INTRODUCTION
The interactions between the immune and nervous systems are the major concern of psychoneuroimmunology. Current literature repeatedly highlighted the role of inflammation in depression pathogenesis and relapse 1,2. Regarding, cytokine production pattern is indicated to be dysregulated in MDD patients with inflammatory etiology. Several meta-analyses reported elevated levels of TNF-ɑ, IL6, and IL-1ß in the blood and brain of MDD patients 3,4. IL-17 role in the pathophysiology of depression is also established5. Furthermore, mild stimulation of the immune system with lipopolysaccharides (LPS) could induce the symptoms of depression6,7. Therefore, the contribution of inflammatory signaling pathways to the pathophysiology of the disorder also took into consideration in recent documentations. In this regard, studies reported an imbalanced toll-like receptor (TLR)-mediated inflammatory response in MDD. TLR4 mRNA and protein levels were found to be increased in both the periphery and CNS of MDD patients 4,8. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) inflammatory signaling pathway is also proposed to be pathologically linked to depression 9. Regarding, evidence indicated that JAK2/STAT3 is crucial to neuroimmune system maintenance.
Antidepressants are believed to shift the immune balance toward anti-inflammatory responses. However, provocation of inflammatory responses (e.g. increased TNF-ɑ and IL-6 levels) under treatment with serotonin and norepinephrine reuptake inhibitors (SNRIs) have been reported previously in both human and mouse models 4. Despite the development of various classes of antidepressants, over 30% of patients don’t achieve remission and 60% of remitted patients develop a new depressive episode 2,3. Recent studies suggest that inflammatory status prior to the treatment determines the success of medication in MDD patients at least in the inflammatory form of the disease 1. Moreover, MDD patients with multiple failed antidepressant treatments showed higher plasma levels of TNF and IL-6 10. Despite the existence of relatively large data discussing cytokine protein levels as immune system mediators in response to antidepressants, expression of correlated genes following antidepressant administration has remained disregarded.
During systemic inflammation, pro-inflammatory cytokines can pass through leaky parts of blood-brain barrier and induce neuroinflammation. Penetrating the brain, cytokines modulate the synthesis, release, and reuptake of neurotransmitters relevant to the mood including serotonin, norepinephrine, and dopamine 11. Evidence implied that bupropion decreases IL-1ß, TNF-ɑ, and IFN-γ levels while increases IL-10 levels 12. Given that bupropion is a norepinephrine–dopamine reuptake inhibitor (NDRI) and a serotonin (5-HT) type 3A receptor inhibitor possessing anti-inflammatory properties 13, it is expected to have a double point advantage as an antidepressant. Meanwhile, in an animal study conducted by Helaly et al, bupropion exerted an inflammatory effect at therapeutic doses evidenced by positive NF-κB/ p65 stained microglia and neurocytes, obvious inflammation in hippocampus along with a moderate rise in the mean of serum IL- 6 levels 14. Moreover, the association between bupropion administration and a couple of inflammatory conditions is stated in a considerable number of case reports 15-18. Some investigations have also stated the possibility of bupropion-induced psychotic symptoms19.
Based on the aforementioned observations, we hypothesize that the absence of the desired response to antidepressants, in our case bupropion, in some patients could be due to the not previously-noticed pro-inflammatory properties of the drug. To test the hypothesis, we evaluated the modulation of protein and gene expression of TNF-ɑ, IL-1ß, IL-17, and IL-10 by bupropion. Gene expression of immunomodulatory signaling molecules including TLR2, TLR4, JAK2, and STAT3 was also assessed.