The two studies by Santarelli et al. and Bessa et al. are not entirely contradictory, despite differences in methodology and results that initially suggest otherwise.
Santerelli et al., (2003) used 5-HT1A (serotonin) receptor knock-out mice compared to normal controls to assess neurogenesis and display of depression-related behaviors (time it takes to feed in a novel, anxiety-evoking environment in the novelty suppressed feeding (NSF) task) as a result of antidepressant use (SSRI, tricyclic, controlled with an antipsychotic and vehicle). Unsurprisingly, the knockout mice with non-functioning serotonin receptors did not show neurogenesis and did not show improved behaviors when administered the SSRI fluoxetine. They did, however, find that mice treated with tricyclics showed both neurogenesis and reduced depressive behavior. Santarelli and colleagues also used sham-controlled X-irradiation to the hippocampus prior to testing mice for neurogenesis and depressive behavior through the NSF task. Due to their results, Santarelli and colleagues concluded that antidepressants increase neurogenesis by acting upon their respective neurotransmitter receptors (serotonin/fluoxetine, or norepinephrine/imipramine & desipramine). Their findings in regards to a potential role of hippocampal neurogenesis in antidepressant efficacy carry less weight, given that X-irradiation causes inflammation of tissues surrounding the target area and the behavioral paradigm used is not thoroughly representative of the extensive depressive behaviors displayed in humans.
Bessa et al. (2009), on the other hand, take Santarelli and colleagues' investigation to another level. Bessa and colleagues use three behavioral paradigms to test various depressive behaviors (anxiety through NSF task, anhedonia through sucrose preference test, and learned helplessness through forced swim task) in rats and neuronal remodeling in general (neurogenesis, synaptic plasticity, dendrite density, and dendritic spine shape and density), rather than only neurogenesis. Bessa et al. used MAM to inhibit neurogenesis in the hippocampus, instead of using the X-irradiation technique that Santarelli et al. used. Bessa et al. confirmed that chronic mild stress reduces neurogenesis, while antidepressants increase neurogenesis- but the key difference between Bessa and Santarelli is that Bessa does not indicate that this means neurogenesis translates to improvement in depressive symptoms.
In other words, Bessa and colleagues' additional findings show that hippocampal neurogenesis does occur as a result of antidepressant use, but that when this neurogenesis is impaired, behavioral improvement can still occur. Through the same NSF paradigm used by Santarelli and colleagues, Bessa et al. showed that neurogenesis did seem to be essential for antidepressants to alleviate the anxious behavior that the rats display in the NSF task. However, Bessa and colleagues found through the behavioral tasks that Santarelli et al. did not include (sucrose preference and forced swim) that neurogenesis was not necessary, but changes in synaptic plasticity, synaptic connectivity, and ratios of dendritic spine type were necessary for antidepressants to alleviate anhedonia and learned helplessness.
Because of the differences in methodology between Bessa and Satarelli and colleagues and the subsequent disagreement in conclusions, I would argue that the findings only seem so strikingly different because Santarelli and colleagues used only one measure of "depressive behavior" - anxiety - while Bessa and colleagues tested 3 hallmark behaviors in depressed patients. This is so important when trying to translate these findings to humans, because humans can be diagnosed with clinical depression and NOT display all three of these behaviors; all people with depression do not have anxiety, although there is a high rate of comorbidity. Additionally, the "technological advancement" between 2003 and 2009 allowed Bessa and colleagues to use a more targeted method of decreasing neurogenesis in one brain area than the X-irradiation technique that Santarelli and team used, which likely effected the accuracy, validity, and reproducibility of their findings.
Santerelli et al., (2003) used 5-HT1A (serotonin) receptor knock-out mice compared to normal controls to assess neurogenesis and display of depression-related behaviors (time it takes to feed in a novel, anxiety-evoking environment in the novelty suppressed feeding (NSF) task) as a result of antidepressant use (SSRI, tricyclic, controlled with an antipsychotic and vehicle). Unsurprisingly, the knockout mice with non-functioning serotonin receptors did not show neurogenesis and did not show improved behaviors when administered the SSRI fluoxetine. They did, however, find that mice treated with tricyclics showed both neurogenesis and reduced depressive behavior. Santarelli and colleagues also used sham-controlled X-irradiation to the hippocampus prior to testing mice for neurogenesis and depressive behavior through the NSF task. Due to their results, Santarelli and colleagues concluded that antidepressants increase neurogenesis by acting upon their respective neurotransmitter receptors (serotonin/fluoxetine, or norepinephrine/imipramine & desipramine). Their findings in regards to a potential role of hippocampal neurogenesis in antidepressant efficacy carry less weight, given that X-irradiation causes inflammation of tissues surrounding the target area and the behavioral paradigm used is not thoroughly representative of the extensive depressive behaviors displayed in humans.
Bessa et al. (2009), on the other hand, take Santarelli and colleagues' investigation to another level. Bessa and colleagues use three behavioral paradigms to test various depressive behaviors (anxiety through NSF task, anhedonia through sucrose preference test, and learned helplessness through forced swim task) in rats and neuronal remodeling in general (neurogenesis, synaptic plasticity, dendrite density, and dendritic spine shape and density), rather than only neurogenesis. Bessa et al. used MAM to inhibit neurogenesis in the hippocampus, instead of using the X-irradiation technique that Santarelli et al. used. Bessa et al. confirmed that chronic mild stress reduces neurogenesis, while antidepressants increase neurogenesis- but the key difference between Bessa and Santarelli is that Bessa does not indicate that this means neurogenesis translates to improvement in depressive symptoms.
In other words, Bessa and colleagues' additional findings show that hippocampal neurogenesis does occur as a result of antidepressant use, but that when this neurogenesis is impaired, behavioral improvement can still occur. Through the same NSF paradigm used by Santarelli and colleagues, Bessa et al. showed that neurogenesis did seem to be essential for antidepressants to alleviate the anxious behavior that the rats display in the NSF task. However, Bessa and colleagues found through the behavioral tasks that Santarelli et al. did not include (sucrose preference and forced swim) that neurogenesis was not necessary, but changes in synaptic plasticity, synaptic connectivity, and ratios of dendritic spine type were necessary for antidepressants to alleviate anhedonia and learned helplessness.
Because of the differences in methodology between Bessa and Satarelli and colleagues and the subsequent disagreement in conclusions, I would argue that the findings only seem so strikingly different because Santarelli and colleagues used only one measure of "depressive behavior" - anxiety - while Bessa and colleagues tested 3 hallmark behaviors in depressed patients. This is so important when trying to translate these findings to humans, because humans can be diagnosed with clinical depression and NOT display all three of these behaviors; all people with depression do not have anxiety, although there is a high rate of comorbidity. Additionally, the "technological advancement" between 2003 and 2009 allowed Bessa and colleagues to use a more targeted method of decreasing neurogenesis in one brain area than the X-irradiation technique that Santarelli and team used, which likely effected the accuracy, validity, and reproducibility of their findings.
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