Third-generation antipsychotic cariprazine as a promising drug for the treatment of depressive disorders
![](https://ctmd.psypharma.ru/public/journals/1/cover_issue_67_ru_RU.jpg)
Abstract
Cariprazine is currently approved for the treatment of patients with depressive and mixed episodes of Bipolar I disorder. Several randomized controlled trials have been carried to investigate its efficacy in patients with major depressive disorder. This review summarizes the potential benefits of Cariprazine for the treatment of major symptoms of Bipolar I disorder and major depressive disorder considering its pharmacodynamic properties, efficacy and tolerance. Its preferential affinity for the D3 receptor, with functional selectivity according to the predominant neural environment, contributes to its efficacy in a wide range of psychopathological symptoms (including mood disorder, anhedonia and cognitive impairment), high safety and good tolerance.
Keywords
cariprazine, unipolar depressive disorder, bipolar affective disorder, third-generation antipsychotics, pathogenesis
References
- Villanueva R. Neurobiology of major depressive disorder // Neural Plasticity. – 2013. – Vol. 2013. – Art. 873278. – https://doi.org/10.1155/2013/873278
- Mergl R. et al. Depressive, anxiety, and somatoform disorders in primary care: prevalence and recognition / /Depression and Anxiety. – 2007. – Vol. 24, no. 3. – Pp. 185–195. – https://doi.org/10.1002/da.20192
- Sheehan D.V. Establishing the real cost of depression // Managed Care (Langhorne, Pa.). – 2002. – Vol. 11, no. 8, suppl. – Pp. 7–25.
- Dean J., Keshavan M. The neurobiology of depression: An integrated view // Asian Journal of Psychiatry. – 2017. – Vol. 27. – Pp. 101–111. – https://doi.org/10.1016/j.ajp.2017.01.025
- Мосолов С.Н. Современные биологические гипотезы рекуррентной депрессии (обзор) // Журнал неврологии и психиатрии имени В.В. Корсакова. – 2012. – Т. 112, № 11-2. – С. 29–40.
- Алфимов Р.В., Костюкова Е.Г., Мосолов С.Н. Методы преодоления терапевтической резистентности при рекуррентных депрессиях // Биологические методы терапии психических расстройств. Доказательная медицина – клинической практике. – М.: Социальнополитическая мысль, 2012. – С. 438–473.
- Perez-Caballero L. et al. Monoaminergic system and depression // Cell and Tissue research. – 2019. – Vol. 377. – Pp. 107–113. – https://doi.org/10.1007/s00441-018-2978-8
- Lang U.E., Borgwardt S. Molecular mechanisms of depression: perspectives on new treatment strategies // Cellular Physiology and Biochemistry. – 2013. – Vol. 31, no. 6. – Pp. 761–777. – https://doi.org/10.1159/000350094
- Blier P., Blondeau C. Neurobiological bases and clinical aspects of the use of aripiprazole in treatment-resistant major depressive disorder // Journal of Affective Disorders. – 2011. – Vol. 128. – Pp. S3–S10. – https://doi.org/10.1016/S0165-0327(11)70003-9
- Horacek J. et al. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia // CNS Drugs. – 2006. – Vol. 20. – Pp. 389–409. – https://doi.org/10.2165/00023210-200620050-00004
- Carlsson A. Dopamine receptor agonists: intrinsic activity vs. state of receptor // Journal of Neural Transmission. – 1983. – Vol. 57. – Pp. 309–315. – https://doi.org/10.1007/BF01249001
- Keltner N.L., Johnson V. Aripiprazole: a third generation of antipsychotics begins? // Perspectives in Psychiatric Care. – 2002. – Vol. 38, no. 4. – Art. 157. – https://doi.org/10.1111/j.1744-6163.2002.tb01566.x
- Mailman R.B., Murthy V. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? // Current Pharmaceutical Design. – 2010. – Vol. 16, no. 5. – Pp. 488–501. – https://doi.org/10.2174/138161210790361461
- Rybakowski J. Etiopathogenesis of bipolar affective disorder-the state of the art for 2021 // Psychiatria Polska. – 2021. – Vol. 55, no. 3. – Pp. 481–496. – https://doi.org/10.12740/pp/132961
- Ceskova E., Silhan P. Novel treatment options in depression and psychosis // Neuropsychiatric Disease and Treatment. – 2018. – Vol. 14. – Pp. 741–747. – https://doi.org/10.2147/NDT.S157475
- Hamon M., Blier P. Monoamine neurocircuitry in depression and strategies for new treatments // Progress in Neuro-Psychopharmacology and Biological Psychiatry. – 2013. – Vol. 45. – Pp. 54–63. – https://doi.org/10.1016/j.pnpbp.2013.04.009
- Carlsson A. The contribution of drug research to investigating the nature of endogenous depression // Pharmacopsychiatry. – 1976. – Vol. 9
- De Deurwaerdère P., Di Giovanni G. Serotonergic modulation of the activity of mesencephalic dopaminergic systems: therapeutic implications // Progress in Neurobiology. – 2017. – Vol. 151. – Pр. 175–236. – https://doi.org/10.1016/j.pneurobio.2016.03.004
- Grinchii D., Dremencov E. Mechanism of action of atypical antipsychotic drugs in mood disorders // International Journal of Molecular Sciences. – 2020. – Vol. 21, no. 24. – Art. 9532. – https://doi.org/10.3390/ijms21249532
- Ślifirski G., Król M., Turło J. 5-HT receptors and the development of new antidepressants // International Journal of Molecular Sciences. – 2021. – Vol. 22, no. 16. – Art. 9015. – https://doi.org/10.3390/ijms22169015
- Eshel N. et al. Dopamine neurons share common response function for reward prediction error // Nature Neuroscience. – 2016. – Vol. 19, no. 3. – Pp. 479–486.– https://doi.org/10.1038/nn.4239
- Wise R.A. Dopamine, learning and motivation // Nature Reviews Neuroscience. – 2004. – Vol. 5, no. 6. – Pp. 483–494. – https://doi.org/10.1038/nrn1406
- Wise R.A. Dopamine and reward: the anhedonia hypothesis 30 years on // Neurotoxicity Research. – 2008. – Vol. 14. – Pр. 169-183.– https://doi.org/10.1007/BF03033808
- Pandit R. et al. Melanocortin 3 receptor signaling in midbrain dopamine neurons increases the motivation for food reward // Neuropsychopharmacology. – 2016. – Vol. 41, no. 9. – Pp. 2241–2251.– https://doi.org/10.1038/npp.2016.19
- Grace A.A. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression // Nature Reviews Neuroscience. – 2016. – Vol. 17, no. 8. – Pp. 24– 532. – https://doi.org/10.1038/nrn.2016.57.
- Sultan K.T., Brown K.N., Shi S.H. Production and organization of neocortical interneurons // Frontiers in Cellular Neuroscience. – 2013. – Vol. 7. – Art. 221. – https://doi.org/10.3389/fncel.2013.00221
- Buzsaki G., Draguhn A. Neuronal oscillations in cortical networks // Science. – 2004. – Vol. 304, no. 5679. – Pp. 1926–1929.– https://doi.org/10.1126/science.1099745
- Steullet P. et al. Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: a “central hub” in schizophrenia pathophysiology? // Schizophrenia Research. – 2016. – Vol. 176, no. 1. – Pp. 41–51. – https://doi.org/10.1016/j.schres.2014.06.021
- Taliaz D. et al. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis // Molecular Psychiatry. – 2010. – Vol. 15, no. 1. – Pp. 80–92. – https://doi.org/10.1038/mp.2009.67
- Krishnan V., Nestler E.J. The molecular neurobiology of depression // Nature. – 2008. – Vol. 455, no. 7215. – Pp. 894–902. – https://doi.org/10.1038/nature07455
- Hall J., Thomas K.L., Everitt B.J. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning // Nature Neuroscience. – 2000. – Vol. 3, no. 6. – Pp. 533–535. – https://doi.org/10.1038/75698
- Li P., Snyder G.L., Vanover S.E., Vanover K.E. Dopamine targeting drugs for the treatment of schizophrenia: Past, present and future // Current Topics in Medicinal Chemistry. – 2016. – Vol. 16, no. 29. – Pp. 3385–3403. – https://doi.org/10.2174/1568026616666160608084834
- Martinowich K., Lu B. Interaction between BDNF and serotonin: role in mood disorders // Neuropsychopharmacology. – 2008. – Vol. 33, no. 1. – Pp. 73–83. – https://doi.org/10.1038/sj.npp.1301571
- Szapacs M.E. et al. Exploring the relationship between serotonin and brain-derived neurotrophic factor: analysis of BDNF protein and extraneuronal 5-HT in mice with reduced serotonin transporter or BDNF expression // Journal of Neuroscience Methods. – 2004. – Vol. 140, no. 1–2. – Pp. 81–92. – https://doi.org/10.1016/j.jneumeth.2004.03.026
- Santarelli L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants // Science. – 2003. – Vol. 301, no. 5634. – Pp. 805–809. – https://doi.org/10.1126/science.1083328
- Surget A. et al. Antidepressants recruit new neurons to improve stress response regulation // Molecular Psychiatry. – 2011. – Vol. 16, no. 12. – Pp. 1177–1188. – https://doi.org/10.1038/mp.2011.48
- Mateus-Pinheiro A. et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis // Translational Psychiatry. – 2013. – Vol. 3, no. 1. – Pp. e210-e210. – https://doi.org/10.1038/tp.2012.141
- Chikama K. et al. Chronic atypical antipsychotics, but not haloperidol, increase neurogenesis in the hippocampus of adult mouse // Brain Res. – 2017. – Vol. 1676. – Pp. 77–82. – https://doi.org/10.1016/j.brainres.2017.09.006
- Patrício P. et al. Differential and converging molecular mechanisms of antidepressants’ action in the hippocampal dentate gyrus // Neuropsychopharmacology. – 2015. – Vol. 40, no. 2. – Pp. 338–349. – https://doi.org/10.1038/npp.2014.176
- Bessa J.M. et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling // Molecular Psychiatry. – 2009. – Vol. 14, no. 8. – Pp. 764–773. – https://doi.org/10.1038/mp.2008.119
- Mateus-Pinheiro A. et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis // Translational Psychiatry. – 2013. – Vol. 3, no. 1. – Pp. e210–e210. – https://doi.org/10.1038/tp.2012.141
- Wang H.D., Deutch A.Y. Dopamine depletion of the prefrontal cortex induces dendritic spine loss: reversal by atypical antipsychotic drug treatment // Neuropsychopharmacology. – 2008. – Vol. 33, no. 6. – Pp. 1276–1286. – https://doi.org/10.1038/sj.npp.1301521
- Morais M. et al. The modulation of adult neuroplasticity is involved in the mood-improving actions of atypical antipsychotics in an animal model of depression // Translational psychiatry. – 2017. – Vol. 7, no. 6. – Pp. e1146–e1146. – https://doi.org/10.1038/tp.2017.120
- Schildkraut J.J. The catecholamine hypothesis of affective disorders: a review of supporting evidence // American Journal of Psychiatry. – 1965. – Vol. 122, no. 5. – Pp. 509–522. – https://doi.org/10.1176/ajp.122.5.509
- Bunney W.E. The current status of research in the catecholamine theories of affective disorders // Psychopharmacology Communications. – 1975. – Vol. 1, no. 6. – Pp. 599–609.
- Ashok A. et al. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment // Molecular Psychiatry. – 2017. – Vol. 22. – Pp. 666–679. – https://doi.org/10.1038/mp.2017.16
- Yatham L.N. et al. A positron emission tomography study of dopamine transporter density in patients with bipolar disorder with current mania and those with recently remitted mania // JAMA Psychiatry. – 2022. – Vol. 79, no. 12. – Pp. 1217–1224. – https://doi.org/10.1001/jamapsychiatry.2022.3541
- Jensen N.H. et al. N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, a putative mediator of quetiapine’s antidepressant activity // Neuropsychopharmacology. – 2008. – Vol. 33. – Pp. 2303–2312. – https://doi.org/10.1038/sj.npp.1301646
- Tuppurainen H. et al. Extrapyramidal side-effects and dopamine D(2/3) receptor binding in substantia nigra // Nord J Psychiatry. – 2010 – Vol. 64, no. 4. – Pp. 233–238. – https://doi.org/10.3109/08039480903484076
- Durgam S. et al. An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression // American Journal of Psychiatry. – 2016. – Vol. 173, no. 3. – Pp. 271–281. – https://doi.org/10.1176/appi.ajp.2015.15020164
- Медведев В.Э. Карипразин — современный препарат для лечения шизофрении и биполярного расстройства // Современная терапия психических расстройств. – 2022. – № 3. – С. 51–57. – https://doi.org/10.21265/PSYPH.2022.46.63.006
- Durgam S. et al. Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: a randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder // The Journal of Clinical Psychiatry. – 2016. – Vol. 77, no. 3. – Art. 6112. – https://doi.org/10.4088/JCP.15m10070
- Kiss B., Horti F., Bobok A. Poster# 16 cariprazine, a D3/D2 dopamine receptor partial agonist antipsychotic, displays greater D3 receptor occupancy in vivo compared with other antipsychotics // Schizophrenia Research. – 2012. – No. 136. – Art. S190.– https://doi.org/10.1016/S0920-9964(12)70588-1
- Slifstein M. et al. Cariprazine demonstrates high dopamine D3 and D2 receptor occupancy in patients with schizophrenia: a clinical PET study with [11C]-(+)-PHNO // Neuropsychopharmacology. – 2013. – Vol. 38. – Pp. S520–S521.
- Tohen M. Cariprazine as a treatment option for depressive episodes associated with bipolar 1 disorder in adults: an evidence-based review of recent data // Drug Design, Development and Therapy. – 2021. – Vol. 15. – Pp. 2005–2012. – https://doi.org/10.2147/DDDT.S240860
- Петрова Н.Н. Расстройства аутистического спектра во взрослом возрасте. Обзор // Психиатрия, Психотерапия и Клиническая Психология. – 2022. – Т.13, № 2. – С. 179- 191. – https://doi.org/10.34883/PI.2022.13.2.003
- Yatham L.N. et al. A positron emission tomography study of dopamine transporter density in patients with bipolar disorder with current mania and those with recently remitted mania // JAMA Psychiatry. – 2022. – Vol. 79, no. 12. – Pp. 1217–1224. – https://doi.org/10.1001/jamapsychiatry.2022.3541
- Ragguett R.M., McIntyre R.S. Cariprazine for the treatment of bipolar depression: a review // Expert Rev Neurother. – 2019. – Vol. 19, no. 4. – Pp. 317–323. – httpd://doi.org/10.1080/14737175.2019.1580571
- McIntyre R.S., Suppes T., Earley W., Patel M., Stahl S.M. Cariprazine efficacy in bipolar I depression with and without concurrent manic symptoms: post hoc analysis of 3 randomized, placebo-controlled studies // CNS spectrums. – 2020. – Vol. 25, no. 4. – Pp. 502– 510. – https://doi.org/10.1017/S1092852919001287
- Lam R.W. et al. Combining antidepressants for treatment-resistant depression: a review // Journal of Clinical Psychiatry. – 2002. – Vol. 63, no. 8. – Pp. 685–693. – https://doi.org/10.4088/jcp.v63n0805
- Nelson J.C., Papakostas G.I. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials // American Journal of Psychiatry. – 2009. – Vol. 166, no. 9. – Pp. 980–991. – https://doi.org/10.1176/appi.ajp.2009.09030312
- Wright B.M., Eiland III E.H., Lorenz R. Augmentation with atypical antipsychotics for depression: a review of evidence-based support from the medical literature // Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. – 2013. – Vol. 33, no. 3. – Pp. 344–359. – https://doi.org/10.1002/phar.1204
- Earley W.R. et al. Cariprazine augmentation to antidepressant therapy in major depressive disorder: results of a randomized, double-blind, placebo-controlled trial // Psychopharmacology Bulletin. – 2018. – Vol. 48, no. 4. – Pp. 62–80.
- Pinto J.V. et al. Cariprazine in the treatment of Bipolar Disorder: A systematic review and meta-analysis // Bipolar Disorders. – 2020. – Vol. 22, no. 4. – Pp. 360–371. – https://doi.org/10.1111/bdi.12850
- Vieta E. et al. Long-term safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder // International Clinical Psychopharmacology. – 2019. – Vol. 34, no. 2. – Pp. 76–83. – https://doi.org/10.1097/YIC.0000000000000246
- Fava M. et al. Efficacy of adjunctive low-dose cariprazine in major depressive disorder: a randomized, double-blind, placebo-controlled trial // International Clinical Psychopharmacology. – 2018. – Vol. 33, no. 6. – Pp. 312–321. – https://doi.org/10.1097/YIC.0000000000000235
- Bahji A. et al. Comparative efficacy and tolerability of pharmacological treatments for the treatment of acute bipolar depression: a systematic review and network meta-analysis // Journal of Affective Disorders. – 2020. – Vol. 269. – Pp. 154–184. – https://doi.org/10.1016/j.jad.2020.03.030
- Batinic B. et al. Assessment of cognitive function, social disability and basic life skills in euthymic patients with bipolar disorder // Psychiatr Danub. – 2021. – Vol. 33, no. 3. – Pp. 320–327. – https://doi.org/10.24869/psyd.2021.320
- Tabarés-Seisdedos R. et al. Neurocognitive and clinical predictors of functional outcome in patients with schizophrenia and bipolar I disorder at one-year follow-up // J Affect Disord. – 2008 – Vol. 109, no. 3. – Pp. 286–299. – https://doi.org/10.1016/j.jad.2007.12.234
- Huang M. et al. The role of dopamine D3 receptor partial agonism in cariprazine-Induced neurotransmitter efflux in rat hippocampus and nucleus accumbens // J Pharmacol Exp Ther. – 2019 – Vol. 371, no. 2. – Pp. 517–525. – https://doi.org/10.1124/jpet.119.259879
- Zimnisky R. et al. Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse // Psychopharmacology (Berl). – 2013. – Vol. 22. – Pp. 91– 100. – https://doi.org/10.1007/s00213-012-2896-5
- Stahl S. Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes // CNS Spectr. – 2017. – Vol. 22, no. 5. – Pp. 375–384. – https://doi.org/10.1017/S1092852917000608
- Calabrese F. et al. The role of dopamine D3 receptors in the mechanism of action of cariprazine // CNS Spectrums. – 2020. – Vol. 25, no. 3. – Pp. 343–351. – https://doi.org/10.1017/S109285291900083X 7
- Citrome L. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy // Adv Ther. – 2013. – Vol. 30, no. 2. – Pp. 114–126. – https://doi.org/10.1007/s12325-013-0006-7
- Citrome L. Cariprazine for bipolar depression: What is the number needed to treat, number needed to harm and likelihood to be helped or harmed? // Int J Clin Pract. – 2019. – Vol. 73, no. 10. – Art. 13397. – https://doi.org/10.1111/ijcp.13397
- Nakamura T. et al. Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment) // Drug Des Devel Ther. – 2016. – Vol. 10. – Pp. 327–338. – https://doi.org/10.2147/DDDT.S95100
- Caccia S. et al. A new generation of antipsychotics: pharmacology and clinical utility of cariprazine in schizophrenia // Therapeutics and Clinical Risk Management. – 2013. – Vol. 9. – Pp. 319–328. – https://doi.org/10.2147/TCRM.S35137
- Мосолов С.Н., Алфимов П.В. Роль дофаминовых D3-рецепторов в механизме действия современных антипсихотиков // Современная терапия психических расстройств. – 2014. – № 1. – С. 2-9.
- Earley W. et al. Efficacy of cariprazine on negative symptoms in patients with acute schizophrenia: a post hoc analysis of pooled data // Schizophrenia Research. – 2019. – Vol. 204. – Pp. 282–288. – https://doi.org/10.1016/j.schres.2018.08.020
- Mohr P., Masopust J., Kopeček M. Dopamine receptor partial agonists: Do they differ in their clinical efficacy? // Frontiers in Psychiatry. – 2022. – Vol. 12. – Art. 2491. – https://doi.org/10.3389/fpsyt.2021.781946
- Forte A. et al. Long-term morbidity in bipolar-I, bipolar-II, and unipolar major depressive disorders // J Affect Disord. – 2015 – Vol. 178. – Pp. 71–78. – https://doi.org/10.1016/j.jad.2015.02.011
- Rancans E. et al.The effectiveness and safety of cariprazine in schizophrenia patients with negative symptoms and insufficient effectiveness of previous antipsychotic therapy: an observational study // Int Clin Psychopharmacol. – 2021 – Vol. 36, no. 3. – Pp. 154–161. – https://doi.org/10.1097/YIC.0000000000000351