A recent animal study found that MCP-1 may act as a modulator of neuronal activity and neuroendocrine functions given that the expression of MCP-1 mRNA and protein is regionalized in the CNS in neuroanatomical sites implicated in the development of MDD^14,20 (e.g., the cerebral cortex, hippocampus, paraventricular and supraoptic hypothalamic nuclei, lateral hypothalamus, substantia nigra, and cerebellum).

Other evidence comes from MCP-1's co-localization with neurotransmitters and neuropeptides in well-defined brain nuclei, the so-called cholinergic, dopaminergic, vasopressinergic, and melaninconcentrating hormone (MCH)-expressing neurons,¹⁴ which are primarily involved in the symptomatology and therapeutic mechanism of MDD.²¹ For example, noradrenaline induces production of MCP-1 in astrocytes and thereby mediates neuroprotective actions.²² Additionally, according to a recent animal study investigating a relationship between MCP-1 and stress, exposure to stress produces a moderate increase in MCP-1 through the inhibitory activity of glucocorticoids during the stress reaction. Likewise, the corticosterone treatment of astrocytes significantly reduces production of MCP-1. When the production of glucocorticoids by stressed rats was blocked by the selective inhibitor metyrapone, a large increase in the concentration of MCP-1 was observed in the cortex. Desipramine, one of the noradrenergic antidepressants, was found to increase MCP-1 in the cortex. These data suggest that MCP-1 may play a critical role in altering noradrenaline or glucocorticoids, which may be implicated in the development and treatment of MDD.²³ Additionally, the presence of MCP-1 in magnocellular vasopressinergic neurons raises the possibility that MCP-1 may contribute to the control of eating and drinking behaviors, which strengthens the plausibility of the notion that it could exert neuroendocrine functions.¹⁴ In a recent study investigating a MCP-1 level in cerebrospinal fluid (CSF),²⁴ 137 psychiatric patients with a history of a suicide attempt and 43 healthy controls was investigated. In the study, a subgroup of patients (n=42) was followed up with blood samples 12 years after the initial CSF sampling, when they did not show suicidal behavior. The follow-up chemokine levels were compared to those of psychiatric patients (n=17) who had never attempted suicide. According to the results, the MCP-1 levels were significantly lower in the suicide attempters than in healthy controls. In addition, patients with depression had the lowest CSF levels of MCP-1, although no correlations were found between the level of MCP-1 and severity of depression which was measured by the Montgomery-Asberg Depression Rating Scale. The findings suggest that the exact role of MCP-1 in the context of pathophysiologies associated with suicidal behavior and depression should be further investigated.²⁴

Moreover, MCP-1 has an important role in the modulation of other cytokines. For example, it stimulates the expression of interleukin (IL)-4 in the TH-2 system,^18,25 which is consistently reported to be altered in patients with MDD.²⁶ It should also be noted that IL-4 is involved in the antidepressant treatment response²⁷ as well as in the regulation of IL-6 and IL-8 (both ILs are altered in MDD).^18,27,28

Genetic susceptibility to MDD may be explained by the presence of specific polymorphisms in chemokine genes, leading to abnormal protein expression or functioning.²⁹ It has also been noted that the MCP-1 gene is located on the chromosome 17q11.2-q12 (1.5 kb in length and containing three exons and two introns).³⁰ Intriguingly, this chromosomal region is adjacent to the encoding area for the serotonin transporter gene (5-HTTLPR),³¹ which is one of well-known candidate genes for MDD that has a promising pharmacogenetic profile in relation to antidepressant efficacy. Two polymorphisms in the promoter region of the gene (A-2518G and A-2076T) have been identified.³² The A-2518G polymorphism affects the transcriptional activity of the distal regulatory region and monocyte MCP-1 production.^32,33,34 Recent data have indicated that MCP-1 gene -2518 polymorphism (allele A) was associated with an increased risk for MDD [odds ratio (OR)=1.83, 95% confidence interval (CI)=1.18-2.83], which suggests that the MCP-1 gene -2518 polymorphism may confer susceptibility to MDD.³⁵ A gene-dose effect was also found when the genotypes AA and AG were individually compared with the genotype GG (p for trend=0.008): 1) AA vs. GG, p=0.02, OR=3.06, 95%CI=1.21-7.83; 2) AG vs. GG, p=0.21, OR=1.56, 95%CI=1.56-3.00.³⁵ In a subsequent preliminary study with small MDD (n=34) and bipolar disorder (BD, n=61) samples and a healthy control group,³³ no significant association between the A-2518G polymorphism of the MCP-1 gene and any type of diagnosis was found. However, when the different diagnostic subtypes (MDD vs. BD) were considered, numerical superiority of the AA genotype and of the A allele of the A-2518G polymorphism of the MCP-1 gene was observed in subjects with BD.³³ Moreover, more suicide attempts in subjects with the AA genotype of the A-2518G polymorphism of the MCP-1 gene were also observed in this study.³³ Additionally, a significant association between BD and suicide attempts has been identified in patients with this disorder, who are also more likely to have the AA genotype of the A-2518G polymorphism of the MCP-1 gene. Furthermore, the MCP-1 gene -2518 polymorphism was also consistently associated with the development of BD and schizophrenia,^33,34,36 although another study failed to replicate the association between the MCP-1 gene polymorphism and bipolar disorder.³⁷

Oxidative stress occurs when the redox balance is breached and pro-oxidative processes overwhelm the antioxidant defense system in the brain. Factors favoring oxidative processes may also have roots in genetic endowment, immune activation, psychosocial stress, or energy failure (e.g., stroke).^38,39,40,41 Nitric oxide (NO) is a ubiquitous neurotransmitter involved in a various brain functions and neuropathologies (e.g., dopamine, norepinephrine, and glutamate release and neuronal cell survival) through modulation of oxidative stress-related sequential cascades in the brain. Inflammation or neuronal excitation leading to increased intracellular Ca²⁺ may enhance production of NO. It has been suggested that optimal modulation of NO is also crucial in the development of MDD.⁴² Along with immune activation, neuronal toxicity may also contribute to oxidative stress. Proinflammatory cytokines have been reported to enhance indoleamine 2,3-dioxegenase (IDO) activity^43,44 under stress, promoting the kynurenine pathway instead of the 5-hydroxytryptamine (5-HT) pathway of tryptophan.⁴⁵ As a result, 5-HT synthesis is reduced, and quinolinic acid, known to be neurotoxic,⁴⁶ is increased. MCP-1 has also been associated with the activation of microglia,⁴⁷ probably initiating the release of NO. According to a recent in vitro study,⁴⁸ noradrenalin induces expression of MCP-1 in astrocytes, which is neuroprotective against excitotoxicity in neuronal cells. In primary neurons, MCP-1 reduced NMDA-dependent glutamate release, glutamate-dependent Ca²⁺ entry, adenosine triphosphate (ATP) loss, and LDH release attributable to NMDA or glutamate. MCP-1 also reduced the toxic consequences of oxygen-glucose deprivation in neurons, as did conditioned media from astrocytes, which could be prevented by a blocking antibody for MCP-1. These findings indicate that the neuroprotective effects of noradrenaline may be partly mediated by the induction and release of astrocyte MCP-1.⁴⁸

Excitatory neurotransmitters may cause neuronal death via multiple synergistic injury mechanisms in the CNS.⁴⁹ Of note, one such mechanism is also initiated by microglia and the microglial chemotaxis that can be signaled by MCP-1, leading to excitotoxic neurodegeneration.⁴⁹ The hippocampus, which is critical for mood and emotional regulation, is particularly vulnerable to the excitotoxic brain injury associated with MCP-1.⁵⁰ The aforementioned findings underscore the importance of MCP-1 in modulating certain processes within the cascade of excitotoxic insults consistently suggested as a possible etiological factor in the development of MDD.⁵¹ Furthermore, MCP-1 is associated with the regulation of glial cells, resulting in alterations of neuroprotective substances and nerve growth factors (NGFs) in the CNS, which suggests that MCP-1 plays a role in regulating neuronal cell function through an indirect mechanism involving the modulation of glial cells.⁵²

Associations between MCP-1 and various CNS diseases that are frequently accompanied by comorbid depressive symptoms, such as multiple sclerosis,¹⁵ stroke,⁵³ and Alzheimer's disease,¹⁶ have also been suggested. Interestingly, plasma MCP-1 levels were found to be significantly in patients with chronic renal failure associated with coronary heart disease, who are especially vulnerable to the development of MDD, compared with controls.^54,55 A limited number of studies have also suggested that patients with MDD without conventional risk factors for coronary heart disease may have higher levels of MCP-1 than do healthy controls.⁵⁵

Intriguingly, a recent study that investigated the role of immune dysfunction in MDD (n=40)⁵⁶ found that patients with MDD showed clear evidence of immune alteration; they had higher levels of IL-6 and IL-10 but lower levels of IL-4 in the context of a hypothalamic-pituitary-adrenal axis (HPA) disturbance characterized by higher cortisol levels. In this regard, evidence indicating that the alteration of MCP-1 levels as a biomarker for the development of MDD remains sparse, suggesting that research investigating the role of MCP-1 as a crucial molecule for MDD is still in its infancy. Nonetheless, a recent human study⁵⁶ found that patients with MDD refractory to antidepressant treatment showed significantly lower levels of MCP-1 levels than did responsive patients at baseline, although MDD patients did not differ from healthy controls in terms of MCP-1 levels. This finding is the first to reflect an association between MCP-1 and the outcome of antidepressant treatment.⁵⁶ These data suggest that the lack of a therapeutic benefit from antidepressants may, in part, be associated with alterations in MCP-1 levels. In support of these findings, reported by Carvalho and colleagues, studies examining antidepressants and noradrenergic activity have also demonstrated that antidepressants may have the potential to down-regulate chemokines such as MCP-1 in MDD, suggesting that MCP-1 may be a candidate for a new pharmacological target.⁵⁷

The Table 1 summarizes the potential role of MCP-1 in the development and treatment of MDD.

The possible role of MCP-1 in the development of MDD deserves further exploration, even though currently available findings do not definitely indicate that MCP-1 is directly implicated in the development of MDD. However, it is likely that MCP-1 modulates neuronal activity and neuroendocrine functions such as MCP-1 mRNA and protein that have been highly selectively found in MDD-related CNS regions such as the cerebral cortex and hippocampus. Moreover MCP-1 is colocalized with cholinergic, dopaminergic, vasopressinergic, and melaninconcentrating hormone (MCH)-expressing neurons, which are critical in the development and treatment of MDD. MCP-1 may also regulate the pivotal step in the communication among crucial cytokines such as IL-4, IL-6, and IL-8, which are involved in the pathogenesis of MDD. Additionally, MCP-1 may be a possible modulating factor intervening in the process of excitotoxicity and neurodegeneration. Finally, new evidence that MCP-1 is implicated in the treatment response to antidepressants is also emerging, although this issue should be extensively and further investigated in future well-designed and adequately powered studies. Hence, we can plausibly speculate that MCP-1 plays a potential role in the etiopathogenesis of MDD. The Figure 1 illustrates a schematic involvement in MDD.