Cytokines and serotonin transporter in patients with major depression

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Abstract

Altered cytokine secretion as a mechanism in the etiology of depression is still obscure. The serotonin transporter (5-HTT) may play an important role in the termination of serotonergic neurotransmission by serotonin (5-HT) uptaking into presynaptic neurons and representing as an initial action site for selective 5-HTT reuptake inhibitors (SSRI). In our study, we evaluated whether cytokines and 5-HTT acted as biological markers for depression. Blood samples were collected from 42 participants. The differences in cytokine and 5-HTT mRNA expressions of leukocytes were assessed between the patients with major depression (n = 20) and the healthy controls (n = 22), along with the measurements prior and after treatment with a SSRI, fluoxetine, for 3 months in the follow-up patient group (n = 8). The results revealed that the mRNA expressions of IL-1β, IL-6, IFNγ, TNFα, and 5-HTT were higher in the depressed patients than those of the healthy controls. The higher level of mRNA expressions of IFNγ and 5-HTT diminished after fluoxetine treatment. Furthermore, we found a positive correlation between 5-HTT and cytokines mRNA expressions in total participants, which suggested that pro-inflammatory cytokines and 5-HTT might play critical roles in the pathogenesis of major depression and that their levels were affected by chronic treatment with 5-HTT inhibitors.

Introduction

Several studies had demonstrated that major depression occurred because of abnormal changes in neurotransmitter function, and alterations in the endocrine and immune functions (Syvalahti, 1994, Connor and Leonard, 1998, Anisman and Merali, 2002, Capuron and Dantzer, 2003, Schiepers et al., 2005). A significant association had been found between major depression and impaired immune responses, such as zymosan-induced neutrophil phagocytosis (O'Neill and Leonard, 1990), mitogen-stimulated lymphocyte proliferation (Kronfol and House, 1989), and natural killer cell activity (Irwin et al., 1992, Jozuka et al., 2003, Trzonkowski et al., 2004). In contrast, enhanced effects such as concentrations of acute phase proteins, plasma pro-inflammatory cytokines (IL-1β, IL-6, IFNγ, and TNFα), soluble cytokine receptors (IL-2 and IL-6 receptors), and mitogen-stimulated cytokine production (IL-1β, IL-6, IFNγ, and TNFα) from peripheral blood mononuclear cells (PBMC) in depressed patients (Sluzewska et al., 1995, Sluzewska et al., 1996, Song et al., 1998, Anisman and Merali, 2002, Hestad et al., 2003, Suarez et al., 2003, Tuglu et al., 2003, O'Brien et al., 2004, Thomas et al., 2005) had also been reported. However, studies on these immune parameters appeared to be controversial (Seidel et al., 1995, Sluzewska et al., 1995, Weizman et al., 1994, Kenis and Maes, 2002, Steptoe et al., 2003, Brambilla et al., 2004, Kubera et al., 2004). The discrepancies among studies possibly depended on the evaluation of various subtypes of depression, differences in severity of the disease, limited sample sizes, and treatment with or without antidepressant medication.

The serotonin transporter (5-HTT) might play a role in the termination of serotonergic neurotransmission by serotonin (5-HT) uptaking into presynaptic neurons, and representing as an initial action site for selective 5-HTT reuptake inhibitors (SSRI) (Stahl, 1998). 5-HTT was thought as a potential substrate for the pathophysiology of suicide, and was highly correlated with depressive symptoms (Purselle and Nemeroff, 2003). For investigations of neuronal serotonin reuptake, 5-HTT across the human platelet membrane had widely been used as a cell model. Some studies had indicated a reduction in platelet 5-HTT (Tuomisto and Tukiainen, 1976, Meltzer et al., 1981, Meltzer and Arora, 1988) and [3H]imipramine binding sites (Paul et al., 1981, Mellerup and Plenge, 1988) in patients with depression, suggesting that 5-HTT or its regulation might be altered in depression as a trait marker. However, Mellerup and Plenge (1988) reported that there were still controversial findings in platelets. Therefore, the radioligand binding assay in platelets might not be suitable for verifying depression.

In addition to the plasma membrane of serotonergic neurons, platelets, and placenta (Ramamoorthy et al., 1993), the presence of 5-HTT in human immune cells (lymphocytes) had been observed (Faraj et al., 1994, Lesch et al., 1996, Marazziti et al., 1998). Lymphocytes were thought to potentially act as a neural probe for studying psychiatric disorders (Gladkevich et al., 2004). Cytokines modulated 5-HTT mRNA expression in vitro has been reported (Morikawa et al., 1998, Mossner et al., 1998, Mossner et al., 2001, Ramamoorthy et al., 1995). However, the relationship between cytokines and 5-HTT in patients with major depression was not clear. Our study aimed to compare, using reverse transcriptase-polymerase chain reaction (RT-PCR), the differences in the mRNA expressions of 5-HTT and cytokines (IL-1β, IL-6, IFNγ, and TNFα) of PBMC instead of measuring serum concentrations in the patients with major depression (n = 20) and the healthy controls (n = 22), as well as the follow-up patient group (n = 8) prior and after treatment in order to determine whether these parameters acted as biological markers of depression.

Section snippets

Participants

Twenty study participants were recruited from the psychiatric outpatient clinic at the local university hospital, and 22 healthy controls were from a nearby community. The 42 study samples (mean age 46.0 ± 10.9 years) consisted of 17 (38.6%) men and 27 (61.4%) women. Thirty-two (72.7%) were married; 23 (52.3%) had more than 12 years of education; and 33 (75.0%) were employed. All study participants' information were blinded to the psychiatrist (C-CC), who interviewed the participants for the

Results

We recruited 20 participants (5 men and 15 women; mean age = 47.0 ± 13.6 years) with major depression as defined by DSM-IV, and 22 healthy controls (12 men and 10 women; mean age = 45.0 ± 8.0 ). No significant differences were found between the patients with depression and the healthy controls in the factors such sex (p = 0.4263), marital status (p = 0.4768), education (p = 0.1068), employment status (p = 0.0932), smoking (p = 0.9999), or exercise (p = 0.2306). The baseline mean HDRS score was 27.6 ± 8.2 for those

Cytokines regulated the immune function against depression

The hypothesis that the immune system might play a pathogenetic role in major depression was supported by the findings on elevated serum levels and in vitro production of cytokines. However, these literatures were not consistent, possibly due to an incomplete control for numerous confounding influences in earlier studies (Haack et al., 1999). In our study, we tried to control possible confounding factors, such as no instances of a common cold, influenza, or any other inflammation over the

Conclusion

Major depression had traditionally been viewed as a disorder resulting from abnormalities in the central nervous system (e.g., monoaminergic neurotransmitter changes), which gave rise to altered behavior and further influenced endocrine and immune dysfunction. It had been suggested, however, that the behavioral deficits, central monoamine abnormalities, and HPA axis activation seen in depressed patients might in fact be secondary to alterations in immune function, at least in some cases of

Acknowledgments

This work was supported by grants NSC88-2314-B-006-193 and NSC89-2314-B-273-008 from the National Science Council, Taiwan.

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