An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression
Open accessAbstract
OBJECTIVE: The authors evaluated the efficacy, safety, and tolerability of cariprazine, an atypical antipsychotic candidate, in adult patients with acute bipolar I depression. METHOD: This was an 8-week multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study in adult patients with bipolar I disorder experiencing a current major depressive episode. Patients were randomly assigned (1:1:1:1) to receive placebo or cariprazine at 0.75, 1.5, or 3.0 mg/day. The primary and secondary efficacy parameters were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions severity subscale (CGI-S), respectively, analyzed using a mixed-effects model for repeated measures on the modified intent-to-treat population. RESULTS: The intent-to-treat population comprised 571 patients (141 in the placebo group and 140, 145, and 145 in the cariprazine 0.75-, 1.5-, and 3.0-mg/day groups). Cariprazine at 1.5 mg/day showed significantly greater improvement on MADRS total score change from baseline to week 6 compared with placebo; the least squares mean difference was -4.0 (95% CI=-6.3, -1.6; significant after adjustment for multiple comparisons). Cariprazine at 3.0 mg/day showed greater MADRS score reduction than placebo (-2.5, 95% CI=-4.9, -0.1; not significant when adjusted for multiple comparisons). The 0.75 mg/day dosage was similar to placebo. A similar pattern for significance was observed on the CGI-S (1.5 mg/day: least squares mean difference=-0.4, 95% CI=-0.6, -0.1; 3.0 mg/day: -0.3, 95% CI=-0.5, -0.0). The most common adverse events (≥10%) in cariprazine-treated patients were akathisia and insomnia; weight gain was slightly higher with cariprazine than with placebo. CONCLUSIONS: Cariprazine at 1.5 mg/day demonstrated consistent efficacy compared with placebo across outcomes and was generally well tolerated, suggesting efficacy for the treatment of bipolar I depression.
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Cariprazine currently has evidence for efficacy in acute manic and depressive episodes but not yet for maintenance treatment.
“We do not provide specific recommendations for the use of cariprazine, as there is currently only evidence for efficacy in acute manic and depressive episodes262, 392 and not yet for maintenance treatment (level 4).”
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 [262]
The Efficacy Outcomes section reports significant improvement in bipolar I depression with cariprazine 1.5 mg/day versus placebo at week 6; the introduction also reports evidence from trials in manic or mixed states. This was an eight-week study and did not assess maintenance treatment, so it cannot establish the broader claim that maintenance efficacy evidence did not yet exist. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCariprazine has demonstrated efficacy for acute bipolar depression through a large RCT and a pooled analysis of a failed RCT and a positive RCT.
“Additional second‐line options include cariprazine, with efficacy demonstrated through a large RCT262 and a pooled analysis of a failed RCT and a positive RCT263 (level 2), although there is less clinical experience supporting its use.”
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Cites
Hamilton, M. (1960) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.23.1.56 · Cited by 32,817 · 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
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
Posner, K., Brown, G. K., Stanley, B., Brent, D. A., Yershova, K. V., Oquendo, M. A., Currier, G. W., Melvin, G. A., Greenhill, L., Shen, S., et al. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.10111704 · Cited by 5,157 · see citing works
A RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS
Simpson, G. M., B., M., B., G., Angus, J. W. S., P., F. R. C., & M., D. P. (1970) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.1970.tb02066.x · Cited by 3,265 · see citing works
A Rating Scale for Drug-Induced Akathisia
Barnes, T. R. E. (1989) · The British Journal of Psychiatry · doi:10.1192/bjp.154.5.672 · Cited by 2,179 · see citing works
ECDEU Assessment Manual: (591322011-001)
Guy, W. (1976) · PsycEXTRA Dataset · doi:10.1037/e591322011-001 · Cited by 1,896 · see citing works
Depression, Stress, and Anhedonia: Toward a Synthesis and Integrated Model
Pizzagalli, D. A. (2014) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-050212-185606 · Cited by 1,155 · see citing works
Tohen, 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-citationPacchiarotti, I., Bond, D. J., Baldessarini, R. J., Nolen, W. A., Grunze, H., Licht, R. W., Post, R. M., Berk, M., Goodwin, G. M., Sachs, G. S., et al. (2013) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2013.13020185 · Cited by 770 · 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-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
Kiss, B., Horváth, A., Némethy, Z., Schmidt, E. M., Laszlovszky, I., Bugovics, G., Fazekas, K., Hornok, K., Orosz, S., Gyertyán, I., et al. (2010) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.160432 · Cited by 368 · see citing works
Self-citationLoebel, A. D., Cucchiaro, J. B., Silva, R., Kroger, H., Hsu, J., Sarma, K., & Sachs, G. S. (2013) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2013.13070984 · Cited by 340 · 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
Thase, M. E., Jonas, A., Khan, A., Bowden, C. L., Wu, X., McQuade, R. D., Carson, W. H., Marcus, R. N., & Owen, R. (2008) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e3181618eb4 · Cited by 251 · see citing works
Rendleman, R. L., & Walkup, J. T. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4377-0435-8.00049-4 · Cited by 197 · see citing works
Selective Activation of Postsynaptic 5-HT1A Receptors Induces Rapid Antidepressant Response
Blier, P. U. (1997) · Neuropsychopharmacology · doi:10.1016/s0893-133x(96)00242-4 · Cited by 184 · see citing works
Suppes, T. M., Datto, C. J., Minkwitz, M. C., Nordenhem, A., Walker, C., & Darko, D. F. (2009) · Journal of Affective Disorders · doi:10.1016/j.jad.2009.10.007 · Cited by 170 · see citing works
Correll, C. U., Frederickson, A. M., Kane, J. M., & Manu, P. (2008) · Bipolar Disorders · doi:10.1111/j.1399-5618.2008.00625.x · Cited by 158 · see citing works
Bipolar Depression: Overview and Commentary
Baldessarini, R. J., Vieta, E., Calabrese, J. R., Tohen, M. F., & Bowden, C. L. (2010) · Harvard Review of Psychiatry · doi:10.3109/10673221003747955 · Cited by 156 · see citing works
Self-citationGyertyán, I., Kiss, B., Sághy, K., Laszy, J., Szabó, G., Szabados, T., Gémesi, L. I., Pásztor, G., Zájer-Balázs, M., Kapás, M., et al. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.07.002 · Cited by 150 · see citing works
Dopamine D3 receptor as a new pharmacological target for the treatment of depression
Leggio, G. M., Salomone, S., Bucolo, C., Platania, C. B. M., Micale, V., Caraci, F., & Drago, F. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.07.022 · Cited by 144 · see citing works
Durgam, S., Starace, A., Li, D., Migliore, R., Ruth, A., Németh, G., & Laszlovszky, I. (2014) · Bipolar Disorders · doi:10.1111/bdi.12238 · Cited by 130 · see citing works
Self-citationMorbidity in 303 first‐episode bipolar I disorder patients
Baldessarini, R. J., Salvatore, P., Khalsa, H.-M. K., Gebre‐Medhin, P., Imaz, H., González-Pinto, A. M., Pérez, J., Cruz, N., Maggini, C., & Tohen, M. F. (2010) · Bipolar Disorders · doi:10.1111/j.1399-5618.2010.00812.x · Cited by 127 · see citing works
Sachs, G. S., Greenberg, W. M., Starace, A., Lu, K., Ruth, A., Laszlovszky, I., Németh, G., & Durgam, S. (2015) · Journal of Affective Disorders · doi:10.1016/j.jad.2014.11.018 · Cited by 127 · see citing works
Self-citationTohen, M. F., McDonnell, D., Case, M. G., Kanba, S., Ha, K., Fang, Y., Katagiri, H., & Gomez, J.-C. (2012) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.112.108357 · Cited by 127 · see citing works
Calabrese, J. R., Keck, P. E., Starace, A., Lu, K., Ruth, A., Laszlovszky, I., Németh, G., & Durgam, S. (2014) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.14m09081 · Cited by 122 · see citing works
Self-citationCruz, N., Sanchez-Moreno, J., Torres, F., Goikolea, J. M., Valentí, M., & Vieta, E. (2010) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145709990344 · Cited by 121 · see citing works
Self-citationModerate and severe depression
Müller, M. J., Szegedi, A., Wetzel, H., & Benkert, O. (2000) · Journal of Affective Disorders · doi:10.1016/s0165-0327(99)00162-7 · Cited by 116 · see citing works
Pattern-mixture models with proper time dependence
Kenward, M. G. (2003) · Biometrika · doi:10.1093/biomet/90.1.53 · Cited by 110 · see citing works
Dopamine receptor D3 deficiency results in chronic depression and anxiety
Moraga‐Amaro, R., Gonzalez, H., Pacheco, R., & Stehberg, J. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.055 · Cited by 106 · see citing works
The Effect of Antipsychotics on the High-Affinity State of D2 and D3 Receptors
Graff‐Guerrero, A., Mamo, D. C., Shammi, C., Mizrahi, R., Marcon, H., Barsoum, P., Rusjan, P., Houle, S., Wilson, A. A., & Kapur, S. (2009) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2009.43 · Cited by 100 · see citing works
Fruyt, J. D., Deschepper, E., Audenaert, K., Constant, E., Floris, M., Pitchot, W., Sienaert, P. A., Souery, D., & Claes, S. J. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881111408461 · Cited by 94 · see citing works
Bech, P., Tanghøj, P., Andersen, H. F., & Overø, K. F. (2002) · Psychopharmacology · doi:10.1007/s00213-002-1147-6 · Cited by 91 · see citing works
Mizrahi, R., Agid, O., Borlido, C., Suridjan, I., Rusjan, P., Houle, S., Remington, G. J., Wilson, A. A., & Kapur, S. (2011) · Schizophrenia Research · doi:10.1016/j.schres.2011.05.005 · Cited by 81 · see citing works
Attenuation of anhedonia by cariprazine in the chronic mild stress model of depression
Papp, M., Gruca, P., Łasoń, M., Adham, N., Kiss, B., & Gyertyán, I. (2014) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000070 · Cited by 80 · see citing works
Lombardo, I., Sachs, G. S., Kolluri, S., Kremer, C. M. E., & Yang, R. (2012) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e31825ccde5 · Cited by 73 · see citing works
The application of enhanced parallel gatekeeping strategies
Chen, X., Luo, X., & Capizzi, T. (2004) · Statistics in Medicine · doi:10.1002/sim.2005 · Cited by 47 · see citing works
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Research works printed but not linked: 1
- Ahuja S, Bose A, Lu K, et al: A multicenter, randomized, double- blind trial to evaluate the effect of cariprazine in bipolar depression. Poster presented at the Autumn Conference of the International Society for CNS Clinical Trials and Methodology, Amelia Island, Fla, Oct 3-4, 2011
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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
Self-citationMalhi, G. S., Bell, E., Bassett, D., Boyce, P., Bryant, R., Hazell, P., Hopwood, M., Lyndon, B., Mulder, R., Porter, R., et al. (2021) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867420979353 · Cited by 614 · see citing works
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Barton, B. B., Segger, F., Fischer, K., Obermeier, M., & Musil, R. (2020) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2020.1713091 · Cited by 216 · see citing works
Grunze, H., Vieta, E., Goodwin, G. M., Bowden, C., Licht, R. W., Azorin, J.-M., Yatham, L., Mosolov, S., Möller, H.-J., Kasper, S., et al. (2018) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2017.1384850 · Cited by 187 · see citing works
Self-citationMcGirr, A., Vöhringer, P. A., Ghaemi, S. N., Lam, R. W., & Yatham, L. N. (2016) · The Lancet Psychiatry · doi:10.1016/s2215-0366(16)30264-4 · Cited by 149 · see citing works
Self-citationBahji, A., Ermacora, D., Stephenson, C., Hawken, E. R., & Vazquez, G. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.03.030 · Cited by 139 · see citing works
Kadakia, A., Dembek, C., Heller, V., Singh, R., Uyei, J., Hagi, K., Nosaka, T., & Loebel, A. (2021) · BMC Psychiatry · doi:10.1186/s12888-021-03220-3 · Cited by 79 · see citing works
Papp, M., Gruca, P., Lason-Tyburkiewicz, M., Litwa, E., Niemczyk, M., Tota-Glowczyk, K., & Willner, P. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4651-4 · Cited by 40 · see citing works
Nunez, N. A., Singh, B., Romo‐Nava, F., Joseph, B., Veldic, M., Cuellar‐Barboza, A., Cabello Arreola, A., Vande Voort, J. L., Croarkin, P., Moore, K. M., et al. (2020) · Bipolar Disorders · doi:10.1111/bdi.12859 · Cited by 31 · see citing works
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- Authors
- Durgam, S., Earley, W., Lipschitz, A., Guo, H., Laszlovszky, I., Németh, G., Vieta, E., Calabrese, J. R., & Yatham, L. N.
- Affiliations
- University of British Columbia (CA)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2016-03-01
- Volume
- 173
- Issue
- 3
- Pages
- 271-281
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- OpenAlex
- W2135166041
- Cited by
- 209
- References
- 40
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 24 · 2023: 24 · 2022: 19 · 2021: 42 · 2020: 18 · 2019: 20 · 2018: 14 · 2017: 12 · 2016: 14
- FWCI
- 10.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- cariprazine, bipolar I depression, atypical antipsychotics, major depressive episode, antidepressant efficacy, drug safety and tolerability, akathisia, insomnia, weight gain, dose comparison, Montgomery-Asberg Depression Rating Scale, Clinical Global Impression Scale, mood stabilizers
- MeSH terms
- Adult, Bipolar Disorder, Depression, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Piperazines, Psychiatric Status Rating Scales, Antipsychotic Agents, Treatment Outcome, Drug Monitoring
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