In today's society, more and more people are being diagnosed with psychiatric illnesses such as major depressive disorder (MDD) or suicidal behavior, and all sorts of reasons cause them. While the exact cause of MDD is not fully understood, it is believed to result from a combination of both biological and environmental factors. In order to be diagnosed with MDD, patients must be experiencing typical "depressive" symptoms for at least two weeks and most of the day, every day. These symptoms include anhedonia, change in appetite/weight, persistent sadness, loss of energy, psychomotor agitation, and thoughts of death or suicide. While a patient does not need to have all these symptoms, it is clear that if they are consistently present with them, they need to seek medical attention immediately. It was mentioned earlier how the causes behind MDD were not fully understood; however, what could be the root causes of this disorder? To answer this question, two articles will be examined. The first is by Brain Powers et al., who, in the article "Sex differences in the transcription of glutamate transporters in major depression and suicide," focused on how glutamate contributed to both MDD and suicide. The second article, titled "Depression Pathogenesis and Treatment: What Can We Learn from Blood mRNA Expression?" by Nilay Hepgul et al., discusses possible pathogenetic treatments for depressive symptoms through the eyes of blood mRNA expression.
Starting with "Sex differences in the transcription of glutamate transporters in major depression and suicide," Brain Powers et al. explored how disorders such as MDD and suicide are influenced by both sex and neurotransmitters. Previous research has shown higher mRNA expression of glutamate receptors in the dorsolateral prefrontal cortex of females diagnosed with MDD. This study aimed to measure the mRNA expression that encodes glutamate transports in the DLPFC of 111 subjects. Fifty-one of these subjects were previously deceased due to suicide (MDD-S), 28 MDD-diagnosed subjects were still alive, and 32 control individuals had no history of neurological illness. The study aimed to determine if levels of mRNA expression encoding the gene for glutamate transporters had significant differences across the three groups. The researchers use the RNA "extracted from gray matter, and complementary DNA was prepared." (Powers 3) They then used a multinarrative analysis of covariance to compare the levels of glutamate transporter gene expression across the three groups. They also performed a univariate analysis of covariance or a post-hoc analysis of individual genes. This was to dive deeper into different groups' expression levels of specific glutamate transporter genes, such as EAAT1, EAAT2, VGLUT1, and VGLUT2. The results demonstrated that females, contrary to males, had higher gene expression of both EAATs and VGLUTs than the control group. Specifically, VGLUT1 (F(1,48) = 4.90, p = 0.03) and VGLUT2 (F(1,48) = 6.85, p = 0.01) had significantly increased gene expression of female subjects diagnosed with MDD compared to control. On the contrary, male VGLUT (F(4,49) = 1.05, p = 0.389) had no significant difference in gene expression compared to control, despite being diagnosed with MDD (4). This indicates sex-dependent differences in glutamate transporter expression in the dorsolateral prefrontal cortex in MDD patients. This could be the reason behind elevated synaptic levels of glutamate, specifically in females. Female MDD subjects also displayed increased expression of EAATs, which could be a response generated to regulate glutamate levels. These findings are consistent in both MDD-S and MDD-NS patients, implying that glutamate transporters' expression is variant on the sex of humans. Now that it has been established that glutamate transporters such as VGLUTs and EAATs are sex-influenced, what techniques can be used to treat depressive disorders such as MDD?
In the article "Depression pathogenies and treatment: what can we learn from blood mRNA expression?" researchers Nilay Hepgul et al. summarize data showing how patients diagnosed with MDD exhibit "altered pattern of expression in several genes." (Hepgul 1) Mainly, they are looking at patterns of 'state-related' gene expression changes in those who undergo remission or are on antidepressant treatment. This article utilizes studies from various previous research, each with different approaches. For example, Tsao et al. in 2006, found that expression of "IL-1B, IL-6, TNF-a and IFN-y genes was significantly higher of patients with MDD compared to healthy controls." (Hepgul 2) They also demonstrated that specific genes, such as INF-gamma expression, were reduced after certain treatments (fluoxetine), which suggested that antidepressants may also have anti-inflammatory properties. A more recent and prevalent case study was by Cattaneo et al. in 2010, where they conducted two experiments focusing on the expression of specific genes in patients diagnosed with MDD. Their main focus was on genes BDNF and VGF. BDNF, a brain-derived neurotrophic factor, is a neurotrophin associated with neuronal maintenance, survival, plasticity, and neurotransmitter regulation. Cattaneo et al. found that patients diagnosed with MDD had a lower expression of BDNF. This suggests that when patients exhibit MDD, neurons regulated by BDNF become unregulated, causing possible neuronal degeneration or damage. This could explain why patients with MDD have symptoms such as psychomotor agitation. The neurons utilized for those functions are no longer regulated and maintained, and after prolonged deficiency in maintenance, they do not fire as fast or as regularly, leading to those MDD symptoms. The article "Depression pathogenies and treatment: what can we learn from blood mRNA expression?" provides adequate studies centered around mRNA in blood. These findings highlight that the use of peripheral blood gene expression is essential for not only diagnosing patients potentially with depressive disorders but also for clinical approaches. Antidepressants that help regulate those gene expressions can now be synthesized and mass-produced to help patients with specific deficiencies in MDD. Not all patients have the same symptoms, which means that not all have the exact causes. Specifying which gene expression is affected based on the mRNA blood levels gives scientists and researchers avenues to explore to provide more practical and efficient care for those in need.
The main focus of both articles is on the diagnosis of MDD. "Sex differences in the transcription of glutamate transporters in major depression and suicide" explored if glutamate transporter levels are altered when a patient has been diagnosed with MDD, while "Depression pathogenies and treatment: what can we learn from blood mRNA expression?" looks to explore how mRNA levels in the peripheral blood of patients are altered for specific genes relating the MDD. Both articles provide insight into how MDD can be caused and how it can be treated. However, Power's article focuses more specifically on one aspect of MDD diagnosis, whereas Hepgul's article summarizes a variety of biological reasoning behind MDD and any potential treatment for each biological causation of MDD. Powers' article is also focused on the sex dependency for glutamate transporter expression and its correlation with MDD, whereas Hepguls is not focused on sex. Overall, both articles provide great perspectives on the many plausible causes behind MDD and that certain factors, such as peripheral mRNA blood levels and glutamate transporter gene expression, are crucial for diagnostics and clinical treatment approaches.
Works Cited
Hepgul, Nilay, et al. “Depression pathogenesis and treatment: What can we learn from blood mrna expression?” BMC Medicine, vol. 11, no. 1, 2013, https://doi.org/10.1186/1741-7015-11-28.
Powers, Brian, et al. “Sex differences in the transcription of glutamate transporters in major depression and suicide.” Journal of Affective Disorders, vol. 277, 2020, pp. 244–252, https://doi.org/10.1016/j.jad.2020.07.055.
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