Santarelli vs Bessa: A Comparison of Methodology

While reading the papers from Santarelli et al and Bessa et al, I found several intriguing differences in the approach they took to their experiments. The paper from Santarelli et al that was published previous to the Bessa paper, takes a “top-down” approach to answering the question of whether or not neurogenesis is required for the behavioral effects of anti-depressants. They manipulated the 5HT1a receptor and then measured its effects on BrdU staining, latency to feed in novelty suppressed feeding (NSF), and the efficacy of antidepressant treatments. In this way, they picked a molecular mechanism, which they predicted may simulate a depressive phenotype. On the other hand, Bessa et al induced a depressive phenotype by exposing their animals to a chronic mild stress paradigm and tested its effects on many factors such as anhedonia, learned helplessness, NSF, neurogenesis, and dendritic morphology. In some ways, I think that the Bessa paper’s approach is probably a more accurate model of human depression. We don’t fully understand the complex mechanisms of depression in humans, so to assume that a 5HT1a knockout mouse will achieve the same experimental conditions seems like a huge generalization. I also assume that humans with depression don’t have a full knockout of their 5HT1a receptors, since that would have most likely have implications beyond mood regulation.

Another difference between the two papers that caught my eye was the differing approaches in blocking neurogenesis. The Santarelli paper used x-ray radiation which is “likely to induce inflammation and requires a period of recovery before antidepressants can be administered,” according to Bessa et al. They did in fact begin antidepressant treatment concurrently with the x-ray radiation which may have created a confounding variable of the effects of inflammation on the efficacy of antidepressant drugs. The Bessa paper, however, chose to use a drug-based approach by administering methylazoxymethanol (MAM), a cytostatic agent that arrests cell division. In this way, they avoided the issue of the effects of inflammation in the brain, however, their approach was not localized to the SGZ. They did attempt to control the damage done on other areas of the body by keeping the dosage low, but it is difficult to tell if there are subtle effects from this deficit in mitosis. The Santarelli approach did offer some specificity by using lead plates to somewhat limit the area of exposure to the radiation. Because of the limitations of science and technology, scientists sometimes have to "pick their battles" when choosing the methods with which they manipulate their experiments. In these cases, we must ask ourselves if the data in these papers is really comparable because of the severe difference in their methodology.