The Use of Cariprazine in the Treatment of Major Depression with Insufficient Response for Antidepressant: Effects on Symptomatic Domains

Background: antidepressants (ADs) are recognized as first-line drugs in the treatment of depressive disorder. However, therapeutic response is only achieved in 50–75% of cases, necessitating the search for additional treatment strategies, including augmentation of antidepressant therapy. In this connection the study of atypical antipsychotics as adjunctive therapy, including cariprazine, is of particular interest. Numerous studies have demonstrated its efficacy and safety in the treatment of schizophrenia, bipolar affective disorder type 1, as well as major depressive disorder (MDD). At the same time its impact on MD symptomatic domains remains insufficiently studied. The Aim of review was to search for and analyze current data on the trans-symptomatic effect of cariprazine in MD treatment. Materials and Methods: The search was carried out using keywords and their combinations depending on the special features of search algorithms of scientific electronic databases PubMed, Google Scholar, Cyberlenika, ELibrary.ru. Results: in accordance with the developed criteria for inclusion and non-inclusion of publications in the study, 7 works devoted to the assessment of the efficacy and safety of cariprazine in MD patients with an insufficient response to antidepressant monotherapy were included in the final analysis. Conclusions: A literature review demonstrated the potential of cariprazine use in MD patients with insufficient response to antidepressant therapy. Data on the effects of cariprazine on individual symptoms of depression were obtained, allowing psychiatrists to make more informed decisions when selecting an antipsychotic for augmentation, based on a thorough psychopathological assessment of the patient's condition. In this case, it seems promising to study the relationship between the dosage of cariprazine and the severity of individual symptomatic effects, as well as to determine the optimal dose, taking into account the balance of efficacy and tolerability.

1. World Health Organization (WHO). Depressive Disorder (Depression). WHO, 2023 (https://www.who.int/news-room/fact-sheets/detail/depression).

2. Silant’eva OS. Depressiya v molodezhnoj srede: svoevremennoe vyyavlenie i profilaktika. Aktual’nye problemy gumanitarnyh i estestvennyh nauk. 2009;(2):321–322. (In Russ.).

3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. American Psychiatric Association Publishing. 2022.

4. Gillissie ES, Le GH, Rhee TG, Cao B, Rosenblat JD, Mansur RB, Ho RC, McIntyre RS.Evaluating Anhedonia as a risk factor in suicidality: A meta-analysis. J Psychiatr Res. 2023;158:209–215. doi: 10.1016/j.jpsychires.2022.12.024

5. Winer ES, Nadorff MR, Ellis TE, Allen JG, Herrera S, Salem T. Anhedonia predicts suicidal ideation in a large psychiatric inpatient sample. Psychiatry Res. 2014;218(1– 2):124–128. doi:10.1016/j.psychres.2014.04.016

6. Sivolap YuP, Portnova AA. First-line antidepressants: selective serotonine reuptake inhibitors. Medical Council.2025;19(12):64–72. (In Russ.). doi: 10.21518/ms2025-282

7. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller H. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 2: update 2013 on the acute and continuation treatment of unipolar depressive disorders. The World J Biol Psychiatry. 2013;14:334–85. doi: 10.3109/15622975.2013.804195

8. Cuijpers P, Karyotaki E, Weitz E, Andersson G, Hollon SD, van Straten A. The effects of psychotherapies for major depression in adults on remission, recovery and improvement: a meta-analysis. J Affect Disord. 2014 Apr;159:118–26. doi: 10.1016/j.jad.2014.02.026. Epub 2014 Feb 24. PMID: 24679399.

9. Chigareva O, Smirnova D, Astafeva D, Gradinar A, Izmailova O, Sheyfer M, Cumming P, Sack A, Gayduk AJ. Comparing the Anti-Depressive Effect of Electroconvulsive Therapy (ECT) Versus Transcranial Magnetic Stimulation (TMS) in the Treatment of Patients with Depression. Psychiatria Danubina. 2023;35(2):48–55.

10. Shmukler AB. Kariprazin (reagila) — novyj atipichnyj antipsihotik s unikal’nym spektrom psihotropnoj aktivnosti. Social and Clinical Psychiatry. 2020; 30(1):110. (In Russ.).

11. Edinoff A, Ruoff MT, Ghaffar YT, Rezayev A, Jani D, Kaye AM, Cornett EM, Kaye AD, Viswanath O, Urits I. Cariprazine to Treat Schizophrenia and Bipolar Disorder in Adults. Psychopharmacol Bull. 2020;50(4):83– 117. doi: 10.64719/pb.4374

12. Fava M, Durgam S, Earley W, Lu K, Hayes R, Laszlovszky I, Németh G. Efficacy of adjunctive low-dose cariprazine in major depressive disorder: a randomized, double-blind, placebo-controlled trial. Int Clin Psychopharmacol. 2018;33(6):312–321. doi: 10.1097/YIC.0000000000000235

13. Sachs GS, Yeung PP, Rekeda L, Khan A, Adams JL, Fava M. Adjunctive Cariprazine for the Treatment of Patients With Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study. Am J Psychiatry. 2023 Mar 1;180(3):241–251. doi: 10.1176/appi.ajp.20220504. Epub 2023 Feb 15. PMID: 36789515.

14. Fava M, Masand PS, Maletic V, Chen C, Adams JL, Kerolous M. Efficacy of Adjunctive Cariprazine on Anxiety Symptoms in Patients With Major Depressive Disorder: Post Hoc Analysis of a Randomized Placebo-Controlled Trial. J Clin Psychiatry. 2025;86(2):24m15506. doi: 10.4088/JCP.24m15506. PMID: 40315101.

15. McIntyre RS, Maletic V, Masand P, Wilson AC, Yu J, Adams JL, Kerolous M. The effect of adjunctive cariprazine on symptoms of anhedonia in patients with major depressive disorder. J Affect Disord. 2025;385:119366. doi: 10.1016/j.jad.2025.05.026. Epub 2025 May 6. PMID: 40339720.

16. Papakostas GI, Masand PS, Clayton AH, Maletic V, Adams JL, Rekeda L, Singh MK, Kerolous M. Efficacy and Clinical Relevance of Adjunctive Cariprazine Treatment in Patients with Major Depressive Disorder: Post Hoc Analyses from a Phase III Study. Neuropsychiatr Dis Treat. 2026;22:561112. doi: 10.2147/NDT.S561112. PMID: 41948533; PMCID: PMC13051242.

17. Riesenberg R, Yeung PP, Rekeda L, Sachs GS, Kerolous M, Fava M. Cariprazine for the Adjunctive Treatment of Major Depressive Disorder in Patients With Inadequate Response to Antidepressant Therapy: Results of a Randomized, Double-Blind, Placebo-Controlled Study. J Clin Psychiatry. 2023 Aug 16;84(5):22m14643. doi: 10.4088/JCP.22m14643. PMID: 37585254.

18. Vieta E, Earley WR, Burgess MV, Durgam S, Chen C, Zhong Y, Barabássy Á, Németh G. Long-term safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder. Int Clin Psychopharmacol. 2019;34(2):76–83. doi: 10.1097/YIC.0000000000000246

19. Stößel A, Brox R, Purkayastha N, Hübner H, Hocke C, Prante O, Gmeiner P. Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior. Bioorg Med Chem. 2017;25(13):3491– 3499. doi: 10.1016/j.bmc.2017.04.036

20. Martel JC, Gatti McArthur S. Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia. Front Pharmacol. 2020; 11:1003. doi: 10.3389/fphar.2020.01003

21. Lukmanova KA, Butoma BG, Aksenova IO, Kocyubinskij AP. The effects of cariprazine, aripiprazole, and brexpiprazole on lipid and carbohydrate metabolism and weight gain: a narrative review Bekhterev Review of Psychiatry and Medical Psycho logy. 2026;59(4):25–36. (In Russ.). doi: 10.31363/2313-7053-2025-4-1145

22. Mohsin TS, Kadhem GJ, Idrees SJH, Alrubaye H. The Role Of Serotonin In Sleep And Mood Regulation: A Comparative Physiological Review Of Healthy And Depressed Populations. Int J Environ Sci. 2025; 11(21s):185–196. doi: 10.64252/kj1gxm35

23. Morozov PV, Medvedev VE. Kariprazin — novyj antipsihotik dlya lecheniya endogennyh psihicheskih rasstrojstv. Psychiatry and psychopharmacotherapy. 2014;16(1):9–14. (In Russ.).