Austrian psychiatrist JuliusRitter Wagner-Jauregg was awarded a Nobel prize for his discovery of thetherapeutic effects;  that parasite plasmodium vivax had for individualssuffering with dementia (Allerberger, 1997; “TheNobel Prize in Physiology or Medicine 1927,” 2014). This could be theearliest example illustrating the relation immune system and psychiatricdisorders. In a subgroup of individuals who suffer with depression it has beenreported that there are changes in levels of cytokines and other inflammatorymediators (such as natural killer cells and T-cells) (Maes, 1994; Maes et al., 1992; Myint, Leonard, Steinbusch, & Kim,2005; Rothermundt et al., 2001).

Macrophage or cytokine hypotheses of depressionsuggest that depression is a result of “external and internal stressors” due towhich depressive behaviour is triggered in said individuals exposed to thesestressors as a consequence of resulted increase in proinflammatory cytokines(interleukin 1 an d interleukin 6) and cell-mediated immune response (Haapakoski, Ebmeier, Alenius, & Kivimäki, 2016).Harrison et al. (2009) report that whenparticipants were administered typhoid vaccine elevated reporting of depressivesymptoms was observed in relation to control group. This was explained to be causeddue to increased levels of cytokines (interleukin 6). In another study it wasreported that administration of selective serotonin reuptake inhibitor (Citalopram)had resulted in decrease in reported depressive symptoms associated withendotoxin-induced depression (Hannestad,DellaGioia, Ortiz, Pittman, & Bhagwagar, 2011).  Coppen & Bolander-Gouaille (2005) havesuggested that foliate and vitamin B12 deficiencies could potentially have arole by influencing the immune system and its components. They have alsoreported that the levels of Vitamin B12 and folate in red blood cells couldinfluence the efficacy of the drug therapy. Specifically low levels of foliateand vitamin B12 were associated with the diminished efficacy of SSRIs andtricyclic classes of antidepressants.

Cytokines such as interferon-?(IFN- ?) are administered to patients with cancer and hepatitis C.Approximately 36% of cancer patients develop major depressive disorder duringthe course of their treatments (Collier &Chapman, 2001). It has been established that proinflammatory cytokinessuch as IFN-  and INF-b can have a direct influenceon the neurotransmitter serotonin (Morikawa,Sakai, Obara, & Saito, 1998; Ramamoorthy et al., 1995). Morikawa (1998) suggest that a possible mechanism is that these cytokines increasethe up-take of serotonin transporter therefore up-regulating the transcriptionof serotonin. Interferon- ? is also known to have modulatory effects on 5-HT1Aand 5-HT2 receptors in the brain (Abeet al.

, 1999; Kugaya, Kagaya, Uchitomi, Yokota, & Yamawaki, 1996). Evidence suggests that cytokines such as INF- ?,TNF- ?, INF-b andINF-g canalso increase expression of Indoleamine 2,3-Deoxygenase (IDO) (Fujigaki et al., 2001; Guillemin et al., 2001;Pemberton, Kerr, Smythe, & Brew, 1997; Takikawa, Kuroiwa, Yamazaki, &Kido, 1988; Taylor & Feng, 1991). Increased expression of IDO isshown to diminish concentration of tryptophan a precursor to serotonin whichcould cause reduced concentration of serotonin in brain (Bonaccorso et al., 2002). Administration of anti-inflammatory medicationshave shown to have anti-depressant effects in cancer patients. In a study whena group od patients were administered  “reboxetine, augmentation with thecyclooxygenase-2 (COX-2) inhibitor celecoxib” ((pp.

2) DellaGioia & Hannestad, 2010) had shown significant improvementin contrast to the placebo (DellaGioia &Hannestad, 2010). In a different study by Dr. Golam Khandker andcolleagues have reported that anti-cytokine medications have often accompaniedanti-depressant effects in synchrony with meta-analytical results and theseeffects were significant in contrast to administration of a placebo (Kappelmann, Lewis, Dantzer, Jones, & Khandaker,2018). In another study it was suggested thatautoimmune disorders could be a factor of significance if an individual couldpotentially develop depression.

It was reported by authors that presence ofautoimmune disorders lead to an 45% increase in diagnosis of depression (Benros et al., 2013). This could be explainedand consistent with the above presented evidence as autoimmune disorders arelikely to increase the concentrations of proinflammatory cytokines and otherinflammatory media that could result in the depressive symptoms.A dysfunction in serotonergic systems is relatedwith hypercortisolemia and the increase in proinflammatory cytokines both ofwhich have been associated with depression. Glucocorticoids and proinflammatorycytokines increase the transformation of tryptophan to kynurenine (Duman & Li, 2012).

Furthermore, thereducing concentration of serotonin causes an increase of  neurotoxins, for example, the glutamateagonist quinolinic acid and further contributes apoptosis of astrocytes,oligodendroglia and neurons (Duman & Li,2012).


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