Plasma levels of TNF-α were significantly decreased in suicidal adolescents with MDD compared to the nonsuicidal MDD group. IFN-γ was significantly elevated in the suicidal and nonsuicidal groups compared to controls. Findings remained evident when controlled for age and gender.
Our finding of decreased TNF-α in suicidal adolescents compared to controls was unexpected. TNF-α is produced by macrophages and circulating monocytes and plays an important role in a wide range of immune reactions, including autoimmune conditions (Vassalli 1992
). TNF-α has been shown to affect central processes through stimulation of vagal afferents and acts as a central nervous system modulator (Rothwell and Hopkins 1995
). Most studies in adult MDD have reported increased TNF-α compared to controls (Tuglu et al. 2003
; Leo et al. 2006
; Pavon et al. 2006
; Kim et al. 2007
). By contrast, many studies have reported decreased TNF-α in adults with obsessive compulsive disorder (OCD) (Brambilla et al. 1997
; Monteleone et al. 1998
; Denys et al. 2004
). The interpretation of the similarity between our finding of decreased TNF-α in suicidal adolescents with MDD and parallel findings in adult OCD will require further study.
With respect to the effect on monoamines, systemic administration of TNF-α was shown to result in increased serotonin (5-HT) levels in the prefrontal cortex (PFC) and decreased 5-HT levels in the paraventricular nucleus (Brebner et al. 2000
). Relatedly, multiple postmortem studies have implicated the PFC serotonergic system in suicide in adolescents and adults (Mann et al. 1989
; Pandey et al. 2002
), providing a possible pathway linking decreased TNF-α to suicidality. It is important to note that, to date, cytokine studies have not included assessment of TNF-α, excluding examination of its influence on brain function in suicidal adults (Mendlovic et al. 1999
; Kim et al. 2008
). Also contributing to the interpretation of the TNF-α finding is the observation that TNF-α knockout mice exhibit increased emotional responses when exposed to stressful conditions (which respond to benzodiazepine treatment), and increased grooming activity compared to wild-type mice (Yamada et al. 2000
Our second finding of increased plasma IFN-γ in suicidal adolescents with MDD compared to controls is consistent with one prior study of cytokines in suicidal adult patients compared to controls (Mendlovic et al. 1999
). However, because we found IFN-γ to be elevated in nonsuicidal MDD patients as well, consistent with many adult MDD studies (Maes et al. 1994
; Seidel et al. 1995
; Myint et al. 2005
; Tsao et al. 2006
; Simon et al. 2008
), it seems that elevated plasma IFN-γ may be related to major depression rather than to active suicidality. One possible link between IFN-γ, MDD, and suicide is the enzyme indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the tryptophan-kynurenine pathway that converts tryptophan (TRP) to kynurenine (KYN), and is mainly induced by IFN-γ (Carlin et al. 1989
; Takikawa et al. 1991; Taylor and Feng 1991
; Daubener and MacKenzie 1999
; Currier et al. 2000
; Fujigaki et al. 2001
). In cases of overstimulation, induction of this pathway may lead to lower TRP concentrations (serotonin substrate), which have been implicated in MDD (Maes et al. 1993
; Wirleitner et al. 2003
). Of relevance to suicide, low peripheral levels of tryptophan were found in children who had made a recent suicide attempt (Pfeffer et al. 1998
). KYN itself can be further metabolized to N
-aspartate (NMDA) receptor agonist and antagonist (Stone and Darlington 2002
), and alterations in NMDA receptors have also been noted in the PFC of suicide victims (Nowak et al. 1995
). However, while IDO is mainly activated by IFN-γ, TNF-α can also synergistically increase IDO transcriptional activation in response to IFN-γ (Robinson et al. 2005
), suggesting that IDO activation may be linked to the depressive state rather than to the suicidal state of the patient sample.
Our findings of immune system dysregulation in suicidal adolescents with MDD should be considered preliminary in light of several limiting factors: (1) the cohort size was relatively modest; (2) a substantial proportion of patients (57%) were receiving psychotropic medications, which have been reported to induce negative immunoregulatory effects in adults with MDD. This possible confound may have limited our ability to discern other group differences between cytokines and contributed to a Type II error (false negative). Importantly, there were no statistical differences between medicated and nonmedicated patients with MDD. Furthermore, due to the small sample, we did not apply a multiple comparison correction in order to preserve statistical power. As such, our significant findings may include Type I errors (false positive). Additionally, it would be important to collect data on a larger number of cytokines and to measure cytokine activity across multiple time points.
In summary, our results support the notion that suicidal behavior in the context of adolescent MDD entails immune system dysregulation. Specifically, the role of decreased TNF-α is suggested. These findings require replication in a larger sample of medication-free adolescents.