Frank M. Schmidt

Hubertus Himmerich

Kenneth C. Kirkby

English

Hrčak - Portal of scientific journals of Croatia

288 Psychiatria Danubina, 2014; Vol. 26, No. 3, pp 288-290 Case report © Medicinska naklada - Zagreb, CroatiaTHE TNF-ALPHA INHIBITOR ETANERCEPT  AS MONOTHERAPY IN TREATMENT-RESISTANT DEPRESSION – REPORT OF TWO CASES  Frank M. Schmidt1, Kenneth C. Kirkby2 & Hubertus Himmerich11Department of Psychiatry and Psychotherapy, University Hospital Leipzig, Leipzig, Germany 2Department of Psychiatry, University of Tasmania, Hobart, Tasmania, Australia received: 21.1.2014; revised: 5.4.2014.; accepted: 24.4.2014 *  *  *  *  *  INTRODUCTIONGrowing evidence links affective disorders and the immune system. Pro-inflammatory cytokines are implicated in the pathogenesis of depression by activation of the tryptophan- and serotonin-degrading enzyme indolamine-2,3-dioxygenase (IDO) (Kiank et al. 2010) and by up-regulating serotonin transporter activity (Zhu et al. 2006), leading to reduced availability of serotonin. Pro-inflammatory cytokines may play future roles in the therapy of depressive disorder, as biomarkers, and as targets for cytokine inhibitors and modifiers of cytokine signalling (Lichtblau et al. 2013). Levels of tumor necrosis factor-  (TNF- ) and its soluble receptors p55 and p75 are increased in acutely depressed patients (Himmerich et al. 2008) and TNF-was increased in depressed compared to healthy females (Kahl et al. 2006). In animals, induction of depressive behaviour by administration of TNF-  was reversed by anti-TNF-  antibody (Kaster et al. 2012). In humans, treatment for psoriasis with the anti-TNF-agent etanercept, a TNF-  receptor p75-Fc fusion protein, was found to have antidepressant effect (Tyring et al. 2006). In an animal model of depression, treatment with etanercept reduced depression-like behaviour (Krügel et al. 2013). In bipolar depression (BD), TNF- -levels are considered as potential trait markers for the disorder, and modulation of TNF-may be a target for antidepressant treatment (Soczynska et al. 2009). The aim of this investigation was to explore possible antidepressant effects of etanercept in two patients suffering from depressive episodes, one in the context of major depressive disorder (MDD), the other bipolar disorder (BD). Following a drug-free wash-out period of 14 days, severity of depressive symptoms was investigated before (baseline = BL) and after 7 (T1), 14 (T2) and 21 (T3) days of etanercept mono-therapy. Measures of depression comprised observer-rated Hamilton Depression Rating Scale (HAMD-21) and self-rated Beck Depression Inventory (BDI-II). Participants gave informed consent for off-label treatment with the TNF- -inhibitor etanercept. Detailed information was provided on the absence of approval of the drug for the treatment of depressive episodes. This procedure was in conformity with German legal requirements governing consent to unapproved treatments (BVerfG 2005, Az 1 BvR 347/98). CASE REPORTS Patient 1 A 58-yr old, unemployed, divorced mother of 2, was admitted with a depressive episode. She had a history of 6 previous inpatient admissions, diagnosed with a recurrent depressive disorder and a history of poly substance abuse of benzodiazepines, opiates and alcohol. Recently instituted pharmacotherapy com-prising trimipramine 100 mg and citalopram 40 mg daily and a series of 12 ECTs only led to partial remission with rapid relapse into benzodiazepine abuse. Following lack of response, antidepressants were discontinued for 2 weeks. Following exclusion of contraindications (Miyasaka et al. 2006), treatment with etanercept 25 mg subcutaneous twice a week as monotherapy was instituted. Compared to BL (HAMD-21 33 points, BDI-II 27 points) depressive severity reduced during course of treatment (T1 HAMD-21 7 points, BDI-II 14 points; T2 HAMD-21 14 points, BDI-II 27 points; T3 HAMD-21 13 points, BDI-II 27 points) (Figure 1). Therapy with etanercept was discontinued after 3 weeks, following a relapse into alcohol but not benzodiazepine dependence during the therapy. Therefore, following cessation of etaner-cept, a depression-focused pharmacotherapy with tia-neptine 3 x 12.5 mg daily was commenced.  Patient 2 A 62-yr old retired, married patient with 23 previous admissions for bipolar disorder (BD) since age 30. Hospitalised with a recent exacerbation of a severe depressive episode, characterized by increased anhe-donia, tearfulness, extensive rumination, disruption of sleep, loss of appetite and suicidal thoughts. Following a lack in response to first- and second-line pharmaco-Frank M. Schmidt, Kenneth C. Kirkby & Hubertus Himmerich: THE TNF-ALPHA INHIBITOR ETANERCEPT AS MONOTHERAPY IN TREATMENT-RESISTANT DEPRESSION – REPORT OF TWO CASES          Psychiatria Danubina, 2014; Vol. 26, No. 3, pp 288-290 289 therapy, treatment with tranylcypromine 40 mg, lamotrigine 100 mg and aripiprazole 10 mg, partial sleep deprivation twice a week plus daily bright light therapy and 12 sessions of ECT three times weekly had no marked antidepressive effect. Following 14 days drug-free, etanercept 25 mg was commenced, twice a week. HAMD-21- and BDI-II-scores slightly decreased during the three weeks (HAMD-21-scores: 24 points at BL, 21 at T1, 20 at T2, 17 at T3; BDI-II-scores: 31 points at BL, 26 at T1, 34 at T2, 24 at T3) (Figure 1). TNF-  levels at BL (6.9 pg/ml) was within the reference limit of <8.1 pg/ml and rose during treatment (T1 92.2 pg/ml; T2 138.0 pg/ml; T3 209 pg/ml). No side effects were observed. Medication with mirtazapine and lithium was recommenced rapidly after the 3 weeks of etanercept treatment, based on a past history of response. The therapeutic option of deep brain stimu-lation was discussed with the patient.  DISCUSSION We report the administration of the anti-TNF-  drug etanercept in two patients suffering from depressive episodes, in MDD and in BD. Though the literature supports a significant antidepressant effect of anti-TNF- drugs in animal models of depression and reduced depressive symptoms in patients with psoriasis, etanercept treatment in these 2 cases did not lead to an unequivocal response.  When interpreting the results, it should be noted that both patients had a low probability of anti-depressant response, given lengthy past psychiatric histories and non-response to prior conventional treatment. Secondly, HAMD-21 scores dropped in both patients, in patient 1 formally meeting the criteria for response with a reduction of 60 % after 3 weeks. In contrast, BDI-II scores remained around baseline levels. Since patients with chronic or enduring de-pressive episodes often have difficulties in perceiving small changes in symptoms, as outlined in the ‘theory of mind’ (Foerstl 2009), it is possible that improve-ments were not recognized by the patients. Further, the observational period of 3 weeks might have been too short to demonstrate a marked effect. Tyring reported an antidepressive effect after 8 weeks of etanercept treatment (Tyring et al. 2006), and an antidepressive-like response in rats was observed after 35 days of drug-administration (Krügel et al. 2013). Alternatively, the rapid but short-lasting response seen at day 7 in MDD patient 1 may be attributed to a rapid blockade of circulating TNF- . The paradoxical, previously reported (Bhatia & Kast 2007) and hypothetically autoregulatory increase in TNF- -levels, as observed in patient 2, may have contributed to a relapse in depressive symptoms during treatment.  Further, an influence of the previous drug abuse in patient 1 and previous medication on TNF- -levels and etanercept effects (Munzer et al. 2013), extending beyond the 14 day wash-out period, cannot be ruled out.  The effectiveness of etanercept treatment may also be influenced by baseline levels of TNF- . Normal baseline levels in patient 2 potentially reduced the sites for etanercept action from the outset. Further, the response to treatment may have been negatively influenced by the paradoxical effect of etanercept in inducing TNF- -elevations. Unfortunately, TNF- -levels were not determined in patient 1.  In the future, the effect of anti-TNF- -medication could be compared between patients with and without elevated TNF- -levels preceding therapy, and the course of TNF- -levels during treatment should be registered as possible covariate.  Figure 1. Course of HAMD-21and BDI-II depression ratings at baseline (BL), 7 (T1), 14 (T2) and 21 (T3) days of etanercept treatment, in patient 1 and patient 2  Frank M. Schmidt, Kenneth C. Kirkby & Hubertus Himmerich: THE TNF-ALPHA INHIBITOR ETANERCEPT AS MONOTHERAPY IN TREATMENT-RESISTANT DEPRESSION – REPORT OF TWO CASES          Psychiatria Danubina, 2014; Vol. 26, No. 3, pp 288-290 290 CONCLUSIONS In conclusion, this first-time application of etanercept in two patients suffering from unipolar and bipolar disorder revealed equivocal antidepressant effects. This should be reassessed in a clinical trial on etanercept or other non-antibody anti-TNF-  drugs in antidepressant treatment. Acknowledgements: None.Conflict of interest:All authors declare no conflict of interest. Hubertus Himmerich declares research support in terms of chemical substances from the Wyeth Pharma GmbH, Novartis and AstraZeneca, speaker honoraria from AstraZeneca, Servier, Bristol-Myers Squibb and Lilly, and travel grants from AstraZeneca and Servier. The study was financially supported by the Claussen-Simon-Foundation. References 1. Bhatia A, Kast RE: Tumor necrosis factor (TNF) can paradoxically increase on etanercept treatment, occasio-nally contributing to TNF-mediated disease. J Rheumatol 2007; 34:447-9. 2. Förstl H: Theory of mind. Neurobiologie und Psychologie sozialen Verhaltens. Springer-Verlag, Berlin, Heidelberg, New York, Hongkong, London, Mailand, Paris, Tokio, Wien, 2007. 3. Himmerich H, Fulda S, Linseisen J, Seiler H, Wolfram G, Himmerich S, et al.: Depression, comorbidities and the TNF-alpha system. Eur Psychiatry 2008; 23:421-9. 4. Kahl KG, Greggersen W, Rudolf S, Stoeckelhuber BM, Bergmann-Koester CU, Dibbelt L, et al.: Bone mineral density, bone turnover, and osteoprotegerin in depressed women with and without borderline personality disorder. Psychosom Med 2006; 68:669-74. 5. Kaster MP, Gadotti VM, Calixto JB, Santos AR, Rodrigues AL: Depressive-like behavior induced by tumor necrosis factor-  in mice. Neuropharmacol 2012; 62:419-26. 6. Kiank C, Zeden JP, Drude S, Domanska G, Fusch G, Otten W, et al.: Psychological stress-induced, IDO1-dependent tryptophan catabolism: implications on immunosuppression in mice and humans. PLoS One 2010; 5:e11825.7. Krügel U, Fischer J, Radicke S, Sack U, Himmerich H: Antidepressant effects of TNF-  blockade in an animal model of depression. J Psychiatr Res 2013; 47:611-6. 8. Lichtblau N, Schmidt FM, Schumann R, Kirkby KC, Himmerich H: Cytokines as biomarkers in depressive disorder: Current standing and prospects. Int Rev Psych 2013; 25:592–603. 9. Miyasaka N, Takeuchi T, Eguchi K: Guidelines for the proper use of etanercept in Japan. Mod Rheumatol 2006; 16:63e7.10. Munzer A, Sack U, Mergl R, Schönherr J, Petersein C, Bartsch S, Kirkby KC, Bauer K, Himmerich H: Impact of antidepressants on cytokine production of depressed patients in vitro. Toxins (Basel) 2013; 5:2227-40.  11. Soczynska JK, Kennedy SH, Goldstein BI, Lachowski A, Woldeyohannes HO, McIntyre RS: The effect of tumor necrosis factor antagonists on mood and mental health-associated quality of life: novel hypothesis-driven treatments for bipolar depression? Neurotoxicology 2009; 30:497-521.12. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, et al.: Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-cont-rolled randomised phase III trial. Lancet 2006; 367:29-35. 13. Zhu CB, Blakely RD, Hewlett WA: The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsycho-pharmac 2006; 31:2121-31. Correspondence: Frank M. Schmidt, MD Department of Psychiatry and Psychotherapy, University Hospital Leipzig Semmelweisstr. 10, 04103 Leipzig, Germany E-mail: Frank.Schmidt2@medizin.uni-leipzig.de 

THE TNF-ALPHA INHIBITOR ETANERCEPT AS MONOTHERAPY IN TREATMENT-RESISTANT DEPRESSION – REPORT OF TWO CASES

Abstract

Similar works

Full text

Available Versions

Hrčak - Portal of scientific journals of Croatia