Neurobiological Mechanisms in Major Depressive Disorder

The featured paper is ‘Neurobiological mechanisms in major depressive disorder’ by Marije aan het Rot and colleagues and freely available here.

Despite brevity, this is a complex paper to get to grips with. There is no stated methodology although this is typically the case in other review articles I have seen. The authors state that they will review the neurobiological research that will explain the lack of immediacy in the actions of the monoamine antidepressants as well as explaining why they don’t act for all people. Not all of the material in the review was relevant to these aims. For instance there is a brief discussion of ECT which considers the pragmatics of this approach rather than taking forwards the central argument.

In my opinion the central argument here was that there is a system that produces the features of depression and which consists of serotonin, serotonin receptors and related alleles, corticotrophin releasing factor and receptors, the hypothalamic-pituitary-adrenal axis, the hippocampus, amygdala and external stressors.

The authors cite evidence that suggests that serotonin transporter alleles predispose towards depression and that this might mediate increased sensitivity of the Amygdala to external stressors. They further suggest that the short allele of the serotonin transporter gene might play a more prominent role in this regards although cautioning on inconsistent findings in this area. They then go onto examine Brain Derived Neurotrophic Factor (BDNF) and cite evidence suggesting a role in arborisation in the Hippocampus during development and beyond, an influence on serotonergic neurons in the Raphe Nucleus and resulting innervation of multiple cortical areas by these same neurons. The intriguing associations of the Met form of the BDNF gene are discussed and the suggestion that this predisposes towards depression via Hippocampal sensitivity to stress. They then add a third strand to the central model which focuses on corticotrophin releasing factor and how this is released in response to stress. Figure 3 in the paper integrates the release of CRF with the action of the Hippocampus and Amygdala on the Hypothalamus.

The authors then examine a number of other neurotransmitter systems before looking at treatments and future directions. The initial aim of the review can be challenged however. Thus there is evidence that the antidepressants act quickly with various symptoms improving even within the first week and that altering methodology can influence detection of this phenomenon. Furthermore, there is more recent evidence suggesting that response in the short term is associated with remission although such research needs replication. Nevertheless, the authors have drawn together a number of areas in which research in depression is focusing which offers the reader a resource for directing their further studies.

Steps to Treatment = 7 (Model refinement, testing of model, model informing treatment approaches, trialling informed treatment, further replication if successful, meta-analysis, policy)


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The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

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