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The Plasma Levels of Interleukin-12 in Schizophrenia, Major Molecular Psychiatry (2002) 7, 1107–1114 2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs Y-K Kim1, I-B Suh2, H Kim1, C-S Han1, C-S Lim2, S-H Choi3 and J Licinio4 1Department of Psychiatry, Korea University Ansan Hospital, College of Medicine, Korea; 2Clinical Pathology, Korea University Ansan Hospital, Korea; 3Yong-In Mental Hospital, Kusungmyun, YongIn-Kun, Kyunggi-Do, Korea; 4UCLA Neuropsychiatric Institute and Brain Research Institute, CA, USA Interleukin-12 (IL-12) plays a key role in promoting T helper 1 (Th1) responses and subsequent cell-mediated immunity. Given the role of cytokines in the pathogenesis of psychiatric dis- orders, the dysregulation of IL-12 in these illnesses would be expected. We measured the plasma levels of IL-12 in 102 psychiatric patients (43 schizophrenia, 34 major depression and 25 bipolar disorder) and 85 normal controls. In addition, IL-12 levels of the patients were meas- ured after an 8-week treatment to assess whether the levels were affected by medication. The IL-12 levels of the patient group with major depression were significantly higher than that of the control group, whereas no differences were found among the other groups. IL-12 values of the three patient groups decreased significantly after 8 weeks of treatment. These findings support the hypothesis that activation of the inflammatory response system and in particular of Th-1-like cells, is involved in the pathophysiology of major depression and that repeated administration of antidepressive and antipsychotic drugs may suppress IL-12 plasma concen- trations in psychiatric patients. Molecular Psychiatry (2002) 7, 1107–1114. doi:10.1038/sj.mp.4001084 Keywords: interleukin-12; schizophrenia; major depression; mania; inflammatory response system; cytokine Introduction immune activation in schizophrenia has been based on the findings of increased monocyte numbers, increased Over the past 10 years, it has been hypothesized that activity of macrophage, increased proinflammatory schizophrenia and major depression may be cytokine levels such as IL-1, IL-6, IL-18 and tumor accompanied by an activation of inflammatory necrosis factor(TNF)-␣.7–11 Schizophrenia is also response system, which could be related to the patho- characterized by a decrease in IL-2 production12–14 and physiology or etiology of those illnesses. The macro- interferon(IFN)-␥,7,15 traditionally classified as Th1 phage-T lymphocyte theory of schizophrenia1,2 has cytokines, and an increase in IL-416 and IL-10,17,18 tra- proposed that chronically activated macrophages and ditionally classified as Th2 cytokines. On the other T lymphocytes, along with excessive interleukin-2 and hand, there have been reports of an increased Th1 sys- other cytokine secretions are a cause of some cases of tem in schizophrenia, specifically an increased IL-2 schizophrenia. Similarly, the monocyte-T-lymphocyte level in plasma19 and in cerebrospinal fluid20,21 and hypothesis of major depression3 also suggested that increased production of IL-2 and IFN-␥.22 Interestingly, activation of peripheral blood monocytes and T lym- in our previous study,13 we found that decreased IL-2 phocytes play a role in the pathophysiology or patho- production may be associated with an increased IL-2 genesis of that illness.4,5 serum level in schizophrenic patients, supporting the Schizophrenia is characterized by increased nonspe- T cell exhaustion theory that lower IL-2 production cific innate immunity, decreased type 1 T helper cell may be induced by a consequence of overproduction (Th1)-specific cellular immunity, and a Th1–Th2 of in vivo IL-2. imbalance with a shift to the Th2 system.6 The innate It has been postulated that major depression may be accompanied by significant changes in cell-mediated and humoral immunity, and these changes may be Correspondence: Y-K Kim, Department of Psychiatry, Korea Uni- related to the pathophysiology or pathogenesis of that versity Ansan Hospital, College of Medicine, 516 Go-Jan Dong, illness.23–26 Pro-inflammatory cytokines including IL- Ansan city, Kyunggi Province, 425–070, Korea. E-mail: yong- ␤ 4 9 ␣27 kuȰkorea.ac.kr 1 , IL-6, and TNF- in blood are increased in major Received 7 September 2001; revised 5 November 2001; accepted depression. These findings suggest that innate immun- 16 January 2002 ity is activated by secretion from monocytes and Plasma IL-12 levels in psychiatric disorders Y-K Kim et al 1108 macrophages during major depression. Moreover, Lici- phrenia and major depression, and that upon treatment nio and Wong25 suggested that brain cytokines, princi- these increased levels may return to baseline. pally IL-1␤ and IL-1 receptor antagonist, may have a role in the biology of major depression, and that central and peripheral cytokine compartments are integrated Subjects and methods but differentially regulated. Reports on the assessment of the inflammatory Subjects response system in bipolar mania are limited and Among psychiatric patients newly admitted in closed remain controversial, but cell-mediated immunity acti- wards of the Department of Psychiatry, Korea Univer- vation in bipolar mania has been suggested. There have sity Medical Center, during August 1999 to June 2001, been some reports that bipolar mania is related to the we recruited 102 psychiatric patients (43 schizo- activation of the inflammatory response system, phrenia, 34 major depression, and 25 bipolar mania) characterized by increased plasma concentrations of who met the Diagnostic and Statistical Manual (DSM- soluble interleukin-2 receptor (sIL-2R) and sIL-6R,28–30 IV) criteria.40 Each patient was given a diagnostic and increased acute phase proteins.31 assessment based on clinical interviews using a Struc- If the cytokine abnormalities play a causative role in tured Clinical Interview for DSM-IV.41 All patients had the pathophysiology of psychiatric disorders, it is not psychotic or active symptoms at the time of study unreasonable to hypothesize that psychotropic drugs enrollment. All patients were either medication-naive may be able to suppress the release of cytokines. Actu- (first-onset) or medication-free for at least 4 months. ally, typical antipsychotic drugs (eg haloperidol) seem The patients gave informed consent after the procedure to have negative immunoregulatory effects19,28,32 and had been fully explained. atypical neuroleptics (eg clozapine and risperidone) The psychopathological status of the patients was appear to have complex in vivo immunomodulatory assessed by a trained physician (Y-K Kim) using the effects.33,34 On the one hand, antidepressants impair Brief Psychiatric Rating Scale42 for patients with the release of proinflammatory cytokines from acti- schizophrenia, the Hamilton Rating Scale43 for vated monocytes and macrophages and enhance the Depression for patients with major depression, and the expression of anti-inflammatory cytokines. For Rating Scale44 for Mania for bipolar mania. Each example, clomipramine, sertraline, and trazodone patient’s symptoms were assessed on admission and 8 inhibit the stimulated production of IFN-␥, whereas weeks later by the same physician. clomipramine and sertraline increased the production Twenty-nine of 43 schizophrenic patients, 17 of 34 of IL-10 in an in vitro study.35 major depressive disorder patients, and 17 of 25 Interleukin-12 (IL-12) is a heterodimeric cytokine bipolar manic disorder patients completed the 8-week that is produced primarily by monocytes and macro- study. The high rate of drop-outs in our study was phages.36 IL-12 plays a central role in promoting Th1 caused by the study protocol to include patients only responses and, hence, cell-mediated immunity.37 This in hospitalization for the 8 weeks of study. The reasons function is promoted by the IL-12-induced production for the failure of follow-up included the change to out- of IFN-␥ from both resting and activated natural killer patient department treatment before the termination of (NK) cells and T cells, by enhancing the cytotoxic the study (91.4%) and the switch to other drugs due to activity of NK cells, and by cytotoxic T lymphocyte adverse effect or unresponsiveness (9.6%). Among the generation. Thus, IL-12 is a proinflammatory cytokine schizophrenia patients, 17 patients were medicated with immunoregulatory functions that bridge innate with risperidone (mean 7.5 mg; range 6–14 mg), five resistance and antigen-specific adaptive immunity.38 patients with olanzapine (mean 16 mg; range 10– IL-12 produced during early phases of infection and 20 mg), four patients with nemonapride (mean 13.2 inflammation sets the stage for the ensuing antigen-spe- mg; range 8–18 mg), two patients with clozapine cific immune response, favoring differentiation and (270 mg and 300 mg), and one patient with haloperidol function of Th1 T cells while inhibiting the differen- (21 mg). Among the major depression patients, seven tiation of Th2 T cells.39 Thus, given the role of IL-12 patients were medicated with nefazodone (mean in the cascade of cytokine regulation, we hypothesized 318 mg; range 100–450 mg), six patients with paroxet- that another pro-inflammatory cytokine, IL-12 could be ine (mean 36.6 mg; range 20–40 mg), three patients dysregulated in some psychiatric disorders. To our with fluoxetine (mean 46.6 mg; range 40–60 mg), and knowledge, studies of IL-12 have not been undertaken one patient with venlafaxine (300 mg). Among these in the field of psychiatry. Hence, we measured the major depressive disorder patients, five patients were plasma levels of IL-12 in a large cohort of 102 psychi- also given an antipsychotic medication (haloperidol or atric patients (43 schizophrenia, 34 major depression risperidone) for controlling psychotic symptoms. and 25 bipolar disorder) and 85 normal controls. In Among the patients with bipolar disorder, nine addition, IL-12 levels of the patients were measured patients were medicated with lithium (mean after an 8-week treatment to assess whether the levels 1050 mg day−1; range 900–1500 mg day−1), six patients were affected by medication.
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