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Quetiapine v. lithium in the maintenance phase following a first episode of mania: Randomised controlled trial

  • Michael Berk (a1), Rothanthi Daglas (a2), Orwa Dandash (a3), Murat Yücel (a3), Lisa Henry (a2), Karen Hallam (a4), Craig Macneil (a2), Melissa Hasty (a2), Christos Pantelis (a5), Brendan P. Murphy (a6), Linda Kader (a2), Saji Damodaran (a6), Michael T. H. Wong (a6), Philippe Conus (a7), Aswin Ratheesh (a2), Patrick D. McGorry (a2) and Sue M. Cotton (a2)...

Lithium and quetiapine are considered standard maintenance agents for bipolar disorder yet it is unclear how their efficacy compares with each other.


To investigate the differential effect of lithium and quetiapine on symptoms of depression, mania, general functioning, global illness severity and quality of life in patients with recently stabilised first-episode mania.


Maintenance trial of patients with first-episode mania stabilised on a combination of lithium and quetiapine, subsequently randomised to lithium or quetiapine monotherapy (up to 800 mg/day) and followed up for 1 year. (Trial registration: Australian and New Zealand Clinical Trials Registry – ACTRN12607000639426.)


In total, 61 individuals were randomised. Within mixed-model repeated measures analyses, significant omnibus treatment × visit interactions were observed for measures of overall psychopathology, psychotic symptoms and functioning. Planned and post hoc comparisons further demonstrated the superiority of lithium treatment over quetiapine.


In people with first-episode mania treated with a combination of lithium and quetiapine, continuation treatment with lithium rather than quetiapine is superior in terms of mean levels of symptoms during a 1-year evolution.

Corresponding author
Michael Berk, Deakin University, IMPACT Strategic Research Centre, School of Medicine, 75 Pigdon's Road, Waurn Ponds, Geelong, Victoria, 3216, Australia. Email:
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Declaration of interest

This study was supported by an unrestricted grant from AstraZeneca. R.D., M.H. and K.H. worked on a study that has received research support by AstraZeneca. M.B. has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier and Woolworths, has been a speaker for AstraZeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen-Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth, and served as a consultant to AstraZeneca, Bioadvantex, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen-Cilag, Lundbeck Merck and Servier. C.M. has received a grant/research support from Eli Lilly and AstraZeneca, Janssen Cilag and Sanofi Aventis, and served as a consultant to AstraZeneca and Eli Lilly. P.D.M. has received investigator initiated research grants from AstraZeneca, Janssen-Cilag, Eli Lilly and BMS. He has received honoraria for educational events from Janssen-Cilag, Eli Lilly, BMS, AstraZeneca, Pfizer and Lundbeck. C.P. has participated on Advisory Boards for Janssen-Cilag, AstraZeneca, Lundbeck and Servier, has received honoraria for talks presented at educational meetings organised by AstraZeneca, Janssen-Cilag, Eli-Lilly, Pfizer, Lundbeck and Shire.

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1 Angst, J, Sellaro, R. Historical perspectives and natural history of bipolar disorder. Biol Psychiatry 2000; 48: 445–57.
2 Post, RM, Rubinow, DR, Ballenger, JC. Conditioning and sensitisation in the longitudinal course of affective illness. Br J Psychiatry 1986; 149: 191201.
3 Oepen, G, Baldessarini, RJ, Salvatore, P, Slater, E. On the periodicity of manic-depressive insanity, by Eliot Slater (1938): translated excerpts and commentary. J Affect Disord 2004; 78: 19.
4 Berk, M, Berk, L, Dodd, S, Cotton, S, Macneil, C, Daglas, R, et al. Stage managing bipolar disorder. Bipolar Disord 2014; 16: 471–7.
5 Franchini, L, Zanardi, R, Smeraldi, E, Gasperini, M. Early onset of lithium prophylaxis as a predictor of good long-term outcome. Eur Arch Psychiatry Clin Neurosci 1999; 249: 227–30.
6 Kessing, LV, Vradi, E, Andersen, PK. Starting lithium prophylaxis early v. late in bipolar disorder. Br J Psychiatry 2014; 205: 214–20.
7 Maj, M, Pirozzi, R, Magliano, L. Nonresponse to reinstituted lithium prophylaxis in previously responsive bipolar patients: prevalence and predictors. Am J Psychiatry 1995; 152: 1810–1.
8 Baldessarini, RJ, Tondo, L, Baethge, CJ, Lepri, B, Bratti, IM. Effects of treatment latency on response to maintenance treatment in manic-depressive disorders. Bipolar Disord 2007; 9: 386–93.
9 Berk, M, Dodd, S. Recent developments in the treatment of bipolar disorders. Expert Opin Investig Drugs 2003; 12: 1621–32.
10 Bowden, CL, Grunze, H, Mullen, J, Brecher, M, Paulsson, B, Jones, M, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry 2005; 66: 111–21.
11 McIntyre, RS, Brecher, M, Paulsson, B, Huizar, K, Mullen, J. Quetiapine or haloperidol as monotherapy for bipolar mania – a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol 2005; 15: 573–85.
12 Vieta, E, Mullen, J, Brecher, M, Paulsson, B, Jones, M. Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomised, placebo-controlled studies. Curr Med Res Opin 2005; 21: 923–34.
13 Calabrese, JR, Keck, PE Jr, Macfadden, W, Minkwitz, M, Ketter, TA, Weisler, RH, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005; 162: 1351–60.
14 Young, AH, McElroy, SL, Bauer, M, Philips, N, Chang, W, Olausson, B, et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry 2010; 71: 150–62.
15 Keck, PE, Orsulak, PJ, Cutler, AJ, Sanchez, R, Torbeyns, A, Marcus, RN, et al. Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study. J Affect Disord 2009; 112: 3649.
16 Tohen, M, Ketter, TA, Zarate, CA, Suppes, T, Frye, M, Altshuler, L, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry 2003; 160: 1263–71.
17 Bowden, CL. Atypical antipsychotic augmentation of mood stabilizer therapy in bipolar disorder. J Clin Psychiatry 2005; 66 (suppl 3): 12–9.
18 Conus, P, Berk, M, Cotton, SM, Kader, L, Macneil, C, Hasty, MK, et al. Olanzapine or chlorpromazine plus lithium in first episode psychotic mania: an 8-week randomised controlled trial. Eur Psychiatry 2015; 30: 975–82.
19 First, MB, Spitzer, , Robert, L, Miriam, Gibbon, and Williams, , Janet, BW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P). Biometrics Research, New York State Psychiatric Institute, 2002.
20 Young, RC, Biggs, JT, Ziegler, VE, Meyer, DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: 429–35.
21 Overall, JE, Gorham, DR. The Brief Psychiatric Rating Scale. Psychol Rep 1962; 10: 799812.
22 Berk, M, Malhi, GS, Cahill, C, Carman, AC, Hadzi-Pavlovic, D, Hawkins, MT, et al. The Bipolar Depression Rating Scale (BDRS): its development, validation and utility. Bipolar Disord 2007; 9: 571–9.
23 Montgomery, SA, Åsberg, M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–9.
24 Spearing, M, 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: 159–71.
25 Jones, SH, Thornicroft, G, Coffey, M, Dunn, G. A brief mental health outcome scale – reliability and validity of the Global Assessment of Functioning (GAF). Br J Psychiatry 1995; 166: 654–9.
26 Morosini, PL, Magliano, L, Brambilla, L, Ugolini, S, Pioli, R. Development, reliability and acceptability of a new version of the DSM-IV Social Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand 2000; 101: 323–9.
27 Heinrichs, DW, Hanlon, TE, Carpenter, WT. The Quality of Life Scale: an instrument for rating schizophrenic deficit syndrome. Schizophrenia Bull 1984; 10: 388–98.
28 Tohen, M, Hennen, J, Zarate, CM Jr, Baldessarini, RJ, Strakowski, SM, Stoll, AL, et al. Two-year syndromal and functional recovery in 219 cases of first episode major affective disorder with psychotic features. Am J Psychiatry 2000; 157: 220–8.
29 Mallinckrodt, C, Watkin, J, Molenberghs, G, Carroll, R. Choice of the primary analysis in longitudinal clinical trials. Pharm Stat 2004; 3: 161–9.
30 Gueorgieva, R, Krystal, JH. Move over ANOVA: progress in analyzing repeated-measures data and its reflection in papers published in the Archives of General Psychiatry. Arch Gen Psychiatry 2004; 61: 310–7.
31 Rothman, KJ. No adjustments are needed for multiple comparisons. Epidemiology 1990; 1: 43–6.
32 Yildiz, A, Vieta, E, Leucht, S, Baldessarini, RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology 2011; 36: 375–89.
33 Nierenberg, AA, Sylvia, LG, Leon, AC, Reilly-Harrington, NA, Shesler, LW, McElroy, SL, et al. Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE): a pragmatic trial of complex treatment for a complex disorder. Clin Trials 2014; 11: 114–27.
34 Weisler, RH, Nolen, WA, Neijber, A, Hellqvist, A, Paulsson, B, Trial 144 Study Investigators. Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study). J Clin Psychiatry 2011; 72: 1452–64.
35 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: 1089–98.
36 Hartong, EG, Moleman, P, Hoogduin, CA, Broekman, TG, Nolen, WA, LitCar, G. Prophylactic efficacy of lithium versus carbamazepine in treatment-naive bipolar patients. J Clin Psychiatry 2003; 64: 144–51.
37 Berk, M, Kapczinski, F, Andreazza, AC, Dean, OM, Giorlando, F, Maes, M, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 2011; 35: 804–17.
38 Passos, IC, Mwangi, B, Vieta, E, Berk, M, Kapczinski, F. Areas of controversy in neuroprogression in bipolar disorder. Acta Psychiatr Scand 2016; 134: 91103.
39 Calabrese, JR, Vieta, E, El-Mallakh, R, Findling, RL, Youngstrom, EA, Elhaj, O, et al. Mood state at study entry as predictor of the polarity of relapse in bipolar disorder. Biol Psychiatry 2004; 56: 957–63.
40 Vieta, E, Berk, M, Wang, W, Colom, F, Tohen, M, Baldessarini, RJ. Predominant previous polarity as an outcome predictor in a controlled treatment trial for depression in bipolar I disorder patients. J Affect Disord 2009; 119: 22–7.
41 Schalkwijk, S, Undurraga, J, Tondo, L, Baldessarini, RJ. Declining efficacy in controlled trials of antidepressants: effects of placebo dropout. Int J Neuropsychopharmacol 2014; 17: 1343–52.
42 Grande, I, Berk, M, Birmaher, B, Vieta, E. Bipolar disorder. Lancet 2016; 387: 1561–72.
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Quetiapine v. lithium in the maintenance phase following a first episode of mania: Randomised controlled trial

  • Michael Berk (a1), Rothanthi Daglas (a2), Orwa Dandash (a3), Murat Yücel (a3), Lisa Henry (a2), Karen Hallam (a4), Craig Macneil (a2), Melissa Hasty (a2), Christos Pantelis (a5), Brendan P. Murphy (a6), Linda Kader (a2), Saji Damodaran (a6), Michael T. H. Wong (a6), Philippe Conus (a7), Aswin Ratheesh (a2), Patrick D. McGorry (a2) and Sue M. Cotton (a2)...
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