What's the science?
Major depressive disorder (MDD) has previously been associated with various markers of inflammation in the body. For example, some studies have shown that cytokines (proteins secreted by the immune system that can be either pro- or anti-inflammatory) are elevated in the blood and cerebral spinal fluid of individuals with the disorder. Elevated levels of anti-inflammatory cytokines in MDD have also been found; the body may increase production of these cytokines to reduce inflammation. However, a reliable biomarker for MDD or associated inflammation has not been established. This may be due in part to the fact that most studies have focused on MDD patients who were not treatment naïve, therefore, a clear link between MDD, inflammation, and treatment could not be established. This week in Neuron, Syed and colleagues studied inflammation in individuals with MDD who were treatment-naïve.
How did they do it?
171 treatment-naïve patients diagnosed with MDD and 64 healthy individuals (as part of the PReDICT cohort) were included in the study. The patients and healthy controls were not matched on certain demographic criteria (age, sex, body max index and ethnicity), so some analyses included only a subset of matched patients and controls (62 patients and 62 healthy control participants referred to as ‘matched sub-groups’). However, results from the 62 patients were not statistically different from the results from the entire group of 171 patients in most analyses, so the larger group of patients was used (‘total sample’). 29 cytokines, chemokines, or growth factor measures (all inflammatory/immune markers) were collected from blood samples. Patients were randomized to receive 12 weeks of duloxetine or escitalopram treatment (antidepressants) or 16 sessions of cognitive behavioural therapy treatment. The authors examined the effects of time (pre- or post-treatment), group, and treatment response on inflammatory markers.
What did they find?
When the authors compared cytokine levels between healthy controls and the total sample of patients, they found that 6/7 pro-inflammatory cytokine levels and 5/7 anti-inflammatory cytokine levels were elevated in patients with MDD compared to healthy controls (2/7 were diminished). The results indicate abnormal inflammatory regulation in treatment-naïve patients with MDD. Some chemokine and growth factor levels were also elevated, however, some were not elevated when the smaller matched subgroups were compared, indicating the differences in these levels may be due to demographic factors. Inflammasomes (multiprotein complexes that can trigger inflammatory cascades/cytokines upstream) were also elevated in patients with MDD, further suggesting that inflammatory responses are altered in patients with MDD. The authors also applied plasma to peripheral blood mononuclear cells from healthy individuals and found that CD69+CD19+ cells, were reduced, suggesting a reduction in activated B cells (immune cells). The authors next tested whether cytokine levels changed in treatment responders versus non-responders (pooled across treatments). Several pro-inflammatory cytokine levels were reduced following treatment in responders (versus non-responders, in which levels tended to rise). Anti-inflammatory cytokine levels tended to rise over time regardless of treatment response. Memory T cells (immune cells) were also lower in responders versus non-responders, suggesting lower immune memory in responders.
What's the impact?
This is the first comprehensive study of inflammatory markers in treatment-naïve patients with MDD. The results suggest inflammatory dysregulation is common in MDD, and differs by response to treatment. The results have important implication for understanding the effect of MDD on inflammation and the role of treatment in altering the immune response in MDD.
Syed et al., Defective Inflammatory Pathways in Never-Treated Depressed Patients Are Associated with Poor Treatment Response. Neuron (2018). Access the original scientific publication here.