Rational site-directed pharmacotherapy for major depressive disorder
Open accessAbstract
It is now accepted that major depressive disorder (MDD) is not a single pathophysiological entity. It is therefore not surprising that remission rates to a first antidepressant trial are low. In addition, antidepressants may target various neuronal elements for which there are gene polymorphisms, such as the serotonin (5-HT) reuptake transporter, which may modulate response. Acting on a single monoaminergic target, such as inhibiting the 5-HT transporter, may confer efficacy in MDD, but other targets may be used and/or combined in treatment-resistant patients. These include the blockade of norepinephrine transporters, monoamine oxidase, 5-HT(2A), 5-HT(1B) and 5-HT7 receptors, and the activation of 5-HT(1A) and dopamine 2 receptors. While antidepressants may have more than one of these properties, so do atypical antipsychotics. When using the latter medications, however, their regimens should be below those effective in treating psychosis to avoid dopamine 2 antagonism, which could be counter-productive in MDD. In some patients, combining medications from treatment initiation may also provide additional therapeutic benefits.
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By broadly enhancing serotoninergic transmission, SSRI drugs activate gamma-aminobutyric acid interneurons, thereby dampening noradrenergic and dopaminergic input.
“By broadly enhancing serotoninergic transmission, SSRI drugs activate gamma-aminobutyric acid (GABA) interneurons, thereby dampening the noradrenergic as well as the dopaminergic input (Blier, 2014).”
From Effectiveness of Vortioxetine on Emotional Blunting in Patients with Major Depressive Disorder with inadequate response to SSRI/SNRI treatment (2021) · cites this paper as Blier, 2014
In “Possible reasons for low remission rates with a first antidepressant trials” (page unavailable), the paper describes serotonin activating GABA neurons that inhibit noradrenergic and dopaminergic neuron firing. It qualifies the SSRI effect on dopamine, however: decreased dopaminergic firing has not been reported with all SSRIs. The claim presents that effect as general to SSRI drugs. (LLM, conf=0.88)
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- Authors
- Blier, P.
- Affiliations
- Institute of Mental Health Research (CA)
- Corresponding author
- Blier, Pierre
- ORCID
- Blier, Pierre
- Venue
- The International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-06-10
- Volume
- 17
- Issue
- 07
- Pages
- 997-1008
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- OpenAlex
- W2119211687
- Cited by
- 29
- References
- 87
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 1 · 2013: 2
- FWCI
- 0.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Psychology › Clinical Psychology › Psychological Treatments and Disorders
- Keywords
- major depressive disorder, pharmacotherapy, antidepressant response, treatment-resistant depression, genetic polymorphism, serotonin transporter, norepinephrine transporter, monoamine oxidase, serotonin receptors, dopamine D2 receptor, atypical antipsychotics, combination therapy
- MeSH terms
- Animals, Antidepressive Agents, Clinical Trials as Topic, Depressive Disorder, Major, Major Depressive Disorder, Drug Therapy, Combination, Humans, Polypharmacy
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