Antidepressants increase neural progenitor cells in the human hippocampus
Open accessAbstract
Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) increase neurogenesis in the dentate gyrus (DG) of rodents and nonhuman primates. We determined whether SSRIs or TCAs increase neural progenitor (NPCs) and dividing cells in the human DG in major depressive disorder (MDD). Whole frozen hippocampi from untreated subjects with MDD (N=5), antidepressant-treated MDD (MDDT, N=7), and controls (C, N=7) were fixed, sectioned, and immunostained for NPCs and dividing cell markers (nestin and Ki-67, respectively), NeuN and GFAP, in single and double labeling. NPC and dividing cell numbers in the DG were estimated by stereology. Clinical data were obtained by psychological autopsy, and by toxicological and neuropathological examination performed on all subjects. NPCs decreased with age (p = 0.034). Females had more NPCs than males (p = 0.023). Correcting for age and sex, MDDT receiving SSRIs had more NPCs than untreated MDD (p < or = 0.001) and controls (p < or = 0.001), NPCs were not different in SSRI- and TCA-treated MDDT (p = 0.169). Dividing cell number, unaffected by age or sex, was greater in MDDT receiving TCAs than in untreated MDD (p < or = 0.001), SSRI-treated MDD (p = 0.001), and controls (p < or = 0.001). The increase of NPCs and dividing cells in MDDT was localized to the rostral DG. MDDT had a larger DG volume compared with untreated MDD or controls (p = 0.009). Antidepressants increase NPC number in the anterior human DG. Whether this finding is critical or necessary for the antidepressants effect remains to be determined.
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Chronic treatment with a SSRI such as fluoxetine increases hippocampal neurogenesis through the generation of newborn cells in the dentate gyrus.
“Accordingly, chronic treatment with a SSRI such as fluoxetine increased hippocampal neurogenesis through the generation of newborn cells in the DG (Boldrini et al. 2009; Encinas et al. 2006; Malberg et al. 2000; Santarelli et al. 2003; Surget et al. 2011).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Boldrini et al. 2009
The Discussion reports more neural progenitor cells in the human dentate gyrus of patients treated with SSRIs, including fluoxetine, and cites animal findings of increased dentate-gyrus cell proliferation with fluoxetine. But this postmortem study did not establish that the additional dividing cells became newborn neurons; the Discussion notes that its cell-division marker can also label non-neuronal cells. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPost-mortem brains of MDD patients treated with nortriptyline and clomipramine show an increase of neural progenitor cells and dividing cells in the dentate gyrus compared to healthy controls.
“Regarding neurogenesis per se, the analysis of post-mortem brains of MDD patients treated with nortriptyline and clomipramine showed an increase of neural progenitor cells and dividing cells in the DG, as compared to healthy controls (Boldrini et al. 2009).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Boldrini et al. 2009
Deficits in adult hippocampal neurogenesis may explain learning and memory deficits in major depressive disorder and may play a role in selective engagement with negative valence memories, mood regulation, and antidepressant response.
“Deficits in AHN may not only explain the learning and memory deficits in MDD, but also play a role in the selective engagement with negative valence memories, mood regulation and antidepressant response118-122.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [120]
Antidepressants increase adult hippocampal neurogenesis in animal models.
“Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown.”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [4]
Antidepressants increase hippocampal neurogenesis in both animals and humans.
“Several studies have shown that antidepressants increase hippocampal neurogenesis in both animals and humans,1, 2, 3, 4, 5”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [4]
A study on human post-mortem brain tissue has found that antidepressants increase the number of neural progenitor cells in patients with major depression to levels above those present in controls.
“a study on human post-mortem brain tissue has found that antidepressants increase the number of neural progenitor cells in patients with major depression to levels above those present in controls”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [4]
Depressed patients are generally characterized by elevated endogenous levels of glucocorticoids.
“depressed patients are generally characterized by elevated endogenous levels of glucocorticoids.4”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [4]
Antidepressant treatment in major depression patients seems to affect neurogenesis.
“antidepressant treatment in MD patients seems to have an effect on neurogenesis”
From Glucocorticoids, cytokines and brain abnormalities in depression (2011) · cites this paper as Boldrini et al. (2009)
Boldrini et al. showed increased progenitor cells in major depression patients treated with antidepressants; treated patients had more dividing cells in the hippocampus than untreated patients and controls.
“Boldrini et al. (2009) showed increased progenitor cells in MD patients treated with antidepressants. More specifically, patients receiving these drugs had more dividing cells in the hippocampus than untreated patients and controls.”
From Glucocorticoids, cytokines and brain abnormalities in depression (2011) · cites this paper as Boldrini et al. (2009)
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- Authors
- Boldrini, M., Underwood, M. D., Hen, R., Rosoklija, G. B., Dwork, A. J., John Mann, J., & Arango, V.
- Affiliations
- New York State Psychiatric Institute (US)
- Macedonian Academy of Sciences and Arts (MK)
- Corresponding author
- Boldrini, Maura
- Venue
- Neuropsychopharmacology
- Published
- 2009-07-15
- Volume
- 34
- Issue
- 11
- Pages
- 2376-2389
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC2743790
- OpenAlex
- W2030772288
- Cited by
- 686
- References
- 82
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 24 · 2023: 20 · 2022: 31 · 2021: 52 · 2020: 40 · 2019: 40 · 2018: 40 · 2017: 48 · 2016: 40 · 2015: 37 · 2014: 57 · 2013: 53 · 2012: 60
- FWCI
- 17.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Funders
- American Foundation for Suicide Prevention
- National Institute of Mental Health (MH 62185, R01MH064168, R01MH083862, MH64168, MH-40210, R01MH060877, R01MH040210, MH083862, P50MH062185)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- antidepressants, neural progenitor cells, dentate gyrus, hippocampus, major depressive disorder, selective serotonin reuptake inhibitors, tricyclic antidepressants, neurogenesis, dividing cells, Ki-67, nestin, age and sex differences
- MeSH terms
- Adolescent, Adult, Aging, Antidepressive Agents, Antidepressive Agents, Tricyclic, Cell Division, Depressive Disorder, Major, Major Depressive Disorder, Female, Humans, Male, Middle Aged, Neurons, Organ Size, Sex Characteristics, Selective Serotonin Reuptake Inhibitors, Dentate Gyrus, Adult Stem Cells, Young Adult
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