A recent paper, published in Translational Psychiatry, uses monocyte gene expression to gain insight into childhood trauma, suicide risk and inflammatory phenotypes of depression.
Major depressive disorder
Major depressive disorder (MDD) is a highly prevalent disorder. Patients often present in clinic with heterogeneous phenotypes. Researchers have put a lot of effort into exploring the clinical risk factors and biological targets of MDD to identify subgroups that would enable tailored treatment.
Over the past few decades, evidence has demonstrated the potential role of low-grade inflammation in the pathogenesis of MDD. Whilst anti-inflammatory therapy has shown some response, reports are rising of cases of non-responsiveness to this type of therapy. This creates a more complex idea of inflammatory activation in MDD. Researchers found that high levels of inflammatory markers associated with treatment resistance.
Circulating blood monocytes are among the principal cells of the innate immune system and take on a key role in phagocytosis, antigen presentation and cytokine production. Previous work has established abnormal expression patterns of inflammatory-related genes in monocytes of patients with several depressive disorders such as bipolar, unipolar depression and postpartum psychosis.
Clinical characteristics and gene expression
The aim of this study was to assess whether clinical characteristics, such as age, sex, BMI, depression severity, suicide risk and childhood adversity, were linked to changes in gene expression in patients with MDD.
The researchers assessed a previously established inflammation-related gene signature, consisting of 32 genes, in 197 patients with MDD and 151 controls collected during the EU-MOODINFLAME project. This project investigated possible inflammatory biomarkers to advance early diagnosis, treatment and prevention of mood disorders.
The team also performed a hierarchical clustering of the expression of the genes to identify clusters of genes correlating in expression intensity. From this, they identified three distinct gene clusters– downregulated, mixed upregulated and strongly unregulated genes. They investigated whether MDD patients with or without the described clinical characteristics significantly differed in the clusterwise expression of genes.
Not uniformly ‘inflamed’
Using hierarchical clustering of genes, they found a cluster of mainly cytokine producing-related genes. Patients with suicide risk had a significantly higher expression of this gene cluster compared to patients without. Interestingly, researchers observed no inflammatory changes for healthy controls exposed to childhood adversity. This suggests an inflammatory involvement in MDD-prone individuals exposed to early stressors.
The researchers found that about 75% of patients showed overall upregulation, whereas around 25% showed general downregulation of monocyte inflammation-related gene-expression patterns. Only childhood adversity and suicidal risk were different between the up- and downregulated groups. Researchers found that raised inflammatory gene expression in MDD patients associated with childhood adversity and high suicide risk. This differs to the overall reduction in gene expression in MDD patients without childhood diversity and suicide risk. This suggests that inflammatory activation in MDD is not uniform and that there are distinguishable immunological phenotypes of depression. While most patients showed signs of inflammatory activation, others showed downregulation in gene expression of monocytes.
Additional work involving larger groups and other markers is required to gain further insight. Nevertheless, these results indicate the importance of stratification of patient groups. Stratification can be determined by a combination of clinical and immunological characteristics. This will allow for a more personalised treatment approach.