Major Depressive Disorder: Protein Linked to Potential Suicidality

Investigators have shown that changes in toll-like receptor 4 (TLR4) mRNA expression level are significantly associated with major depressive disorder (MDD). The study, which appeared in Neuropsychiatric Disease and Treatment, is a follow-up to an earlier study by the same researchers that first established the connection between TLR4 and MDD.

The most serious consequence of MDD is increased risk of suicide. The etiology and pathophysiology of MDD remains unclear. Earlier studies have suggested that the etiology is heterogeneous, and recent animal and human research has identified a possible role of immune abnormalities in MDD. Among these findings is research indicating that proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were significantly higher in patients with depression than in control subjects.

TLRs are considered one of the pattern recognition proteins of the innate immune response, which serve to mediate the inflammatory response to stress. Alterations in TLRs have been found in psychiatric disorders, such as increased expression in subtypes TLR3, TLR4, TLR5, and TLR7 in patients with MDD and reduced mRNA expression in schizophrenia. TLR4, in particular, has been found to have a regulatory role in the adrenal response to stressful inflammatory stimuli.

In the most recent study, mRNA expression level was measured in 51 patients with MDD (15 males and 36 females) using real-time polymerase chain reaction. A stepwise linear regression forward model was used to evaluate the relationships between Hamilton Depression Rating Scale 17 (HAMD-17) and TLR4 expression.

The results were a bit of a mixed bag. Some sickness behavior-associated symptoms, including suicide, somatic symptoms of anxiety, or performance of work and activities, were not associated with TLR4 expression. However, according to the study, psychological signs of anxiety and loss of weight in HAMD-17 can predict the expression level of TLR4.

The finding that suicidality was not associated with TLR4 levels is in contrast to several post-mortem studies of patients who did commit suicide. The authors suggested that, “…a possible cause for the difference, compared with previous studies, may be that patients who commit suicide differ from those who do not commit suicide. In a previous follow-up study, patients who committed suicide during follow-up had significantly higher Hamilton Depression Rating Scale scores for suicidality.”

Among the limitations of the study are the small sample size and the fact that cytokines were not analyzed. The latter point is important to note, because there is evidence that sickness behaviors, including weight loss and anxiety, are mediated through the effects of proinflammatory cytokines, such as IL-1, TNFα, and IL-6. The association between TLR4 and weight loss or anxiety may be mediated by cytokines. The study authors hope that further investigation in carefully controlled studies will shed additional light on the mechanism of TLR4-associated sickness behavior in patients with MDD.