Combination Therapy for Manic Phases: A Critical Review of a Common Practice
Open accessAbstract
Summary: All relevant guidelines recommend monotherapy as the initial treatment for manic phases of bipolar disorder (BD), with combination therapy reserved for severe cases or as a subsequent choice. However, in routine practice, monotherapy is often not sufficiently effective for acute and/or maintenance therapy. As a consequence, most patients are given combination therapies. An extensive search concerning combination treatment for manic episodes was conducted for relevant international randomized controlled studies, treatment guidelines and comprehensive reviews published since 1980. The scientific literature is sufficiently rich to validate the superiority of combination therapy over monotherapy in the manic phase in terms of efficacy and prevention of relapse; its safety profile is acceptable. Side effects are more frequent with combination therapy as a whole than with monotherapy, and discontinuation rates due to adverse events are higher. Continued administration of antipsychotics after a manic phase is controversial: drug classification, the course of the disease and the predominant polarity should all be considered before treatment is continued. Combinations including olanzapine and asenapine and to a lesser extent risperidone are associated with weight gain, those including quetiapine, haloperidol and asenapine with sedation, and those including aripiprazole with akathisia. This review of literature leads us to suggest that combination therapy including an atypical antipsychotic with lithium or valproate may be considered as a first‐line approach. An appropriate algorithm for making decisions about combination treatment needs to be developed and included in future guidelines.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
On average about 20% more patients will respond to combination therapy than to mood stabilizer monotherapy.
“clinical trials suggest that on average about 20% more patients will respond to combination therapy.142, 145, 146”
From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [146]
The Clinical Trials section reports that several antipsychotic–mood stabilizer combinations were more effective against acute mania than mood stabilizer monotherapy. It does not report that, on average, about 20% more patients responded, so the numerical part of the claim is unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Davis, H. S. (1966) · JAMA · doi:10.1001/jama.1966.03100200106038 · Cited by 1,719 · see citing works
Goodwin, G., Haddad, P. M., Ferrier, I. N., Aronson, J., Barnes, T., Cipriani, A., Coghill, D., Fazel, S., Geddes, J. R., Grunze, H., et al. (2016) · Journal of Psychopharmacology · doi:10.1177/0269881116636545 · Cited by 1,314 · see citing works
Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Beaulieu, S., Alda, M., O’Donovan, C., MacQUEEN, G. M., McIntyre, R. S., Sharma, V., et al. (2012) · Bipolar Disorders · doi:10.1111/bdi.12025 · Cited by 1,209 · see citing works
Extending Indications for Long-Term Pharmacotherapy: Opportunities and Challenges
Kane, J. M. (2002) · American Journal of Psychiatry · doi:10.1176/appi.ajp.159.1.1 · Cited by 989 · see citing works
Cipriani, A., Barbui, C., Salanti, G., Rendell, J., Brown, R., Stockton, S., Purgato, M., Spineli, L. M., Goodwin, G. M., & Geddes, J. R. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60873-8 · Cited by 637 · see citing works
Practice Guideline for the Treatment of Patients With Bipolar Disorder (Revision)
Hirschfeld, R. M. A., Bowden, C. L., Gitlin, M. J., Keck, P. E., Perlis, R. H., Suppes, T. M., Thase, M. E., & Wagner, K. D. (2003) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/foc.1.1.64 · Cited by 586 · see citing works
Yatham, L. N., Kennedy, S. H., Schaffer, A., Parikh, S. V., Beaulieu, S., O’Donovan, C., MacQUEEN, G. M., McIntyre, R. S., Sharma, V., Ravindran, A. V., et al. (2009) · Bipolar Disorders · doi:10.1111/j.1399-5618.2009.00672.x · Cited by 559 · see citing works
Tohen, M. F., Chengappa, K. N. R., Suppes, T. M., Zarate, C. A., Calabrese, J. R., Bowden, C. L., Sachs, G. S., Kupfer, D. J., Baker, R. W., Risser, R. C., et al. (2002) · Archives of General Psychiatry · doi:10.1001/archpsyc.59.1.62 · Cited by 464 · see citing works
Goodwin, G. M. (2009) · Journal of Psychopharmacology · doi:10.1177/0269881109102919 · Cited by 443 · see citing works
DelBello, M. P., Schwiers, M., ROSENBERG, H. L., & Strakowski, S. M. (2002) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-200210000-00011 · Cited by 436 · see citing works
Sachs, G. S., Grossman, F., Ghaemi, S. N., Okamoto, A., & Bowden, C. L. (2002) · American Journal of Psychiatry · doi:10.1176/appi.ajp.159.7.1146 · Cited by 424 · see citing works
Grunze, H., Vieta, E., Goodwin, G. M., Bowden, C. L., Licht, R. W., Möller, H., Kasper, S. F., & WFSBP Task Force on Treatment Guide (2009) · The World Journal of Biological Psychiatry · doi:10.1080/15622970902823202 · Cited by 344 · see citing works
Tohen, M. F., Chengappa, K. N. R., Suppes, T. M., Baker, R. W., Zarate, C. A., Bowden, C. L., Sachs, G. S., Kupfer, D. J., Ghaemi, S. N., Feldman, P. D., et al. (2004) · The British Journal of Psychiatry · doi:10.1192/bjp.184.4.337 · Cited by 326 · see citing works
Gabapentin in bipolar disorder: a placebo‐controlled trial of adjunctive therapy1
Pande, A. C., Crockatt, J. G., Janney, C. A., Werth, J. L., Tsaroucha, G., & Gabapentin Bipolar Disorder Study Group (2000) · Bipolar Disorders · doi:10.1034/j.1399-5618.2000.20305.x · Cited by 315 · see citing works
The Increasing Use of Polypharmacotherapy for Refractory Mood Disorders
Frye, M. A., Ketter, T. A., Leverich, G. S., Huggins, T., Lantz, C., Denicoff, K. D., & Post, R. M. (2000) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v61n0104 · Cited by 315 · see citing works
Practice guideline for the treatment of patients with bipolar disorder (revision).
(2002) · PubMed · Cited by 276 · see citing works
Smith, L. A., Cornelius, V. R., Warnock, A., Tacchi, M. J., & Taylor, D. M. (2007) · Bipolar Disorders · doi:10.1111/j.1399-5618.2007.00468.x · Cited by 269 · see citing works
Sachs, G. S., Chengappa, K. R., Suppes, T. M., Mullen, J., Brecher, M., Devine, N. A., & Sweitzer, D. E. (2004) · Bipolar Disorders · doi:10.1111/j.1399-5618.2004.00115.x · Cited by 260 · see citing works
Yatham, L. N., Grossman, F., Augustyns, I., Vieta, E., & Ravindran, A. (2003) · British Journal of Psychiatry · doi:10.1192/bjp.182.2.141 · Cited by 248 · see citing works
Suppes, T., Vieta, E., Liu, S., Brecher, M., Paulsson, B., & Trial 127 Investigators (2009) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2008.08020189 · Cited by 230 · see citing works
Vieta, E., Suppes, T., Eggens, I., Persson, I., Paulsson, B., & Brecher, M. (2008) · Journal of Affective Disorders · doi:10.1016/j.jad.2008.06.001 · Cited by 227 · see citing works
Smith, L. A., Cornelius, V. R., Warnock, A., Bell, A. J., & Young, A. H. (2007) · Bipolar Disorders · doi:10.1111/j.1399-5618.2007.00490.x · Cited by 186 · see citing works
Müller-Oerlinghausen, B., Retzow, A., Henn, F. A., Giedke, H., & Walden, J. (2000) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-200004000-00012 · Cited by 169 · see citing works
Anticonvulsants in affective disorders
Emrich, H. M., 大熊, 輝., & Müller, A. A. (1984) · Excerpta Medica eBooks · Cited by 165 · see citing works
Vieta, E., T'joen, C., McQuade, R. D., Carson, W. H., Marcus, R. N., Sanchez, R., Owen, R., & Nameche, L. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2008.07101560 · Cited by 160 · see citing works
Carbamazepine and Haloperidol v Placebo and Haloperidol in Excited Psychoses
Klein, E. (1984) · Archives of General Psychiatry · doi:10.1001/archpsyc.1984.01790130061009 · Cited by 150 · see citing works
Bowden, C. L., Vieta, E., Ice, K. S., Schwartz, J. H., Wang, P. P., & Versavel, M. (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.09m05482yel · Cited by 144 · see citing works
Zarate, C. A., & Tohen, M. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.161.1.169 · Cited by 144 · see citing works
The 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
Marcus, R. N., Khan, A., Rollin, L., Morris, B. A., Timko, K., Carson, W. H., & Sanchez, R. (2011) · Bipolar Disorders · doi:10.1111/j.1399-5618.2011.00898.x · Cited by 131 · see citing works
Clinical practice recommendations for bipolar disorder
Malhi, G. S., Adams, D., Lampe, L. A., Paton, M. B., O’Connor, N., Newton, L., Walter, G., Taylor, A., Porter, R., Mulder, R., et al. (2009) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.2009.01383.x · Cited by 125 · see citing works
Brown, E. S., Jeffress, J., Liggin, J. D. M., Garza, M., & Beard, L. (2005) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v66n0613 · Cited by 118 · see citing works
A comparison of haloperidol, lithium carbonate and their combination in the treatment of mania
Garfinkel, P. E., Stancer, H. C., & Persad, E. (1980) · Journal of Affective Disorders · doi:10.1016/0165-0327(80)90029-4 · Cited by 111 · see citing works
Vieta, E., Günther, O., Locklear, J. C., Ekman, M., Miltenburger, C., Chatterton, M. L., Åström, M., & Paulsson, B. (2011) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711000885 · Cited by 106 · see citing works
Anticonvulsants in affective disorders.
Small, J. G. (1990) · PubMed · Cited by 104 · see citing works
New treatment guidelines for acute bipolar mania: A critical review
Nivoli, A., Murru, A., Goikolea, J. M., Crespo, J. M., Montes, J. M. G., González-Pinto, A. M., García‐Portilla, M. P., Bobes, J., Sáiz-Ruiz, J., & Vieta, E. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.10.015 · Cited by 101 · see citing works
Amrollahi, Z., Rezaei, F., Salehi, B., Modabbernia, A., Maroufi, A., Esfandiari, G.-R., Naderi, M., Ghebleh, F., Abhari, S. A. A., Sadeghi, M., et al. (2010) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.08.015 · Cited by 92 · see citing works
Berwaerts, J., Lane, R., Nuamah, I. F., Lim, P., Remmerie, B. M. M., & Hough, D. W. (2010) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.09.011 · Cited by 92 · see citing works
Vieta, E., Cruz, N., García‐Campayo, J., de Arce, R., Crespo, J. M., Vallès, V., Pérez‐Blanco, J., Roca, E., Olivares, J. M., Moríñigo, Á., et al. (2008) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145708008596 · Cited by 89 · see citing works
Asenapine as Adjunctive Treatment for Acute Mania Associated With Bipolar Disorder
Szegedi, A., Calabrese, J. R., Стет, Л., Mackle, M., Zhao, J., & Panagides, J. (2011) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e31823f872f · Cited by 89 · see citing works
Functional Impairment in Patients with Remitted Bipolar Disorder
Rosa, A. R., Franco, C., nez-Aran, A. M. I., Sánchez‐Moreno, J., Reinares, M., Salamero, M., Arango, C., Ayuso‐Mateos, J. L., Kapczinski, F. P., & Vieta, E. (2008) · Psychotherapy and Psychosomatics · doi:10.1159/000151520 · Cited by 87 · see citing works
Olanzapine plus carbamazepinev.carbamazepine alone in treating manic episodes
Tohen, M. F., Bowden, C. L., Ab, S., Bergstrom, R. F., Quinlan, T., Osuntokun, O. O., Wang, W. V., Oliff, H. S., Martényi, F., Kryzhanovskaya, L. A., et al. (2008) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.107.041301 · Cited by 75 · see citing works
Yatham, L. N., Vieta, E., Young, A. H., Möller, H., Paulsson, B., & Vågerö, M. (2007) · International Clinical Psychopharmacology · doi:10.1097/yic.0b013e328080ca57 · Cited by 73 · see citing works
Haro, J. M., Reed, C. C., González-Pinto, A. M., Novick, D., Bertsch, J., & Vieta, E. (2010) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2010.08.001 · Cited by 71 · see citing works
Pharmacological treatment of acute mania in psychiatric in-patients between 1994 and 2004
Wolfsperger, M., Greil, W., Wulf Rössler, A., & Grohmann, R. (2006) · Journal of Affective Disorders · doi:10.1016/j.jad.2006.08.017 · Cited by 70 · see citing works
Lim, P. Z., Tunis, S. L., Edell, W. S., Jensik, S. E., & Tohen, M. F. (2001) · Bipolar Disorders · doi:10.1034/j.1399-5618.2001.30401.x · Cited by 69 · see citing works
Altamura, A. C., Mundo, E., Dell’Osso, B. M., Tacchini, G., Buoli, M., & Calabrese, J. R. (2008) · Journal of Affective Disorders · doi:10.1016/j.jad.2008.01.017 · Cited by 68 · see citing works
Juruena, M. F., Ottoni, G. L., Machado‐Vieira, R., Carneiro, R. M., Weingarthner, N., Marquardt, A. R., Fleig, S. S., Broilo, L., & Busnello, E. A. (2008) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2008.10.012 · Cited by 65 · see citing works
Carlson, B. X., Ketter, T. A., Sun, W., Timko, K., McQuade, R. D., Sanchez, R., Vester‐Blokland, E., & Marcus, R. (2012) · Bipolar Disorders · doi:10.1111/j.1399-5618.2011.00974.x · Cited by 63 · see citing works
Vieta, E., Owen, R., Baudelet, C., McQuade, R. D., Sanchez, R., & Marcus, R. N. (2010) · Current Medical Research and Opinion · doi:10.1185/03007991003779380 · Cited by 53 · see citing works
Use of antipsychotic drugs and lithium in mania
Cookson, J. (2001) · The British Journal of Psychiatry · doi:10.1192/bjp.178.41.s148 · Cited by 53 · see citing works
(2008) · PubMed · Cited by 47 · see citing works
Doubleblind evaluation of the antimanic properties of carbamazepine as a comedication to haloperidol
Möller, H., Kissling, W., Riehl, T., Bäuml, J., Binz, L., & Wendt, G. (1989) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/0278-5846(89)90009-2 · Cited by 43 · see citing works
Woo, Y. S., Bahk, W., Chung, M. Y., Kim, D., Yoon, B.-H., Lee, J. H., Ahn, Y. M., Chung, S., Kim, J., Lee, K. H., et al. (2011) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.1240 · Cited by 38 · see citing works
Quetiapine in the treatment of acute bipolar mania: Efficacy across a broad range of symptoms
McIntyre, R. S., Konarski, J. Z., Jones, M., & Paulsson, B. (2007) · Journal of Affective Disorders · doi:10.1016/j.jad.2007.02.007 · Cited by 33 · see citing works
Brooks, J. O., Goldberg, J. F., Ketter, T. A., et al. (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.09m05214yel · Cited by 33 · see citing works
Kozicky, J.-M., Torres, I. J., Bond, D. J., Lam, R. W. M., & Yatham, L. N. (2011) · International Clinical Psychopharmacology · doi:10.1097/yic.0b013e32834e3bea · Cited by 28 · see citing works
Sussman, N., Mullen, J., Paulsson, B., & Vågerö, M. (2007) · Journal of Affective Disorders · doi:10.1016/j.jad.2007.02.008 · Cited by 27 · see citing works
Ouyang, W., Hsu, M., Yeh, I.-N., & Kuo, C.-C. (2012) · International Journal of Psychiatry in Clinical Practice · doi:10.3109/13651501.2011.644564 · Cited by 13 · see citing works
Should antipsychotics take pole position in mania treatment?
Berk, M., & Malhi, G. S. (2011) · The Lancet · doi:10.1016/s0140-6736(11)61060-x · Cited by 11 · see citing works
Ketter, T. A. (2009) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.7128br4c.e42 · Cited by 9 · see citing works
Efficacy of Aripiprazole in Comorbid Addiction in Bipolar Disorder
Geoffroy, P. A., Goddefroy, G., Rolland, B., & Cottencin, O. (2012) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2012.00301.x · Cited by 8 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 4
- [16]16. Desai NG, Gangadhar BN, Channabasavanna SM, Shetty KT. Carbamazepine hastens therapeutic action of lithium in mania. Proceedings International Conference on New Directions in Affective Disorders. Jerusalem, Israel, 1987:97.
- [18]18. Anand A, Oren DA, Berman RM, Cappiello A, Charney DS. Lamotrigine treatment of lithium failure outpatient mania: a double-blind, placebo-controlled trial. In: Scares JC, Gershon S, editors. Abstract Book on 3rd International Conference on Bipolar disorder. Pittsburgh, PA. Copenhagen: Munksgaard, 1999; 23
- [28]28. P.A. Geoffroy et al. Combination Therapy for Manic Phases 17555949, 2012, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cns.12017 by Mount Vernon Nazarene University, Wiley Online Library on [31/08/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
- [56]56. Geoffroy PA, Etain B, Scott J, et al. Clinical characteristics, biomarkers and therapeutic relevance of early-onset bipolar disorder. J Physiol Paris 2012; In press.
Cited by
Sorted by citations
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
“In general, combination therapy is preferred to mood stabilizer monotherapy because clinical trials suggest that on average about 20% more patients will respond to combination therapy (143, 146, 147).”
BackgroundMalhi, G. S., Bassett, D., Boyce, P., Bryant, R., Fitzgerald, P. B., Fritz, K., Hopwood, M., Lyndon, B., Mulder, R., Murray, G., et al. (2015) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867415617657 · Cited by 842 · see citing works
“However, although efficacy is greater with combination therapy, discontinuation rates are also higher because of adverse effects (De Bartolomeis and Perugi, 2012; Geoffroy et al., 2012; Yatham et al., 2013a).”
BackgroundBourin, M. S., Severus, E., Schronen, J. P., Gass, P., Szamosi, J., Eriksson, H., & Chandrashekar, H. (2014) · International Journal of Bipolar Disorders · doi:10.1186/s40345-014-0014-9 · Cited by 40 · see citing works
- Authors
- Geoffroy, P. A., Etain, B., Henry, C., & Bellivier, F.
- Affiliations
- Inserm (FR)
- Inserm U955 Créteil France
- Corresponding author
- Geoffroy, Pierre Alexis
- Venue
- CNS Neuroscience & Therapeutics
- Publisher
- Wiley
- Published
- 2012-10-25
- Volume
- 18
- Issue
- 12
- Pages
- 957-964
- ISSN
- 1755-5930 (ISSN-L)
- 1755-5949
- PMC
- PMC6493634
- OpenAlex
- W2158514341
- Cited by
- 47
- References
- 63
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 3 · 2016: 5 · 2015: 6 · 2014: 10 · 2013: 4
- FWCI
- 0.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- CNS Neuroscience & Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- AstraZeneca
- Sanofi
- Assistance publique-Hôpitaux de Paris
- Servier
- H. Lundbeck A/S
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- bipolar disorder, manic episodes, combination therapy, monotherapy, atypical antipsychotics, lithium, valproic acid, olanzapine, asenapine, quetiapine, haloperidol, aripiprazole, weight gain, sedation, akathisia, relapse prevention, treatment algorithm
- MeSH terms
- Bipolar Disorder, Drug Therapy, Combination, Humans, Antipsychotic Agents, Valproic Acid, Lithium Chloride, Antimanic Agents
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
