Lamotrigine as add‐on treatment to lithium and divalproex: lessons learned from a double‐blind, placebo‐controlled trial in rapid‐cycling bipolar disorder
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Kemp DE, Gao K, Fein EB, Chan PK, Conroy C, Obral S, Ganocy SJ, Calabrese JR. Lamotrigine as add‐on treatment to lithium and divalproex: lessons learned from a double‐blind, placebo‐controlled trial in rapid‐cycling bipolar disorder. Bipolar Disord 2012: 14: 780–789. © 2012 John Wiley & Sons A/S. Objectives: A substantial portion of the morbidity associated with rapid‐cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add‐on therapy for rapid‐cycling bipolar depression non‐responsive to the combination of lithium plus divalproex. Methods: During Phase 1 of this trial, hypomanic, manic, mixed, and/or depressed outpatients (n = 133) aged 18–65 years with DSM–IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16 weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n = 49) (i.e., remained in or cycled into the depressed phase) were randomly assigned to double‐blind, adjunctive lamotrigine (n = 23) or adjunctive placebo (n = 26). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery‐Åsberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed‐models analysis. Results: During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13/133; 10%) and study non‐adherence (22/133; 17%). Only 14% (19/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double‐blind adjunctive treatment phase, mean ± standard error change from baseline on the MADRS total score was −8.5 ± 1.7 points for lamotrigine and −9.1 ± 1.5 points for placebo (p = not significant; mixed‐models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo. Conclusions: The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double‐blind treatment.
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Triple mood stabilizer therapy has not demonstrated superiority to double mood stabilizer therapy in a single RCT.
“It is likely that combinations of mood‐stabilizing drugs may be more often necessary than monotherapies when rapid cycling is present,220 but triple mood stabilizer therapy has not demonstrated superiority to double mood stabilizer therapy in a single RCT,221 although methodological weaknesses probably limited interpretability of the findings.”
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Cites
(1998) · The Journal of Clinical Psychiatry · Cited by 19,139 · see citing works
A new depression scale designed to be sensitive to change
Montgomery, S. A., & Åsberg, M. (1979) · British Journal of Psychiatry · doi:10.1192/bjp.134.4.382 · Cited by 13,962 · see citing works
(1998) · PubMed · Cited by 10,216 · see citing works
A Rating Scale for Mania: Reliability, Validity and Sensitivity
Young, R. C., Biggs, J. T., Ziegler, V. E., & Meyer, D. A. (1978) · British Journal of Psychiatry · doi:10.1192/bjp.133.5.429 · Cited by 8,744 · see citing works
The Global Assessment Scale: A Procedure for Measuring Overall Severity of Psychiatric Disturbance
Endicott, J. (1976) · Archives of General Psychiatry · doi:10.1001/archpsyc.1976.01770060086012 · Cited by 4,982 · see citing works
Calabrese, J. R., Bowden, C. L., Sachs, G. S., Ascher, J. A., Monaghan, E., Rudd, G. D., & The Lamictal 602 Study Group (1999) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v60n0203 · Cited by 1,054 · see citing works
Self-citationSpearing, M. K., Post, R. M., Leverich, G. S., Brandt, D., & Nolen, W. (1997) · Psychiatry Research · doi:10.1016/s0165-1781(97)00123-6 · Cited by 978 · see citing works
Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression
Sachs, G. S., Nierenberg, A. A., Calabrese, J. R., Marangell, L. B., Wisniewski, S. R., Gyulai, L., Friedman, E. S., Bowden, C. L., Fossey, M. D., Ostacher, M. J., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa064135 · Cited by 937 · see citing works
Self-citationTohen, M., Vieta, E., Calabrese, J., Ketter, T. A., Sachs, G., Bowden, C., Mitchell, P. B., Centorrino, F., Risser, R., Baker, R. W., et al. (2003) · Archives of General Psychiatry · doi:10.1001/archpsyc.60.11.1079 · Cited by 908 · see citing works
Self-citationCalabrese, J. R., Keck, P. E., Macfadden, W., Minkwitz, M., Ketter, T. A., Weisler, R. H., Cutler, A. J., McCoy, R., Wilson, E., Mullen, J., et al. (2005) · American Journal of Psychiatry · doi:10.1176/appi.ajp.162.7.1351 · Cited by 883 · see citing works
Self-citationGeddes, J. R., Burgess, S., Hawton, K., Jamison, K., & Goodwin, G. M. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.161.2.217 · Cited by 661 · see citing works
Bowden, C. L. (2003) · Archives of General Psychiatry · doi:10.1001/archpsyc.60.4.392 · Cited by 653 · see citing works
Calabrese, J. R., Bowden, C. L., Sachs, G. S., Yatham, L. N., Behnke, K., Mehtonen, O. ‐., Montgomery, P., Ascher, J. A., Paska, W., Earl, N. L., et al. (2003) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v64n0906 · Cited by 628 · see citing works
Self-citationThase, M. E., Macfadden, W., Weisler, R. H., Chang, W., Paulsson, B., Khan, A., & Calabrese, J. R. (2006) · Journal of Clinical Psychopharmacology · doi:10.1097/01.jcp.0000248603.76231.b7 · Cited by 559 · see citing works
Self-citationCalabrese, J. R., Suppes, T., Bowden, C. L., Sachs, G. S., Swann, A. C., McElroy, S. L., Kusumakar, V., Ascher, J. A., Earl, N. L., Greene, P. L., et al. (2000) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v61n1106 · Cited by 498 · see citing works
Self-citationGeddes, J. R., Calabrese, J. R., & Goodwin, G. M. (2008) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.107.048504 · Cited by 429 · see citing works
Self-citationYoung, A. H., McElroy, S. L., Bauer, M., Philips, N., Chang, W., Olausson, B., Paulsson, B., Brecher, M., & EMBOLDEN I (Trial 001) Investigators (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.08m04995gre · Cited by 390 · see citing works
McElroy, S. L., Weisler, R. H., Chang, W., Olausson, B., Paulsson, B., Brecher, M., Agambaram, V., Merideth, C., Nordenhem, A., Young, A. H., et al. (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.08m04942gre · Cited by 328 · see citing works
Spectrum of efficacy of valproate in 55 patients with rapid-cycling bipolar disorder
Calabrese, J. R., & Delucchi, G. A. (1990) · American Journal of Psychiatry · doi:10.1176/ajp.147.4.431 · Cited by 266 · see citing works
Self-citationCalabrese, J. R., Shelton, M. D., Rapport, D. J., Youngstrom, E. A., Jackson, K., Bilali, S., Ganocy, S. J., & Findling, R. L. (2005) · American Journal of Psychiatry · doi:10.1176/appi.ajp.162.11.2152 · Cited by 252 · cited 4× · see citing works
“Previous studies of RCBD have shown the rate of bimodal stabilization over six months to be 24% in patients without substance use disorders (6) and to range from 7% to 21% in those with recent substance use disorders (7, 26).”
BackgroundResultInfluentialSelf-citationThe Long-term Course of Rapid-Cycling Bipolar Disorder
Coryell, W. H., Solomon, D., Turvey, C., Keller, M. B., Leon, A. C., Endicott, J., Schettler, P. J., Judd, L. L., & Mueller, T. (2003) · Archives of General Psychiatry · doi:10.1001/archpsyc.60.9.914 · Cited by 251 · see citing works
Calabrese, J. R., Huffman, R., White, R. L., Edwards, S., Thompson, T. R., Ascher, J. A., Monaghan, E., & Leadbetter, R. A. (2008) · Bipolar Disorders · doi:10.1111/j.1399-5618.2007.00500.x · Cited by 243 · see citing works
Self-citationEfficacy and Safety of Lamotrigine as Add-On Treatment to Lithium in Bipolar Depression
van der Loos, M. L. M., Mulder, P. G. H., Hartong, E. G. T. M., Blom, M. B. J., Vergouwen, A. C. M., de Keyzer, H. J. U. E. M., Notten, P., Luteijn, M. L., Timmermans, M. A. Y., Vieta, E., et al. (2008) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.08m04152 · Cited by 243 · see citing works
Graphic representation of the life course of illness in patients with affective disorder
Post, R. M., Roy‐Byrne, P., & Uhde, T. W. (1988) · American Journal of Psychiatry · doi:10.1176/ajp.145.7.844 · Cited by 201 · see citing works
Perugi, G., Micheli, C., Akiskal, H. S., Madaro, D., Socci, C., Quilici, C., & Musetti, L. (2000) · Comprehensive Psychiatry · doi:10.1016/s0010-440x(00)90125-1 · Cited by 199 · see citing works
The Prospective Course of Rapid-Cycling Bipolar Disorder: Findings From the STEP-BD
Schneck, C. D., Miklowitz, D. J., Miyahara, S., Araga, M., Wisniewski, S. R., Gyulai, L., Allen, M. H., Thase, M. E., & Sachs, G. S. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2007.05081484 · Cited by 180 · see citing works
Rapid and Non-Rapid Cycling Bipolar Disorder: A Meta-Analysis of Clinical Studies
Kupka, R. W., Luckenbaugh, D. A., Post, R. M., Leverich, G. S., & Nolen, W. A. (2003) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v64n1213 · Cited by 168 · see citing works
Depressive Illness Burden Associated With Complex Polypharmacy in Patients With Bipolar Disorder
Goldberg, J. F., Brooks, J. O., Kurita, K., Hoblyn, J. C., Ghaemi, S. N., Perlis, R. H., Miklowitz, D. J., Ketter, T. A., Sachs, G. S., & Thase, M. E. (2009) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.08m04301 · Cited by 144 · see citing works
Spectrum of Efficacy of Valproate in 78 Rapid-Cycling Bipolar Patients
Calabrese, J. R., Markovitz, P. J., Kimmel, S. E., & Wagner, S. (1992) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-199202001-00008 · Cited by 144 · see citing works
Self-citationThe BALANCE investigators and collaborators, Geddes, J. R., Goodwin, G. M., Rendell, J., Jm, A., Cipriani, A., Ostacher, M. J., Morriss, R. K., Alder, N. C., & Juszczak, E. (2011) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/foc.9.4.foc488 · Cited by 134 · see citing works
Bipolar rapid cycling: focus on depression as its hallmark.
Calabrese, J. R., Shelton, M. D., Bowden, C. L., RAPPORT, D. J., Suppes, T. M., Shirley, E. R., Kimmel, S. E., & Caban, S. (2001) · PubMed · Cited by 133 · see citing works
Self-citationPsychotropic drug prescription patterns among patients with bipolar I disorder
Levine, J., Chengappa, K. R., Brar, J. S., Gershon, S., Yablonsky, E. J., Stapf, D. M., & Kupfer, D. J. (2000) · Bipolar Disorders · doi:10.1034/j.1399-5618.2000.020205.x · Cited by 112 · see citing works
Kemp, D. E., Gao, K., Ganocy, S. J., Elhaj, O., Bilali, S. R., Conroy, C., Findling, R. L., & Calabrese, J. R. (2009) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.07m04022 · Cited by 103 · see citing works
Self-citationKeitner, G. I., Posternak, M. A., & Ryan, C. E. (2003) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v64n0915 · Cited by 53 · see citing works
Azorin, J., Kaladjian, A., Adida, M., Hantouche, E. G., Hameg, A., Lancrenon, S., & Akiskal, H. S. (2008) · CNS Spectrums · doi:10.1017/s1092852900013900 · Cited by 52 · see citing works
van der Loos, M. L. M., Mulder, P. G. H., Hartong, E. G. T. M., Blom, M. B. J., Vergouwen, A. C. M., van Noorden, M. S., Timmermans, M. A. Y., Vieta, E., Nolen, W. A., & for the LamLit Study Group (2010) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.2009.01537.x · Cited by 41 · see citing works
Langosch, J. M., Drieling, T., Biedermann, N. C., Born, C., Sasse, J., Bauer, H., Walden, J., Bauer, M., & Grunze, H. (2008) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e318185e75f · Cited by 39 · see citing works
Wang, Z., Gao, K., Kemp, D. E., Chan, P. K., Serrano, M. B., Conroy, C. M., Fang, Y., Ganocy, S. J., Findling, R. L., & Calabrese, J. R. (2010) · PubMed · Cited by 34 · see citing works
Self-citationEffectiveness of quetiapine in rapid cycling bipolar disorder: A preliminary study
Goldberg, J. F., Kelley, M. E., Rosenquist, K. J., Hsu, D. J., Filkowski, M. M., & Ghaemi, S. N. (2007) · Journal of Affective Disorders · doi:10.1016/j.jad.2007.04.023 · Cited by 27 · see citing works
Enhancing clinical trial design of interventions for posttraumatic stress disorder
Leon, A. C., & Davis, L. L. (2009) · Journal of Traumatic Stress · doi:10.1002/jts.20466 · Cited by 26 · see citing works
How real are patients in placebo-controlled studies of acute manic episode?
Storosum, J. G., Fouwels, A., Wied, C. C. G., Wohlfarth, T. D., van Zwieten, B. J., & van den Brink, W. (2003) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2003.10.003 · Cited by 19 · see citing works
Bipolar depression: trial-based insights to guide patient care
Kemp, D. E., Muzina, D. J., Mclntyre, R. S., & Calabrese, J. R. (2008) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2008.10.2/dekemp · Cited by 13 · see citing works
Self-citation
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Research works printed but not linked: 1
- [22]First MB Spitzer RL Gibbon M Structured clinical interview for DSM-IV axis I disorder-patient edition (SCID-I/P, Version 2.0, 4/97 revision) New York New York State Psychiatric Institute 1997
Cited by
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Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., Sharma, V., Goldstein, B. I., Rej, S., Beaulieu, S., et al. (2018) · Bipolar Disorders · doi:10.1111/bdi.12609 · Cited by 1,852 · see citing works
“Other RCTs have shown that divalproex is as effective as lithium (221) in preventing relapse of mood episodes.”
BackgroundSelf-citation
- Authors
- Kemp, D. E., Gao, K., Fein, E. B., Chan, P. K., Conroy, C., Obral, S., Ganocy, S. J., & Calabrese, J. R.
- Affiliations
- University Hospitals Cleveland Medical Center (US)
- Corresponding author
- Kemp, David E
- Venue
- Bipolar Disorders
- Publisher
- Wiley
- Published
- 2012-10-29
- Volume
- 14
- Issue
- 7
- Pages
- 780-789
- ISSN
- 1398-5647 (ISSN-L)
- 1399-5618
- PMC
- PMC3640341
- OpenAlex
- W2128560634
- Cited by
- 39
- References
- 43
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 5 · 2021: 3 · 2019: 7 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 2 · 2012: 1
- FWCI
- 1.82
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Bipolar Disorders (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Sanofi
- Stanley Medical Research Institute
- Case Western Reserve University
- National Institutes of Health (5kl2rr024990-05)
- National Institute of Mental Health (R21MH-62650, R21MH062650)
- National Center for Research Resources (KL2-RR-024990, 1KL2 RR024990)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Clinical Psychology › Personality Disorders and Psychopathology
- Keywords
- lamotrigine, rapid cycling bipolar disorder, bipolar depression, adjunctive therapy, lithium, divalproex, treatment-resistant depression, drug tolerability, treatment discontinuation, bimodal response, Montgomery-Asberg Depression Rating Scale, mixed states
- MeSH terms
- Lamotrigine, Adolescent, Adult, Aged, Bipolar Disorder, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Retrospective Studies, Triazines, Valproic Acid, Lithium Chloride, Antimanic Agents, Young Adult
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