Objective(s): Folic acid, a micronutrient supporting the natural defense system, may elevate antidepressant responses, although the lymphocyte serotonergic system has not been explored in folate-supplemented depressed patients. Methods: Twenty-seven patients were randomly assigned to groups receiving fluoxetine (20 mg) and folic acid (10 mg/day) or fluoxetine and placebo for 6 weeks. Clinical outcome was assessed according to the Hamilton Depression Rating Scale (HDRS) at the beginning, during and at the end of treatment. Blood samples were taken, plasma was separated, and lymphocytes were obtained by density gradient centrifugation with Ficoll/Hypaque and differential adhesion to plastic dishes. Fifteen healthy subjects served as controls. Plasma folate, homocysteine and vitamin B₁₂, and serotonin concentration in lymphocytes were determined by HPLC. The HDRS score was significantly lower in patients receiving fluoxetine and folic acid compared with those receiving fluoxetine and placebo after 6 weeks of treatment (7.43 ± 1.65 vs. 11.43 ± 1.31, respectively; p = 0.04). Plasma homocysteine statistically significant decreased after folic acid (p = 0.02), but no significant changes were observed in vitamin B₁₂. Results: Serotonin was significantly reduced after fluoxetine either with folate (p = 0.03) or placebo (p = 0.01) probably by the effect of transporter blockade. 5-Hydroxyindoleacetic acid was lower in lymphocytes of patients receiving folate (p = 0.04), indicating a reduced turnover rate, thus accumulating serotonin in the cells. A significant negative correlation was noted between homocysteine and folate. No significant correlations were present among biochemical parameters and depression severity. Conclusion: Modifications due to treatment with fluoxetine and folic acid may alter lymphocyte function in depression probably indirectly by reducing homocysteine levels and directly on lymphocytes by modifying the serotonergic system.

Serotonin transporter, measured by the specific binding of [³H]paroxetine, has been reported to be reduced in circulating lymphocytes of patients with major depression. Due to this observation, the objective of the present report was to determine the levels of serotonin transporter mRNA in lymphocytes obtained from 29 major depression patients (4 men, age 33.10 ± 1.63 years) and from 30 subjects included as a control group (4 men, age 37.54 ± 2.18 years) using RT-PCR. The patients were diagnosed according to the criteria of the American Psychiatric Association, and had a severity of depression of 32.68 ± 1.55 determined by the Hamilton Rating Scale for Depression. The DNA was submitted to polymerase chain reaction with primers for the 5′ regulatory region of human serotonin transporter, which could show the long and the short allelic forms of the transporter gene for the 5HTTLPR polymorphism. Semiquantitative analysis was performed using β-actin as internal and external standard. Control subjects presented the two allelic forms in 9.09% and depressed patients in 8.69%. The long variant was present in 73% of controls and in 60% of patients, without significant differences. There was a significant reduction in mRNA in depressed patients expressing the long allele. The number of immunofluorescent lymphocytes, labeled with a specific antibody against serotonin transporter, was reduced in the patients, as well as CD3+ lymphocytes. Serotonin and 5-hydroxyindoleacetic acid in platelet-poor plasma or lymphocytes did not differ between depressed patients and controls. The reduction in lymphocyte serotonin transporter described in major depression might be due to a decrease in the level of its mRNA and in the number of cells expressing it. These observations might implicate that functional modifications are associated with nervous-immune interactions in depression.

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Serotonin receptors are present in lymphocytes and might be related to the functionality of these cells in health and in pathology. The serotonergic system is affected in the brain and in peripheral immune cells of depressed patients. The objectives of this work were to evaluate the basal proliferation of lymphocytes, the response to the mitogen concanavalin A, and the role of serotonin 5-HT_1A receptors. Twenty-nine patients, 19–52 years old, were diagnosed for a major depression episode with the Statistical and Diagnostic Manual-IV of the American Psychiatric Association, approved by ethic committees and gave written consent. The Hamilton depression score was 30.60 ± 2.65. An apparently healthy group without a family history of psychiatric illness was included. Blood peripheral lymphocytes were isolated by density gradients with Ficoll/Hypaque and differential adhesion to plastic, cultured in 96-well plaques with RPMI-1640 medium with or without 4 µg/ml of concanavalin A. 8-Hydroxy-2-(di-n-propylamino)tetralin (5–40 nM) and WAY-100,478 (0.1–100 µM), agonist and antagonist of 5-HT_1A receptors, serotonin (12.5–100 nM) or imipramine (0.1–100 µM) were also added. Proliferation was evaluated at 72 h with 3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide, and the optical density was 570 nm. Basal proliferation was three times higher in depressed patients than in controls, whereas no response to mitogen was obtained, and 5-HT_1A receptors significantly reacted to the agonist, with increases of about 31–54% at 10, 20 and 40 nM of the specific agonist, indicating initial activation probably in relation to autoimmunity and overreactivity of these receptors in depression. The antagonist reduced proliferation in mitogen-stimulated lymphocytes, 50% in controls and 70% in depressed patients, with a differential concentration dependency; probably, these receptors are more sensitive in depression due to increased 5-HT_1A receptor transduction. The antagonist also reduced the stimulation produced by the 5-HT_1A agonist. Imipramine caused biphasic effects according to concentrations, showing a possible dual role for serotonin, although all values were significantly higher in depressed subjects. The described alterations might be of relevance in the pathophysiology of depression.

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