Original article 295 Effect of valproate on plasma levels of interleukin-6 in healthy male humans I-Shin Shiah a , Lakshmi N. Yatham b , Chin-Bin Yeh a and Arun V. Ravindran c Valproate exerts many biochemical and physiological effects and may have a modulating effect on the immune system. The present study aimed to determine whether there is a treatment effect of valproate on plasma levels of the pro-inflammatory cytokine, interleukin (IL)-6, in healthy male humans. Plasma levels of IL-6 were measured in 10 healthy male humans before and after 7 days of treatment with 1000 mg per day of valproate (i.e. 500 mg in the morning and 500 mg in the evening). All the healthy subjects had no past or current psychiatric disorder. They reported to the outpatient clinic at 09.00 h for baseline sampling. Subsequently, they were commenced on valproate 1000 mg per day for 7 days. They took the last dose of valproate at 22.00h on the day 7, and post- treatment blood sampling for plasma levels of IL-6 was carried out on day 8. An additional blood sample was also taken from each subject at the same time to measure plasma levels of valproic acid for drug compliance. We found a significant increase in plasma levels of IL-6 after the 7 days of valproate treatment in healthy male subjects. Furthermore, there was a significant positive correlation between the changes in plasma IL-6 and blood levels of valproic acid. The findings of this study are consistent with previous studies on subjects with epilepsy, suggesting a modulating effect of valproate on the pro-inflammatory cytokine IL-6 in humans. However, studies with a larger number of participants and employing a double-blind, placebo-control group are required to confirm the findings, and also the levels of other cytokines should be measured to generalize the effect to the immune system. Int Clin Psychopharmacol 20:295–298  c 2005 Lippincott Williams & Wilkins. International Clinical Psychopharmacology 2005, 20:295–298 Keywords: Cytokines, immune function, interleukin-6, valproate a Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, b Division of Mood Disorders, Department of Psychiatry, The University of British Columbia, Vancouver, BC, Canada and c Mood and Anxiety Program, Center for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada. Correspondence and requests for reprints to I-Shin Shiah, Department of Psychiatry, Tri-Service General Hospital, No. 325, Cheng-Kung Road, Sec. 2, Nei-Hu District, Taipei, 114, Taiwan. Tel: +011 886 2 8792 7431; fax: +011 886 2 8791 2161; e-mail: ishiah@ms45.hinet.net Received 8 March 2005 Accepted 14 June 2005 Introduction Valproate is an effective treatment for bipolar disorder and is often better tolerated than other treatments. It has a better side-effect profile than lithium and carbamaze- pine, and is well tolerated by patients with bipolar disorders (Bowden, 2003). This medication exerts many biochemical and physiological effects (Loscher, 1993), including a proposed modulating effect on the immune system. For example, valproate was shown to reduce serum level of immunoglobulin in some studies (Joubert et al., 1977; Fujiwara et al., 1983) but not in others (Garzon et al., 1985; Lenti et al., 1991). In addition, it increases the number of plaque-forming cells in the spleen and in bacterial infection (Queiroz and Mullen, 1992). More recently, Ichiyama et al. (2000) showed that valproate significantly inhibited production of tumour necrosis factor (TNF)-a and interleukin (IL)-6 induced by lipopolysaccharide (LPS) from human monocytic leukae- mia cells and this inhibition was linked to suppression of nuclear transcription factor kappa B (NF-kB) activation. This inhibitory effect was also seen in human glioma cells (A-172) (Ichiyama et al., 2000). These findings were consistent with valproate-induced reduction of serum immunoglobulin concentration (Joubert et al., 1977; Fujiwara et al., 1983). To date, two previous studies have examined the effects of valproate on immune system markers in bipolar patients (Maes et al., 1995a,b). The first study (Maes et al., 1995b) investigated the effect of valproate on the activity of prolyl endopeptidase (PEP), a serine protei- nase, in 10 manic patients. The authors found that plasma PEP activity significantly decreased following valproate treatment (range 12–23 days, mean dose 1400 ± 592 mg/day). High PEP activity is usually ob- served in muscle, kidney, testes, submandibular gland, thyroid gland, adrenal gland, liver, thymus and cerebral cortex (Kato et al., 1980). PEP may cleave many neuropeptides and hormones that have been implicated in mood disorders, including thyrotropin-releasing hormone, b-endorphin, luteinizing-hormone-releasing hormone, arginin vasopression (Camargo et al., 1983; Wilk, 1983; Ward et al., 1987), and perhaps corticotrophin- releasing hormone and adrenocorticotropic hormone 0268-1315  c 2005 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.