The papers by Santarelli et al. and Bessa et al. provide an excellent example of how scientific publications build off each other in order to fuel the growth of the neuroscience field. In this case, Bessa et al. respond to Santarelli et al. and refute their findings but this happens 6 years later, a factor which is important to note as it implies that Bessa et al. had a greater scope of techniques and technology to design their experiments. With their more exhaustive investigation of the relationship between neurogenesis and antidepressant action, I believe that Bessa et al. presented a more convincing argument that efficacy of antidepressant drugs is linked to plasticity and remodeling of neurons, rather than neurogenesis.
Firstly, Santarelli et al. used only one behavioral paradigm to assess antidepressant efficacy- the novelty suppressed feeding (NSF) test, which is meant to model anxiety-like symptoms associated with a depressive state. However, the criteria for clinical depression includes various symptoms that are not necessarily all modeled using this NSF paradigm. Bessa et al. attempt to address this by including three behavioral tests of depression: NSF test, forced swimming test (FST), and sucrose preference test. Using all three tests in conjunction, Bessa et al. are able to present models of anxiety-like behavior as well as learned helplessness and anhedonia, respectively. Of course, these are not the only symptoms of clinical depression in humans, but this is still an improvement from the 2003 paper.
Moreover, the technique used by Santarelli et al. to eradicate neurogenesis (hippocampal x-irradiation) could have other confounding effects, thus contributing to the lack of antidepressant efficacy. The authors explain that the irradiation clearly works, since there was a drastic reduction of BrdU-positive cells in the SGZ, but they admit that they are unsure if the hippocampal irradiation has other effects on the animal. In fact, other studies have shown that irradiation can affect neural function, which would invalidate this experiment. In contrast, Bessa et al. administered MAM subcutaneously to reduce neurogenesis and tests of general health, specifically locomotor activity and fur quality, were conducted to assess for potential confounds. The results of these tests revealed no significant difference between animals treated with MAM and control animals, making this a more reliable technique.
While I believe that the paper by Bessa et al. is stronger and more comprehensive, it is clear that more work needs to be done to assess the means of efficacy of antidepressant drugs.
Firstly, Santarelli et al. used only one behavioral paradigm to assess antidepressant efficacy- the novelty suppressed feeding (NSF) test, which is meant to model anxiety-like symptoms associated with a depressive state. However, the criteria for clinical depression includes various symptoms that are not necessarily all modeled using this NSF paradigm. Bessa et al. attempt to address this by including three behavioral tests of depression: NSF test, forced swimming test (FST), and sucrose preference test. Using all three tests in conjunction, Bessa et al. are able to present models of anxiety-like behavior as well as learned helplessness and anhedonia, respectively. Of course, these are not the only symptoms of clinical depression in humans, but this is still an improvement from the 2003 paper.
Moreover, the technique used by Santarelli et al. to eradicate neurogenesis (hippocampal x-irradiation) could have other confounding effects, thus contributing to the lack of antidepressant efficacy. The authors explain that the irradiation clearly works, since there was a drastic reduction of BrdU-positive cells in the SGZ, but they admit that they are unsure if the hippocampal irradiation has other effects on the animal. In fact, other studies have shown that irradiation can affect neural function, which would invalidate this experiment. In contrast, Bessa et al. administered MAM subcutaneously to reduce neurogenesis and tests of general health, specifically locomotor activity and fur quality, were conducted to assess for potential confounds. The results of these tests revealed no significant difference between animals treated with MAM and control animals, making this a more reliable technique.
While I believe that the paper by Bessa et al. is stronger and more comprehensive, it is clear that more work needs to be done to assess the means of efficacy of antidepressant drugs.
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