Original article In search of optimal lithium levels and olanzapine doses in the long-term treatment of bipolar I disorder. A post-hoc analysis of the maintenance study by Tohen et al. 2005 W.E. Severus a, *, I.A. Lipkovich b , R.W. Licht c , A.H. Young d , W. Greil a , T. Ketter e , W. Deberdt f , M. Tohen g a Department of Psychiatry, University of Munich, Nussbaumstrasse 7, 80336 Munich, Germany b Eli Lilly and Company, Indianapolis, Indiana 46285, USA c Mood Disorders Unit, Aarhus University Psychiatric Hospital, Skovagervej 2, 8240, Risskov, Denmark d Institute of Mental Health, Department of Psychiatry, University of British Columbia, Suite 430, 5950 University Boulevard, Vancouver, BC V6T 1Z3, Canada e Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401, Quarry Road, Room 2124, Stanford, CA 94305-5723, USA f Eli Lilly Benelux, Stoofstraat 52, 1000 Brussels, Belgium g Division of Mood and Anxiety Disorders, University of Texas Health Science Center, 7703, Floyd Curl Drive, San Antonio, TX 78229, USA 1. Introduction Lithium and olanzapine are generally accepted as first-line options for the long-term treatment (i.e., maintenance treatment, prophylactic treatment) of bipolar disorders [34]. However, there is a substantial amount of uncertainty regarding the most efficacious plasma concentration/dose of these drugs for this indication [1]. Lithium levels between 0.6 and 0.8 mmol/L are widely recommended for the prophylaxis of new episodes, although this range has never been formally studied [1,27]. For many patients, increases in maintenance lithium levels ( 0.8 mmol/L) are thought to provide greater protection from additional episodes or sub-threshold symptoms with functional impairment [11,12]. However, there is a lack of formal study for this assumption [1,27]. In fact, even the superiority of lithium levels > 0.8 mmol/L, compared to those between 0.4 and 0.6 mmol/L, has only been demonstrated for the prevention of manic, but not depressive episodes [9]. Given that higher lithium levels (> 0.8 mmol/L) are generally associated with more side effects and a narrower safety margin than lower levels [7,9], it seems important to re-examine the potential value of higher lithium dose levels. Compared to placebo, olanzapine 5 to 20 mg/day, has been shown to delay relapse in manic, depressive, or mixed mood European Psychiatry 25 (2010) 443–449 ARTICLE INFO Article history: Received 11 August 2009 Received in revised form 30 September 2009 Accepted 31 October 2009 Keywords: Lithium Olanzapine Maintenance treatment Bipolar disorders ABSTRACT Purpose. – The aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder. Methods. – A post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non- random assignments of dose during treatment. Results. – The LoLi group (< 0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR] = 1.96, p = 0.042), but not depressive (HR = 2.11, p = 0.272) episodes, compared to the combined medium (0.6–0.79 mmol/L) and high lithium level ( 0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L;  0.8 mmol/L) for new manic/mixed (HR = 0.96, p = 0.893) or depressive (HR = 0.95, p = 0.922) episodes. The LoOL group (< 10 mg/day) showed a significantly increased risk of depressive (HR = 2.24, p = 0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10–20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR = 0.94, p = 0.895). Conclusion. – Lithium levels  0.6 mmol/L and olanzapine doses  10 mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder. ß 2010 Elsevier Masson SAS. All rights reserved. * Corresponding author. Tel.: +0049 89 5160 5511; fax: +0049 89 5160 5809. E-mail address: Emanuel.Severus@med.uni-muenchen.de (W.E. Severus). 0924-9338/$ – see front matter ß 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2009.10.009