Searches for ketamine, theta-burst stimulation, and infusion benefits found no passage supporting rapid mood elevation or the claimed comparison in durability. (LLM, conf=0.76)

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  1. [9]9. Miller IW, Keitner GI, Schatzberg AF, et al. Psychosocial functioning before and after treatment with sertraline or imipramine. J Clin Psy- chiatry. 1998;59:608-619.
  2. [13]13. Paykel ES. Residual symptoms and relapse in depression. Medi- cographia. 2009;31:157-163.

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Authors
Culpepper, L., Muskin, P. R., & Stahl, S. M.
Affiliations
  • Boston University (US)
  • Columbia University Irving Medical Center (US)
  • University of Cambridge (GB)
Corresponding author
Culpepper, Larry
ORCID
Venue
The American Journal of Medicine
Publisher
Elsevier BV
Published
2015-09
Volume
128
Issue
9
Pages
S1-S15
ISSN
0002-9343 (ISSN-L)
DOI
10.1016/j.amjmed.2015.07.001
OpenAlex
W1784745783
Cited by
77
References
110
Citations by year
2026: 2 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 14 · 2020: 11 · 2019: 14 · 2018: 5 · 2017: 4 · 2016: 2 · 2015: 2
FWCI
3.12
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Social Sciences › Psychology › Clinical Psychology › Psychological Treatments and Disorders
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Keywords
major depressive disorder, residual depressive symptoms, treatment-resistant depression, antidepressant efficacy, antidepressant tolerability, antidepressant side effects, medication adherence, combination therapy, augmentation therapy, personalized treatment, neurobiology of depression, neurotransmitters, brain circuits, remission
MeSH terms
Major Depressive Disorder, Humans, Monoamine Oxidase Inhibitors, Psychotropic Drugs, Remission Induction, Antipsychotic Agents, Treatment Outcome, Molecular Targeted Therapy

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