Major depressive disorder (MDD) is a severe clinical form of depression, a more broadly defined mood disorder associated with persistent feelings of sadness and loss of interest.
Major depressive disorder (MDD) places enormous strain on the population and national systems. At least 10 percent of U.S. residents will experience it at least once in their lifetime. Furthermore, MDD results in over $210 billion in healthcare costs and lost productivity.
Because major depressive disorder (MDD) is a complex illness influenced by a complex array of genetic, psychological, and biological factors, distinguishing its subtypes may be crucial for developing effective treatment strategies.
To better define the underlying mechanisms of major depressive disorder (MDD), a new study (which has not yet been peer-reviewed) examined biologically distinct subtypes of MDD based on their contrasting, atypical energy-related symptoms (AERS).
Perhaps the most important thing in this article is the presented immunometabolic model, which eliminates a serious diagnostic problem.
«"Modern diagnostic criteria consider opposite symptom directions as equivalent; weight gain or loss, as well as increased or decreased sleep duration, are all taken into account when making a single diagnosis," the researchers explain.
While this facilitated standardization, it could lead to ineffective one-size-fits-all treatments and delayed progress in treatment.
As the researchers note, «individuals with the same diagnosis of major depressive disorder exhibit different symptom profiles, which may reflect the manifestation of partially different pathophysiological mechanisms.».
To limit the sample size in these cases, they conducted three genome-wide association meta-analyses covering over 460,000 individuals of European descent, comparing three subtypes of major depressive disorder.
These include AERS+, which includes hypersomnia (excessive sleepiness) with weight gain, and AERS-, which includes insomnia with weight loss, as well as an «intermediate» variant – unclassified major depressive disorder, which presents with a combination of symptoms.
The analysis revealed two biophysiological profiles. For example, AERS+ correlated with the highest body mass index (BMI). However, this was not solely dependent on this indicator, as it was also characterized by a higher relapse rate, more severe functional impairment, earlier disease onset, and a higher prevalence of comorbidities or chronic conditions.
In total, the researchers found 27 genome-wide loci, or DNA variations, associated with diseases, including several previously undescribed.
Four of these loci were associated with AERS+ (with an estimated population prevalence of 1.5 percent), including a gene previously linked to BMI and MDD, as well as a non-coding RNA associated with cortical inhibitory neurons—nerve cells that suppress the action of other neurons in the brain.
Ten loci were associated with AERS (estimated prevalence 5 percent), including those associated with more «favorable» metabolic traits, such as «a risk-increasing allele [gene variant] associated with lower waist circumference.».
Furthermore, other genetic variants associated with an increased risk of developing AERS are also associated with a reduced risk of developing type 2 diabetes, as well as a possible link to schizophrenia, suggesting a common mechanism through gene regulation.
Unlike AERS+, this subtype of major depressive disorder appears to be associated with excitatory neurons that activate, rather than suppress, other brain cells.
The researchers also identified 13 loci for unclassified major depressive disorder (estimated prevalence of 8.5 percent), which represents a subtype between the other two. Indeed, they noted that "the unclassified subtype is partially, but not entirely, a genetic mixture of AERS+ and AERS-.".
In a more in-depth study, the researchers found a significant positive genetic correlation between AERS+ and five metabolic markers: BMI, waist circumference, metabolic syndrome, type 2 diabetes, and blood glucose levels. Conversely, these traits were significantly and negatively correlated with AERS-.
The researchers also report a correlation between AERS- and anorexia nervosa, and between AERS+ and ADHD, hypertension, and coronary heart disease.
Additionally, the AERS+ score was negatively correlated with «good» HDL cholesterol and positively correlated with C-reactive protein, a marker of inflammation produced in the liver and associated with major depressive disorder.
AERS+ patients also had a profile indicative of impaired cholesterol transport, insulin resistance, and a proinflammatory state associated with an increased risk of atherosclerosis and other cardiovascular diseases.
Thus, people with AERS+ MDD have biological characteristics strikingly similar to those of someone prone to metabolic syndrome. In people with AERS- MDD, the situation may be almost the opposite.
Overall, this work demonstrates "significant differences in genetic architecture" between subtypes of major depressive disorder.
The study also suggests that immunometabolic factors may alter subtypes of major depressive disorder without directly causing them, possibly through biological mechanisms such as stress response systems that modulate inflammation in the body, or insulin sensitivity.
The results obtained are consistent with homeostasis disturbances that impair energy metabolism management and manifest as problems with appetite, weight, and sleep.
See also: Vagus nerve stimulation improves symptoms in severe depression at 70%, a large US study has shown.
As a result, this work further clarifies why symptoms and comorbidities are inconsistent across broad generalizations of major depressive disorder.
«"It remains unclear whether metabolic dysfunction is part of the causal relationship with AERS+ or whether it primarily modifies its symptomatic presentation, but either interpretation has implications for the study and subsequent treatment of depression," the researchers say.
A preprint of this study is available on medRxiv.
This article was fact-checked by Rebecca Dyer and edited by Michael Irving. While we pride ourselves on our process, we're only human. If you spot an error, please let us know.
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