Lithium as add-on to quetiapine XR in adult patients with acute mania: a 6-week, multicenter, double-blind, randomized, placebo-controlled study

Michel S Bourin, Emanuel Severus, Juan P Schronen, Peter Gass, Johan Szamosi, Hans Eriksson, Hongally Chandrashekar, Michel S Bourin, Emanuel Severus, Juan P Schronen, Peter Gass, Johan Szamosi, Hans Eriksson, Hongally Chandrashekar

Abstract

Quetiapine extended release (XR) and lithium are treatments with proven efficacy in acute mania. This randomized study evaluated the efficacy and safety of lithium or placebo as add-on to quetiapine XR in adult patients with manic or mixed symptoms of bipolar I disorder. In this 6-week, double-blind study (Trial D144AC00003), adult patients with DSM-IV-TR-diagnosed bipolar I disorder (current episode manic or mixed), a Young Mania Rating Scale (YMRS) total score ≥20, and score ≥4 on two of four core YMRS items were administered quetiapine XR (400 to 800 mg/day) and randomly assigned to receive add-on lithium (600 to 1,800 mg/day) or placebo. The primary efficacy end point was change in the YMRS total score from baseline to day 43, analyzed using a mixed-model for repeated measures (MMRM) approach. Secondary efficacy and safety end points were also measured. Rating scales were administered by trained staff. Three hundred fifty-six patients treated with quetiapine XR were randomized to add-on lithium (n = 173) or placebo (n = 183). Two hundred ninety-one patients (81.7%) completed the study. At day 43, least squares mean change in YMRS total score was -22.8 for add-on lithium and -20.1 for add-on placebo, a statistically significant treatment group difference of -2.69 (p < 0.001). On secondary measures, add-on lithium was associated with significant improvements in response, remission, illness severity, and overall illness versus add-on placebo (p < 0.05). The number needed to treat was 9.1 for response and 7.9 for remission for add-on lithium compared with add-on placebo. Lithium in combination with quetiapine XR was generally well tolerated, with a similar profile to quetiapine XR in combination with placebo. The addition of lithium to quetiapine XR therapy was associated with significantly greater efficacy than placebo as add-on and was generally well tolerated in patients with acute bipolar I mania. This study was registered under Clinicaltrials.gov Identifier NCT00931723.

Keywords: Bipolar mania; Lithium; Quetiapine XR.

Figures

Figure 1
Figure 1
Patient disposition.aOne randomized patient did not receive study treatment.
Figure 2
Figure 2
Mean change in YMRS total score (with 95% CIs) from baseline (observed case data, ITT set).
Figure 3
Figure 3
Mean changes in YMRS item scores from baseline (ITT set, MMRM analysis).

References

    1. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.
    1. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672–676. doi: 10.1192/bjp.154.5.672.
    1. Bourin M, Thibaut F. How to assess drugs in the treatment of acute bipolar mania? Front Pharmacol (Online ahead of print) 2013;4:4.
    1. Bowden CL. Efficacy of lithium in mania and maintenance therapy of bipolar disorder. J Clin Psychiatry. 2000;61(suppl 9):35–40.
    1. Brooks JO, III, Goldberg JF, Ketter TA, Miklowitz DJ, Calabrese JR, Bowden CL, Thase ME. Safety and tolerability associated with second-generation antipsychotic polytherapy in bipolar disorder: findings from the Systematic Treatment Enhancement Program for Bipolar Disorder. J Clin Psychiatry. 2011;72(2):240–247. doi: 10.4088/JCP.09m05214yel.
    1. Connolly KR, Thase ME (2011) The clinical management of bipolar disorder: a review of evidence-based guidelines. Prim Care Companion CNS Disord 13(4)ᅟ.
    1. Cutler AJ, Datto C, Nordenhem A, Minkwitz M, Acevedo L, Darko D. Extended-release quetiapine as monotherapy for the treatment of adults with acute mania: a randomized, double-blind, 3-week trial. Clin Ther. 2011;33(11):1643–1658. doi: 10.1016/j.clinthera.2011.10.002.
    1. Emsley R, Turner HJ, Schronen J, Botha K, Smit R, Oosthuizen PP. Effects of quetiapine and haloperidol on body mass index and glycaemic control: a long-term, randomized, controlled trial. Int J Neuropsychopharmacol. 2005;8(2):175–182. doi: 10.1017/S1461145705005067.
    1. First MB, Williams JBW, Spitzer RL, Gibbon M. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Clinical Trials Version (SCID-CT) New York: Biometrics Research, New York State Psychiatric Institute; 2007.
    1. Garlow SJ. Interventions for acute mood episodes in patients with bipolar disorder. J Clin Psychiatry. 2008;69(2):e05. doi: 10.4088/JCP.0208e05.
    1. Geoffroy PA, Etain B, Henry C, Bellivier F. Combination therapy for manic phases: a critical review of a common practice. CNS Neurosci Ther. 2012;18(12):957–964. doi: 10.1111/cns.12017.
    1. Goodwin GM. Evidence-based guidelines for treating bipolar disorder: revised second edition–recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2009;23(4):346–388. doi: 10.1177/0269881109102919.
    1. Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. 2. New York: Oxford University Press; 2007.
    1. Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ, Kasper S. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania. World J Biol Psychiatry. 2009;10(2):85–116. doi: 10.1080/15622970902823202.
    1. Guy W. ECDEU Assessment Manual for Psychopharmacology. Revised Edition. Washington, DC: US Department of Health, Education and Welfare; 1976.
    1. Hardoy MC, Garofalo A, Carpiniello B, Calabrese JR, Carta MG. Combination quetiapine therapy in the long-term treatment of patients with bipolar I disorder. Clin Pract Epidemiol Ment Health. 2005;1:7. doi: 10.1186/1745-0179-1-7.
    1. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276. doi: 10.1093/schbul/13.2.261.
    1. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–389. doi: 10.1192/bjp.134.4.382.
    1. Nemeroff CB, Kinkead B, Goldstein J. Quetiapine: preclinical studies, pharmacokinetics, drug interactions, and dosing. J Clin Psychiatry. 2002;63(suppl 13):5–11.
    1. Nivoli AM, Colom F, Murru A, Pacchiarotti I, Castro-Loli P, Gonzalez-Pinto A, Fountoulakis KN, Vieta E. New treatment guidelines for acute bipolar depression: a systematic review. J Affect Disord. 2011;129(1–3):14–26. doi: 10.1016/j.jad.2010.05.018.
    1. Nord M, Nyberg S, Brogren J, Jucaite A, Halldin C, Farde L. Comparison of D(2) dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects. Int J Neuropsychopharmacol. 2011;14(10):1357–1366. doi: 10.1017/S1461145711000514.
    1. Oral TE. Treatment of acute mania. Neuro Endocrinol Lett. 2005;26(suppl 1):9–25.
    1. Plosker GL. Quetiapine: a pharmacoeconomic review of its use in bipolar disorder. Pharmacoeconomics. 2012;30(7):611–631. doi: 10.2165/11208500-000000000-00000.
    1. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164(7):1035–1043. doi: 10.1176/appi.ajp.164.7.1035.
    1. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266–1277. doi: 10.1176/appi.ajp.2011.10111704.
    1. Quiroz JA, Machado-Vieira R, Zarate CA, Jr, Manji HK. Novel insights into lithium's mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology. 2010;62(1):50–60. doi: 10.1159/000314310.
    1. Sachs GS, Gardner-Schuster EE. Adjunctive treatment of acute mania: a clinical overview. Acta Psychiatr Scand Suppl. 2007;434:27–34. doi: 10.1111/j.1600-0447.2007.01056.x.
    1. Sachs G, Chengappa KN, Suppes T, Mullen JA, Brecher M, Devine NA, Sweitzer DE. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord. 2004;6(3):213–223. doi: 10.1111/j.1399-5618.2004.00115.x.
    1. Sanchez-Moreno J, Martinez-Aran A, Tabares-Seisdedos R, Torrent C, Vieta E, Ayuso-Mateos JL. Functioning and disability in bipolar disorder: an extensive review. Psychother Psychosom. 2009;78(5):285–297. doi: 10.1159/000228249.
    1. Seroquel XR (quetiapine fumarate) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP. Available at: ; 2013.
    1. Shim SS, Hammonds MD, Tatsuoka C, Feng IJ. Effects of 4-weeks of treatment with lithium and olanzapine on long-term potentiation in hippocampal area CA1. Neurosci Lett. 2012;524(1):5–9. doi: 10.1016/j.neulet.2012.06.047.
    1. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11–19. doi: 10.1111/j.1600-0447.1970.tb02066.x.
    1. Smith LA, Cornelius V, Warnock A, Tacchi MJ, Taylor D. Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials. Bipolar Disord. 2007;9(6):551–560. doi: 10.1111/j.1399-5618.2007.00468.x.
    1. Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 1997;73(3):159–171. doi: 10.1016/S0165-1781(97)00123-6.
    1. Stokes PE, Kocsis JH, Arcuni OJ. Relationship of lithium chloride dose to treatment response in acute mania. Arch Gen Psychiatry. 1976;33(9):1080–1084. doi: 10.1001/archpsyc.1976.01770090070006.
    1. Suppes T, Vieta E, Liu S, Brecher M, Paulsson B. Maintenance treatment for patients with bipolar I disorder: results from a North American study of quetiapine in combination with lithium or divalproex (trial 127) Am J Psychiatry. 2009;166(4):476–488. doi: 10.1176/appi.ajp.2008.08020189.
    1. Suppes T, Datto C, Minkwitz M, Nordenhem A, Walker C, Darko D. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord. 2010;121(1–2):106–115. doi: 10.1016/j.jad.2009.10.007.
    1. Suppes T, Vieta E, Gustafsson U, Ekholm B. Maintenance treatment with quetiapine when combined with either lithium or divalproex in bipolar I disorder: analysis of two large randomized, placebo-controlled trials. Depress Anxiety. 2013;30(11):1089–1098. doi: 10.1002/da.22136.
    1. Szegedi A, Calabrese JR, Stet L, Mackle M, Zhao J, Panagides J. Asenapine as adjunctive treatment for acute mania associated with bipolar disorder: results of a 12-week core study and 40-week extension. J Clin Psychopharmacol. 2012;32(1):46–55. doi: 10.1097/JCP.0b013e31823f872f.
    1. Tohen M, Chengappa KN, Suppes T, Zarate CA, Jr, Calabrese JR, Bowden CL, Sachs GS, Kupfer DJ, Baker RW, Risser RC, Keeter EL, Feldman PD, Tollefson GD, Breier A. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry. 2002;59(1):62–69. doi: 10.1001/archpsyc.59.1.62.
    1. Vieta E, Suppes T, Eggens I, Persson I, Paulsson B, Brecher M. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126) J Affect Disord. 2008;109(3):251–263. doi: 10.1016/j.jad.2008.06.001.
    1. Vieta E, T’joen C, McQuade RD, Carson WH, Jr, Marcus RN, Sanchez R, Owen R, Nameche L. Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study. Am J Psychiatry. 2008;165(10):1316–1325. doi: 10.1176/appi.ajp.2008.07101560.
    1. Vieta E, Suppes T, Ekholm B, Udd M, Gustafsson U. Long-term efficacy of quetiapine in combination with lithium or divalproex on mixed symptoms in bipolar I disorder. J Affect Disord. 2012;142(1–3):36–44. doi: 10.1016/j.jad.2012.04.014.
    1. Yatham LN, Paulsson B, Mullen J, Vagero AM. Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol. 2004;24(6):599–606. doi: 10.1097/01.jcp.0000144887.66319.2f.
    1. Yatham LN, Kennedy SH, Schaffer A, Parikh SV, Beaulieu S, O’Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Young AH, Alda M, Milev R, Vieta E, Calabrese JR, Berk M, Ha K, Kapczinski F. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 2009;11(3):225–255. doi: 10.1111/j.1399-5618.2009.00672.x.
    1. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–435. doi: 10.1192/bjp.133.5.429.

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