The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling
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The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.
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In rodents undergoing chronic mild stress or stress induced by corticosterone and whose neurogenesis has been ablated, some behavioral depression-like signs are ameliorated independently of neurogenesis, while some others are dependent.
“In summary, the results of several experiments indicated very clearly that in rodents undergoing chronic mild stress or stress induced by corticosterone and whose neurogenesis has been ablated, some behavioral depression-like signs are ameliorated independently of neurogenesis, while some others are dependent (Airan et al., 2007;Bessa et al., 2009;Surget et al., 2008;David et al., 2009).”
From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as Bessa et al., 2009
The Discussion reports that antidepressants ameliorated CMS-induced depression-like behaviors equally in rats with and without MAM treatment, supporting neurogenesis-independent improvement. It also says neurogenesis seemed essential for reducing CMS-induced anxiety in the novelty-suppressed feeding test, but distinguishes that anxiety-like outcome from the depression-like signs of anhedonia and learned helplessness. This paper studied chronic mild stress, not corticosterone-induced stress. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMounting evidence seems to indicate that neurogenesis might not be required for the therapeutic action of antidepressants.
“Furthermore, mounting evidence seems to indicate that neurogenesis might not be required for the therapeutic action of antidepressants (Bessa et al. 2009).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Bessa et al. 2009
In rodents, chronic but not acute treatment with conventional antidepressants reverses stress-induced dendritic atrophy.
“Chronic, but not acute, administration of conventional antidepressants also reverses stress-induced dendritic atrophy in rodents[126]”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [126]
Sample sizes were based on previous published studies.
“The sample sizes were based on previous published studies.9, 20”
From Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression (2017) · cites this paper as [9]
At short-term, behavioral improvements induced by antidepressants rely on hippocampal neuronal remodeling.
“at short-term, behavioral improvements induced by ADs rely on hippocampal neuronal remodeling,9”
From Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression (2017) · cites this paper as [9]
The uCMS protocol used was validated and previously described.
“Rats were subjected to a validated uCMS protocol for 6 weeks, as previously described9, 20, 23”
From Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression (2017) · cites this paper as [9]
ADs, including imipramine, reverse the shrinkage in dendritic branching induced by stress and allow the re-establishment of the normal neuronal network.
“in line with previous studies demonstrating that ADs, including imipramine, reverse the shrinkage in dendritic branching induced by stress and allows the re-establishment of the normal neuronal network,9”
From Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression (2017) · cites this paper as [9]
Fluoxetine treatment and further stress re-exposure also induced dendritic atrophy of the DG granule neurons, similar to the immediate effects induced by uCMS protocol in non-treated animals.
“Besides boosting adult neurogenesis, fluoxetine treatment and further stress re-exposure also induced dendritic atrophy of the DG granule neurons, similar to the immediate effects induced by uCMS protocol in non-treated animals.9”
From Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression (2017) · cites this paper as [9]
Residual changes and reported impairments in DG synaptic plasticity may account for the re-appearance of depressive, anxiety and cognitive deficits on uCMS re-exposure.
“These residual changes, together with reported impairments in DG synaptic plasticity9, 28, 29 may account for the re-appearance of depressive, anxiety and cognitive deficits on uCMS re-exposure.”
From Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression (2017) · cites this paper as [9]
In rodents, exposure to chronic stressors induces alterations in dendritic remodeling and decreases adult hippocampal neurogenesis.
“In rodents, exposure to protocol of chronic stressors, that modeling some features of psychiatric disorders symptoms, induce alterations in dendritic remodeling and decrease adult hippocampal neurogenesis (38, 44, 99).”
From Translational investigation of the therapeutic potential of Cannabidiol (CBD): Toward a new age (2018) · cites this paper as [99]
Long-term use of antidepressants can increase spine density or decrease atrophy of spines and dendrites after chronic stress.
“Other studies have concluded that long-term use of antidepressants can increase spine density or decrease atrophy of spines and dendrites after chronic stress.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [48]
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Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression
Levy, M. J. F., Boulle, F., Steinbusch, H. W., van den Hove, D. L. A., Kenis, G., & Lanfumey, L. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4950-4 · Cited by 308 · see citing works
Depression during pregnancy and postpartum: Contribution of stress and ovarian hormones
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Depression, Antidepressants, and Neurogenesis: A Critical Reappraisal
Hanson, N. D., Owens, M. J., & Nemeroff, C. B. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.220 · Cited by 302 · see citing works
Micheli, L., Ceccarelli, M., D’Andrea, G., & Tirone, F. (2018) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.09.002 · Cited by 288 · see citing works
Regulation of hippocampal H3 histone methylation by acute and chronic stress
Hunter, R. G., McCarthy, K. J., Milne, T. A., Pfaff, D. W., & McEwen, B. S. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911143106 · Cited by 290 · see citing works
Stress, anxiety, and dendritic spines: What are the connections?
Leuner, B., & Shors, T. J. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2012.04.021 · Cited by 284 · see citing works
Neuronal plasticity and neurotrophic factors in drug responses
Castrén, E., & Antila, H. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.61 · Cited by 284 · see citing works
Fuchikami, M., Thomas, A., Liu, R., Wohleb, E. S., Land, B. B., DiLeone, R. J., Aghajanian, G. K., & Duman, R. S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1414728112 · Cited by 265 · see citing works
“Neuropsychopharmacology 30(12):2275–2282.”
BackgroundSpine synapse remodeling in the pathophysiology and treatment of depression
Duman, C. H., & Duman, R. S. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.01.022 · Cited by 257 · see citing works
Depression in neurodegenerative diseases: Common mechanisms and current treatment options
Galts, C., Bettio, L. E. B., Jewett, D. C., Yang, C. C., Brocardo, P. S., Rodrigues, A. L. S., Thacker, J. S., & Gil‐Mohapel, J. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.04.002 · Cited by 268 · see citing works
Review: adult neurogenesis contributes to hippocampal plasticity
Toda, T., & Gage, F. H. (2017) · Cell and Tissue Research · doi:10.1007/s00441-017-2735-4 · Cited by 262 · see citing works
“…most studies have shown that the ablation of adult-born neurons does not affect the baseline levels of anxiety (David et al. 2009; Kitamura et al. 2009; Saxe et al. 2006), suggesting that adult neurogenesis is important for the stress response but not in every case (Bessa et al. 2009).”
BackgroundNeuronal plasticity and antidepressant actions
Castrén, E., & Hen, R. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2012.12.010 · Cited by 243 · see citing works
Sex differences in the antidepressant-like effects of ketamine
Carrier, N., & Kabbaj, M. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.12.009 · Cited by 251 · see citing works
“, 2009; Shansky and Morrison, 2009) effects that are reversed by classical antidepressant treatments (Bessa et al., 2009; Hajszan et al., 2009; Norrholm and Ouimet, 2001; Wood et al., 2004) as well as by acute ketamine treatment (Li et al.”
BackgroundDuman, R. S. (2014) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2014.16.1/rduman · Cited by 249 · see citing works
Lehmann, M. L., & Herkenham, M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0577-11.2011 · Cited by 234 · see citing works
“, 2001) or stressinduced IL dendritic retraction produces deficits in fear extinction (Bessa et al., 2009), leading to anxiety disorders.”
BackgroundPetrik, D., Lagace, D. C., & Eisch, A. J. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.09.003 · Cited by 241 · see citing works
“As shown in Table 1, there are currently 21 publications that have examined the depression- and anxiety-related behavioral consequences of decreasing neurogenesis in laboratory animals (Airan et al., 2007; Bessa et al., 2009; David et al., 2009; Fuss et al., 2010a; Holick et al., 2008; Jayatissa et al., 2009; Lagace e…”
BackgroundMethodInfluentialGalea, L. A. M., Wainwright, S. R., Roes, M., Duarte‐Guterman, P., Chow, C., & Hamson, D. K. (2013) · Journal of Neuroendocrinology · doi:10.1111/jne.12070 · Cited by 238 · see citing works
Magariños, A. M., Li, C. J., Gal Toth, J., Bath, K. G., Jing, D., Lee, F. S., & McEwen, B. S. (2011) · Hippocampus · doi:10.1002/hipo.20744 · Cited by 232 · see citing works
Zhu, X.-H., Yan, H., Zhang, J., Qu, H.-D., Qiu, X., Chen, L., Li, S.-J., Cao, X., Bean, J. C., Chen, L. H., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.6414-09.2010 · Cited by 227 · see citing works
“Exposure to CMS increased the latency to feed (F(3,24) 7.1; p 0.01; post hoc analysis, p 0.001 control vs saline group), an effect that was partially reversed by fluoxetine ( p 0.01 vs saline group), in agreement with previous reports (Bessa et al., 2009).”
InfluentialTanti, A., & Belzung, C. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.08.017 · Cited by 220 · see citing works
Mathews, D. C., Henter, I. D., & Zarate, C. A. (2012) · Drugs · doi:10.2165/11633130-000000000-00000 · Cited by 220 · see citing works
“Such changes would effectively limit the number of exposed glutamate receptors and as a result, drugs thought to reduce glutamatergic neurotransmission may prevent dendritic retraction and protect brain synapses.([46,51]) Interestingly, glutamatergic neurotransmission may further be altered at the genetic level, where…”
BackgroundRole of adult hippocampal neurogenesis in stress resilience
Levone, B. R., Cryan, J. F., & O'Leary, O. F. (2015) · Neurobiology of Stress · doi:10.1016/j.ynstr.2014.11.003 · Cited by 218 · see citing works
“However, it is also important to note that negative findings have also been reported (Surget et al., 2011; Bessa et al., 2009; David et al., 2009).”
BackgroundResultInfluentialThe impact of chronic stress on the rat brain lipidome
Oliveira, T. G., Chan, R., Bravo, F. V., Miranda, A. M., Caridade-Silva, R., Zhou, B., Marques, F., Pinto, V., Cerqueira, J., Paolo, G. D., et al. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.14 · Cited by 219 · see citing works
Self-citationDuman, R. S. (2014) · Depression and Anxiety · doi:10.1002/da.22227 · Cited by 213 · see citing works
Monteiro, S., Roque, S., de Sá-Calçada, D., Sousa, N., Correia-Neves, M., & Cerqueira, J. J. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2015.00006 · Cited by 216 · see citing works
“Although not often used in mice, CUS protocols are widely used in rats and were shown to be highly effective in inducing a stress-related phenotype (6, 11, 12, 36).”
MethodSelf-citationDuman, R. S. (2009) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2009.11.3/rsduman · Cited by 210 · see citing works
Brummelte, S., & Galea, L. A. M. (2010) · Hormones and Behavior · doi:10.1016/j.yhbeh.2010.07.012 · Cited by 211 · see citing works
“This dissociation is consistent with other studies (Bessa et al., 2008), including another animal model of postpartum depression from our laboratory (Green and Galea, 2008) but inconsistent with a number of other studies showing a link between depressive like behavior in the forced swim test and hippocampal cell proli…”
Garza, J. C., Guo, M., Zhang, W., & Lu, X.-Y. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.161 · Cited by 209 · see citing works
Alboni, S., van Dijk, R. M., Poggini, S., Milior, G., Perrotta, M., Drenth, T., Brunello, N., Wolfer, D. P., Limatola, C., Amrein, I., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2015.142 · Cited by 207 · see citing works
Sex hormones and adult hippocampal neurogenesis: Regulation, implications, and potential mechanisms
Mahmoud, R., Wainwright, S. R., & Galea, L. A. M. (2016) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2016.03.002 · Cited by 201 · see citing works
“…reviewed above, that chronic stress decreases hippocampal neurogenesis in animal models of depression (Gould et al., 1997; Santarelli et al., 2003; Bessa et al., 2009), but that antidepressant drugs can both prevent (Czeh et al., 2001; Alonso et al., 2004) and reverse (Malberg and Duman, 2003;…”
BackgroundInfluentialActivating newborn neurons suppresses depression and anxiety-like behaviors
Tunc‐Ozcan, E., Peng, C., Zhu, Y., Dunlop, S. R., Contractor, A., & Kessler, J. A. (2019) · Nature Communications · doi:10.1038/s41467-019-11641-8 · Cited by 201 · see citing works
“Therefore, increased neurogenesis may be necessary for the effects of anti-depressants, although this remains controversial because of the lack of speci fi city of the techniques used to target newborn neurons 17 – 19 .”
Salvadore, G., Nugent, A. C., Lemaître, H., Luckenbaugh, D. A., Tinsley, R., Cannon, D. M., Neumeister, A., Zarate, C. A., & Drevets, W. C. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.11.011 · Cited by 188 · see citing works
“However, most of the patients (79%) enrolled in this study were receiving antidepressant drugs at the time of scanning, potentially limiting the interpretability and generalizability of the results, particularly given previous evidence that these agents upregulate neurotrophin expression (Duman and Monteggia, 2006), c…”
Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine
Deyama, S., & Duman, R. S. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.172837 · Cited by 186 · see citing works
“Chronic fluoxetine or imipramine treatment also reverse the spine deficits in hippocampal and cortical regions caused by CUS exposure (Bessa et al., 2009); chronic fluoxetine treatment has been reported to reverse depression-like behavior and the reduction in dendritic length and spine density in CA1 pyramidal neurons…”
BackgroundWang, Y.-S., Shen, C., & Jiang, J. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104520 · Cited by 183 · see citing works
Adult Neurogenesis and Mental Illness
Schoenfeld, T. J., & Cameron, H. A. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.230 · Cited by 183 · see citing works
“Bessa et al (2009) found increased latency to eat under similar conditions; however, the dose of MAM used to inhibit neurogenesis may decrease motivation to eat independent of its effects on neurogenesis (Dupret et al, 2005; Shors et al, 2001).”
BackgroundMethodHuang, Y., Coupland, N. J., Lebel, R. M., Carter, R., Seres, P., Wilman, A. H., & Malykhin, N. V. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.01.005 · Cited by 179 · see citing works
“This is in agreement with previous animal studies that found that antidepressant treatment can prevent CA and DG spine loss (54–56), CA and DG dendritic retraction (54,57), and astrocyte loss (58).”
ResultEpigenetic mechanisms of major depression: Targeting neuronal plasticity
Uchida, S., Yamagata, H., Seki, T., & Watanabe, Y. (2018) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12621 · Cited by 181 · see citing works
Guardiola‐Lemaitre, B., De Bodinat, C., Delagrange, P., Millan, M. J., Munoz, C., & Mocaër, E. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12720 · Cited by 182 · see citing works
“These findings, which may be related to regulation of microtubule dynamics and/or dendritic remodelling, as also seen with fluoxetine (Bessa et al., 2009), are in agreement with the findings that (sub)chronic administration of different classes of antidepressants (imipramine, desipramine, fluvoxamine) can affect MAP-2…”
ResultHippocampal neuroplasticity in major depressive disorder
Malykhin, N. V., & Coupland, N. J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.04.047 · Cited by 178 · see citing works
Campos, A. C., Fogaça, M. V., Scarante, F. F., Joca, S. R. L., Sales, A. J., Gomes, F. V., Sonego, A. B., Rodrigues, N. S., Galve-Roperh, I., & Guimarães, F. S. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00269 · Cited by 175 · see citing works
“Repeated antidepressant treatment also prevents stress-induced hippocampal dendritic atrophy (Bessa et al., 2009) and facilitates adult hippocampal neurogenesis in rodents (Malberg et al., 2000; Santarelli et al., 2003).”
BackgroundConvergent Mechanisms Underlying Rapid Antidepressant Action
Zanos, P., Thompson, S. M., Duman, R. S., Zarate, C. A., & Gould, T. D. (2018) · CNS Drugs · doi:10.1007/s40263-018-0492-x · Cited by 171 · see citing works
“antidepressant treatment restores dendritic atrophy induced by chronic stress in rodents [235].”
BackgroundLee, T., Jarome, T., Li, S.-J., Kim, J. J., & Helmstetter, F. J. (2009) · NeuroReport · doi:10.1097/wnr.0b013e328332bb09 · Cited by 173 · see citing works
Musazzi, L., Treccani, G., Mallei, A., & Popoli, M. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.11.009 · Cited by 172 · see citing works
Yau, S.-Y., Lau, B. W.-M., Tong, J.-B., Wong, R., Ching, Y.-P., Qiu, G., Tang, S.-W., Lee, T. M. C., & So, K.-F. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024263 · Cited by 169 · see citing works
“It has been reported in a rat model using 2-week exposure to unpredictable chronic stress that antidepressants improved depressive behaviours that is neurogenesis independent, but is associated with dendritic remodeling in the prefrontal cortex and hippocampus”
BackgroundGlutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments
Kadriu, B., Musazzi, L., Henter, I. D., Graves, M., Popoli, M., & Zarate, C. A. (2019) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy094 · Cited by 165 · see citing works
Dellarole, A., Morton, P. D., Brambilla, R., Walters, W. M., Summers, S. H., Bernardes, D., Grilli, M., & Bethea, J. R. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.04.003 · Cited by 164 · see citing works
“, 2011), other authors demonstrated that re-establishment of neuronal plasticity, rather than neurogenesis, is the basis for the restoration of behavioral homeostasis by antidepressants (Bessa et al., 2009).”
Wainwright, S. R., & Galea, L. A. M. (2013) · Neural Plasticity · doi:10.1155/2013/805497 · Cited by 164 · see citing works
Cavalleri, L., Merlo Pich, E., Millan, M. J., Chiamulera, C., Kunath, T., Spano, P. F., & Collo, G. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.241 · Cited by 156 · see citing works
“BDNF-TrkB signaling has been extensively studied as a potential substrate for the influence of antidepressants on functional(65) and structural plasticity.(24,26,66) Increased BDNF synthesis and release in rodent frontocortical/hippocampal circuits were observed after acute exposure to either ketamine(5,14,17) or AMPA…”
BackgroundClinically Significant Drug Interactions with Newer Antidepressants
Spina, E., Trifirò, G., & Caraci, F. (2011) · CNS Drugs · doi:10.2165/11594710-000000000-00000 · Cited by 160 · see citing works
Disconnection and reconnection: The morphological basis of (mal)adaptation to stress
Sousa, N., & Almeida, O. F. X. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.08.006 · Cited by 159 · see citing works
Self-citationPharmacological Blockade of 5-HT7 Receptors as a Putative Fast Acting Antidepressant Strategy
Mnie‐Filali, O., Faure, C., Lambás‐Señas, L., Mansari, M. E., Belblidia, H., Gondard, E., Etiévant, A., Scarna, H., Didier, A., Bérod, A., et al. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.13 · Cited by 158 · see citing works
“As it has been recently proposed (Bessa et al., 2009), neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus, rather than neurogenesis itself, could be responsible for the latter behavioural phenotypes of 5-HT 7 mutant mice.”
BackgroundRemodeling of axo-spinous synapses in the pathophysiology and treatment of depression
Licznerski, P., & Duman, R. S. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2012.09.057 · Cited by 157 · see citing works
“Chronic administration of fluoxetine or the tricylic antidepressant imipramine is reported to rescue dendrite atrophy and spine loss in hippocampal CA3 and medial PFC layer II/III pyramidal neurons caused by chronic stress (Bessa et al., 2009).”
Depression, stress, epilepsy and adult neurogenesis
Danzer, S. C. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.05.023 · Cited by 157 · see citing works
“Instead, enhanced neuronal plasticity may be important (Wang et al., 2008; Bessa et al., 2009).”
BackgroundBranchi, I. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.08.011 · Cited by 156 · see citing works
“This suggests that an intimate relationship between these two phenomena is likely to exist (Pittenger and Duman, 2008; Bessa et al., 2009).”
BackgroundWager‐Smith, K., & Markou, A. (2010) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.09.010 · Cited by 150 · see citing works
“It should be noted, however, that a minority of studies did not find any neurogenesis-dependence to antidepressant effects on behavior (Bessa et al. 2009, Holick et al. 2008), and the dependence appears to vary in behavioral endpoint-specific (David et al. 2009), and antidepressant-specific (Surget…”
BackgroundInfluentialSustained remission from depressive-like behavior depends on hippocampal neurogenesis
Mateus-Pinheiro, A., Pinto, L., Bessa, J. M., Morais, M., Alves, N. D., Monteiro, S., Patrício, P., Almeida, O. F. X., & Sousa, N. (2013) · Translational Psychiatry · doi:10.1038/tp.2012.141 · Cited by 149 · see citing works
“Pilot studies showed that MAM did not adversely influence general health parameters, such as locomotor activity (ambulation in an open field, swimming speed in a water maze) and fur quality.(8,16,17) Here, we found no significant alterations induced by MAM in appetite drive (Supplementary Figure S1), in swimming perfo…”
BackgroundMethodInfluentialSelf-citationGABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response
Gunn, B. G., Cunningham, L., Mitchell, S. G., Swinny, J. D., Lambert, J. J., & Belelli, D. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.06.001 · Cited by 149 · see citing works
“However, it should be noted that the therapeutic actions of certain antidepressant compounds have been reported to occur in a neurogenesis-independent manner (Surget et al., 2008; Bessa et al., 2009).”
Endocrine substrates of cognitive and affective changes during pregnancy and postpartum.
Workman, J. L., Barha, C. K., & Galea, L. A. M. (2011) · Behavioral Neuroscience · doi:10.1037/a0025538 · Cited by 148 · see citing works
Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine
Wohleb, E. S., Gerhard, D. M., Thomas, A., & Duman, R. S. (2016) · Current Neuropharmacology · doi:10.2174/1570159x14666160309114549 · Cited by 151 · see citing works
“Chronic administration of the selective serotonin-reuptake inhibitor (SSRI) fluoxetine is able to increase spine density [48] and block the stress-induced atrophy of dendrites and spines following chronic stressors [49, 50].”
Tau protein is essential for stress-induced brain pathology
Lopes, S., Vaz‐Silva, J., Pinto, V., Dalla, C., Kokras, N., Bedenk, B. T., Mack, N., Czisch, M., Almeida, O. F. X., Sousa, N., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1600953113 · Cited by 147 · see citing works
“Clinical and preclinical studies have shown that prolonged exposure to stressful conditions impairs structural and functional plasticity of the hippocampal formation related to stress-driven cognitive and mood deficits (7, 8, 23).”
BackgroundMethodResultInfluentialSelf-citationLi, W., Ali, T., Zheng, C., Liu, Z., He, K., Shah, F. A., Ren, Q., Rahman, S. U., Li, N., Yu, Z., et al. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02091-5 · Cited by 147 · see citing works
“Furthermore, previous results studying the molecular and cellular mechanisms of fluoxetine show ambiguous results of BDNF level and neurogenesis [78, 79], [80], [81–85], demanding further investigations to delineate the pharmacological basis of fluoxetine.”
ResultChronic mild stress paradigm as a rat model of depression: facts, artifacts, and future perspectives
Strekalova, T. V., Liu, Y., Kiselev, D., Khairuddin, S., Chiu, J. L. Y., Lam, J., Chan, Y., Pavlov, D., Proshin, A. T., Lesch, K., et al. (2022) · Psychopharmacology · doi:10.1007/s00213-021-05982-w · Cited by 146 · see citing works
Neuronal Correlates of Depression
Chaudhury, D., Liu, H., & Han, M.-H. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2044-6 · Cited by 139 · see citing works
Phoumthipphavong, V., Barthas, F., Hassett, S., & Kwan, A. C. (2016) · eneuro · doi:10.1523/eneuro.0133-15.2016 · Cited by 132 · see citing works
“Therefore, our results and studies in the field (Bessa et al., 2009; Li et al., 2010, 2011; Voleti et al., 2013) support a structural basis for antidepressant actions that may generalize beyond specific frontal cortical regions or pharmacological agents.”
BackgroundResultInfluentialDysfunctional hippocampal activity affects emotion and cognition in mood disorders
Femenía, T., Gómez-Galán, M., Lindskog, M., & Magara, S. (2012) · Brain Research · doi:10.1016/j.brainres.2012.03.053 · Cited by 143 · see citing works
Morley‐Fletcher, S., Mairesse, J., Soumier, A., Banasr, M., Fagioli, F., Gabriel, C., Mocaër, E., Daszuta, A., McEwen, B. S., Nicoletti, F., et al. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2280-x · Cited by 141 · see citing works
“…induced by chronic corticosterone treatment, only some “therapeutic effects” of fluoxetine are neurogenesisdependent (David et al. 2009), and there is also evidence that antidepressants retain their “therapeutic” efficacy when neurogenesis is blocked by a cytostatic drug (Bessa et al. 2009).”
McKernan, D. P., Dinan, T. G., & Cryan, J. F. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.04.006 · Cited by 138 · see citing works
“Besides neurogenesis, it has also been shown that antidepressants play a key role in neuronal remodelling (Bessa et al., 2008) and synaptic plasticity (reviewed in Castren, 2004).”
BackgroundBatalha, V. L., Pego, J. M., Fontinha, B. M., Costenla, A. R., Valadas, J. S., Baqi, Y., Radjainia, H., Müller, C. E., Sebastião, A. M., & Lopes, L. V. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.8 · Cited by 136 · see citing works
Ampuero, E., Rubio, F. J., Falcon, R., Sandoval, M., Diaz-Veliz, G., Gonzalez, R. E., Earle, N., Dagnino-Subiabre, A., Aboitiz, F., Orrego, F., et al. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.04.035 · Cited by 132 · see citing works
Dwyer, J. M., & Duman, R. S. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.11.011 · Cited by 134 · see citing works
“Chronic treatment with typical antidepressants can also reverse the neuronal atrophy and decrease in spine density in the hippocampus and PFC produced by chronic stress (57).”
- Authors
- Bessa, J. M., Ferreira, D., Melo, I., Marques, F., Cerqueira, J. J., Palha, J. A., Almeida, O. F. X., & Sousa, N.
- Affiliations
- University of Minho (PT)
- Max Planck Society (DE)
- Corresponding author
- Sousa, N
- Venue
- Molecular Psychiatry
- Published
- 2008-11-04
- Volume
- 14
- Issue
- 8
- Pages
- 764-773
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W1983617759
- Cited by
- 598
- References
- 46
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 11 · 2023: 33 · 2022: 30 · 2021: 38 · 2020: 26 · 2019: 33 · 2018: 31 · 2017: 48 · 2016: 37 · 2015: 44 · 2014: 53 · 2013: 38 · 2012: 48
- FWCI
- 23.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
- Funders
- Pfizer
- Sanofi
- Fundação para a Ciência e a Tecnologia (PTDC/SAU-NEU/72699/2006)
- National Cancer Institute (N02-CB-07008)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- antidepressants, neurogenesis, hippocampus, neuronal remodeling, dendritic remodeling, synaptic plasticity, depression, chronic mild stress, fluoxetine, imipramine, methylazoxymethanol, anhedonia, learned helplessness, prefrontal cortex, neuroplasticity
- MeSH terms
- Affect, Analysis of Variance, Animals, Antidepressive Agents, Behavior, Animal, Depression, Drug Combinations, Fluoxetine, Hippocampus, Imipramine, Indoles, Male, Methylazoxymethanol Acetate, Mitosis, Neuronal Plasticity, Pyrrolidines, Stress, Psychological, Rats, Wistar, Prefrontal Cortex, Receptors, Corticotropin-Releasing Hormone, Rats, Cytostatic Agents, Neurogenesis, Antidiuretic Hormone Receptor Antagonists
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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