Cariprazine and cognition in patients with schizophrenia and bipolar disorder: A systematic review

Cariprazine and cognition in patients with schizophrenia and bipolar disorder: A systematic review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cariprazine and cognition in patients with schizophrenia and bipolar disorder: A systematic review LORENA Garcia-Fernandez, Veronica Romero, Inmaculada Peñuelas-Calvo, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3857313/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Cariprazine is a recently incorporated drug whose differential characteristic is its partial agonism for the D3 receptor, with great affinity for it, higher than dopamine itself. Preclinical studies with animal models have shown a manifest pro cognitive effect. The objective of this study is to conduct a systematic review examining the effects of cariprazine on cognitive measures in patients with schizophrenia and bipolar disorder. Methods Two independent reviewers searched PubMed, Web of Science, Scopus, and Cochrane Library databases to December 31st 2023 following the PRISM guideline. Additional studies were identified through hand-searching of references of the included studies. Eligible studies were those randomized controlled trials published in English evaluating the effects of the use of cariprazine on cognitive outcomes in patients with mental disorders. Quality assessment followed the Jadad scale recommendations. Results From a total of 136 initial reports, up to 5 studies comprising 6104 patients with schizophrenia, bipolar I mania and bipolar I depression were included in the systematic review. In patients with schizophrenia, the use of cariprazine showed better cognitive outcomes compared to placebo in both early and late stages. Furthermore, cariprazine showed cognitive advantages over risperidone in patients with a predominance of negative symptoms and over aripiprazole when the variables power and continuity of attention were measured. In patients with bipolar disorder, cariprazine showed cognitive improvements compared to placebo. Most studies seem to find a greater pro cognitive effect with low doses of cariprazine (1.5-3 mg/d). Conclusions Overall, cariprazine improved cognitive measures compared to placebo, especially in patients with greater baseline impairment and when low doses are used. Thus, the use of cariprazine in patients with schizophrenia and bipolar disorder could become an effective therapeutic option to enhance cognition as well as other inherent symptoms of both disorders. Systematic review registration PROSPERO CRD42023485028. Cariprazine cognition schizophrenia bipolar mania bipolar depression systematic review Figures Figure 1 Introduction Psychotic disorders and, specifically schizophrenia, constitute a group of diseases that affect different symptomatic domains known as positive, negative, affective and cognitive symptoms. All those domains have shown to be related but they are considered independent features ( 1 ) and therefore, require a differentiated therapeutic approach. Cognition has been identified as a core feature of schizophrenia ( 2 ). Cognitive deficits have been observed in the initial stages of the disease as well as in chronic patients, in patients in remission, in naive patients and even in high-risk mental states or in first-degree relatives of people affected by the disease ( 3 ). Moreover, cognitive deficits have been identified in practically all affected people presenting a heterogeneous and diffuse impairment that affects almost all cognitive domains performing between 1–2 standard deviations (SD) below the average in healthy people ( 4 ). Cognition has also been postulated as one of the main domains of schizophrenia and bipolar disorder, especially affecting important areas of life such as community functioning, problems coping, successful employment and independent living ( 5 ). In addition, cognitive performance has also been associated with the ability to successfully benefit from the different psychotherapeutic remediation programs available ( 6 ). Though, despite the cognitive advances achieved in pharmacological ( 7 ) and non-pharmacological approaches ( 8 , 9 ) for people with schizophrenia, cognitive improvement remains an unmet therapeutic target. Nonetheless, to date, current antipsychotic medications have shown little potential to improve cognition in schizophrenia and bipolar disorder patients, but the appearance of the so-called third generation antipsychotics has allowed the scientific community to hypothesize about the pro cognitive effects of these drugs ( 10 ). Those agents act as partial agonists with a lower intrinsic receptor activity that enables them to act as either functional agonists or antagonists depending on the surrounding neurotransmitter environment ( 11 ). Therefore, a D2 receptor partial agonist behaves as an antagonist in a hyperdopaminergic environment, and as an agonist when hypodopaminergia predominates ( 12 , 13 ). This interesting mechanism of action gives this group of antipsychotics the ability to address the positive symptoms generated by states of hyperdopaminergia in the mesolimbic circuit and, also the negative and cognitive ones, related to mesocortical hypodopaminergia ( 13 ). Research has shown incipient results that, although promising, are still inconclusive and without the desirable clinical relevance ( 14 ). Furthermore, the appearance of cariprazine is of special interest. Cariprazine is a partial agonist at the dopamine D2 and D3 receptors and serotonin 5-HT1A receptors, and antagonist at the 5-HT2B receptors ( 15 ). It differs from the rest of the drugs belonging to this group in its specific binding for the D3 receptor, mainly expressed in the mesolimbic pathway, higher than dopamine itself, resulting in full D3 receptor occupancy at clinically relevant doses ( 16 ). Cariprazine, especially through the D3 receptor partial agonist effect, has already demonstrated pro cognitive activity in phencyclidine animal models ( 17 ). In vitro studies have also emphasized the pro cognitive properties of cariprazine observed in D3 Knockout mice, which has not been found in the wild ones ( 18 ). Therefore, the role of the D3 receptor has been postulated as crucial in addressing cognitive impairment in people with schizophrenia and bipolar disorder and, as a consequence, cariprazine, due to its specific D3 receptor profile, might improve the cognitive deficits inherent to the disease. Recently, several studies have been published on the pro cognitive effects of cariprazine in patients with schizophrenia and bipolar disorder, although a systematic review has not yet been carried out with the exception of a minireview that only included 2 clinical studies publish before 2021 ( 19 ). Therefore, we ought to systematically review all available studies regarding the effectiveness of cariprazine in the cognitive impairments suffered by people with psychotic symptoms, especially patients with schizophrenia and bipolar disorder. Methods Selection criteria and search strategy We carried out a systematic review regarding cariprazine and cognition in people with schizophrenia and bipolar disorder, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines 2020 version ( 20 ). Search Methods and Results are highlighted in Fig. 1 . The protocol was registered on PROSPERO (registration number: CRD42023485028). Patients with a mental disorder of any age in any stage of the disease have been included. Studies in populations receiving treatment with cariprazine in all flexible doses have also been included. Studies included in this review were limited to English-language and studies published before December 2023. Articles in languages other than English have been excluded. Search was limited to human studies and included randomized controlled trials (RCTs). Narrative reviews, case reports, conference abstracts, letters or editorials have been excluded. Any follow-up period length has been included. PubMed (medline), Web of Science, Scopus and the Cochrane database were searched for articles related to the effectiveness of cariprazine on cognitive functioning. The search terms used were (CARIPRAZINE AND COGNIT*) using ‘humans’ as filter. In addition, a manual search of the reference lists of the included studies was performed for additional eligible studies. The electronic search was conducted until December 31st, 2023. The Participant (patients with schizophrenia, bipolar I mania and bipolar I depression), Intervention (cariprazine), Comparator (placebo or any other antipsychotic agent), and Outcome (cognitive improvement) (PICO) framework was used to define the inclusion criteria. Data collection and risk of bias assessment Two reviewers (LGF, VRF) independently screened the titles and abstracts of potentially eligible articles, reviewed full text articles, and checked inclusion criteria. Differences were discussed and in case of doubt the study methodology was carefully analyzed. A senior reviewer (RRJ) was consulted if consensus was not achieved. The methodological quality of the RCTs was addressed using the Jadad scale ( 21 ) which evaluates the quality of each trial on a five-domain scale (randomization and allocation, methodology to generate randomization, blinding, methodology of blinding and, withdrawals and dropouts), able to affect the global quality of the report. Each study included in the review has been assigned a numerical value that ranges from 0 (high risk of bias) to 5 (low risk of bias). To evaluate the quality of the post hoc studies, the original pivotal studies from which the sample has been selected have been taken as a reference. Outcome measures To describe the results, the comparison statistics presented by each of the reviewed studies have been used. Results obtained have been reflected as the mean change from baseline to the end of the follow up period, pooled in the intention to treat (ITT) population and also in specific population subgroups created based on the degree of cognitive impairment. Median (M) and standard deviation (SD) change from baseline, Least squares mean change (LSMC), Least squares mean difference (LSMD), and effect sizes (ES) for the change from baseline to end of follow up have been used to present the data. Results Studies selection The electronic search initially identified 136 papers in the screened database, including full-text articles, case reports and congress communications. Up to 5 additional records were selected through the searched report´s references and other sources. Next, 37 records were removed as they were duplicates. Of the 104 pooled articles retrieved on the basis of their titles and abstracts, 85 were excluded due to different reasons that are described in Fig. 1 . At this point, a total of 19 articles were screened on the basis of full texts and finally, according to study inclusion criteria, 5 studies with post hoc analysis of positive phases II/III double blinded randomized controlled trials were included in this systematic review ( 22 – 26 ). Figure 1 shows the search process according to the PRISMA flow-chart. Regarding the different mental disorders, up to 3 studies assessed the cognitive improvement in people with schizophrenia, one of them in a population with predominance of negative symptoms (PPNS); a fourth study explored the cognitive performance in 3 samples of patients with different diagnoses: schizophrenia, bipolar I major depression and bipolar I mania and mixed episodes and, lastly, 1 final trial evaluated the cognitive benefit in patients with bipolar I major depression. The details of each study are reported in Table 1 . Table 1 Summary of the reviewed studies. First author, and date Study design Population, N Age, years Duration Comparison (n), doses Outcome Quality* Fleischhacker et al, 2019 Post hoc analysis from 1 randomized, double-blind, controlled trial Schizophrenia, (negative symptoms), N = 456 18–65 26 weeks CAR (N = 227) 3–6 mg/d vs RIS (N = 229) 3–6 mg/d Marder Disorganized Thoughts factor LSMD (CAR vs RIS − 0.63, p < 0.05) Meltzer Cognitive Subscale LSMD (CAR vs RIS − 0.53, p < 0.05) Difficulty in Abstract Thinking item LSMD (CAR vs RIS − 0.17, p < 0.05) 5 Marder et al, 2019 Post hoc analysis from 3 randomized, double-blind, controlled trials Schizophrenia (acute exacerbation), N = 1466 18–60 6 weeks CAR (N = 1024) 1,5 – 9 mg/d vs PBO (N = 442) Marder Disorganized Thoughts factor LSMD (CAR vs PBO − 2, p < 0.0001) Marder Disorganized Thoughts factor ES (CAR vs PBO 0.47, p CAR 1.5-3 mg/d 5 Vieta et al, 2021 Post hoc analysis from 1 randomized, double-blind, controlled trial Bipolar I (major depression), N = 393 18–65 8 weeks CAR (N = 135) 1,5 mg/d vs CAR (N = 126) 3 mg/d vs PBO (N = 132) FAST Cognitive subscale LSMD (CAR 1.5 mg/d vs PBO − 1.2, p < 0.01) 4 Falkai et al, 2022 Post hoc analysis from 3 randomized, double-blind, controlled trials Schizophrenia (acute exacerbation), Early stage, N = 460 Late stage, N = 414 18–60 6 weeks Early stage patients CAR (N = 302) vs PBO (N = 140) Late stage patients CAR (N = 271) vs PBO (N = 125) Marder Disorganized Thoughts factor Early stage LSMD (CAR vs PBO − 1.2; ES 0.39, p < 0.001) Late stage LSMD (CAR vs PBO − 1.3, ES 0.39, p < 0.01) 5 McIntyre et al, 2023 Post hoc analysis from 3 randomized, double-blind, controlled trials Schizophrenia, N = 520 18–60 6 weeks PoA CAR (N = 124) 3 mg/d CAR (N = 137) 6 mg/d ARI (N = 130) 10 mg/d vs PBO (N = 129) CoA CAR (N = 122) 3 mg/d CAR (N = 135) 6 mg/d ARI (N = 130) 10 mg/d vs PBO (N = 128) PoA (ms) Median (SD) change from baseline ITT - PBO 27.3 (597.5); CAR 3 mg/d 59 (595) p = 0.0036; CAR 6 mg/d 5.7 (781.8), p = 0.1272; ARI 10 mg/d 44.2 (828.1), p = 0.4104 Differences in PoA median change from baseline (CAR vs ARI) ITT - CAR 3 mg/d, p = 0.0006; CAR 6 mg/d, p = 0.0260 Differences in PoA in high cognitive impairment group (49,8%) CAR 3 mg/d vs PBO LSMC − 240, p = 0.0080 CAR 3 mg/d vs ARI LSMC − 210, p = 0.0064 CoA Median (SD) change from baseline ITT - PBO 0 (11.7); CAR 3 mg/d 2 (10.5), p = 0.0005); CAR 6 mg/d 1 (14.1), p = 0.0168; ARI 10 mg/d 0 (13.9), p = 0.1685 Differences in CoA in high cognitive impairment group (54,4%) CAR 3 mg/d vs PBO LSMC 4.9, p = 0.0012 CAR 6 mg/d vs PBO LSMC 4.0, p = 0.0073 ARI 10 mg/d vs PBO LSMC 4.0, p = 0.0160 4 Post hoc analysis from 3 randomized, double-blind, controlled trials Bipolar I major depression, N = 1383 18–65 6 weeks CAR (N = 461) 1,5 mg/d CAR (N = 462) 3 mg/d vs PBO (N = 460) MADRS Concentration Difficulties item LSMC (CAR vs PBO) ITT - PBO (− 1.2); CAR 1.5 mg/d -1.6; p < 0.0001 and CAR 3 mg/d – 1.4; p 0.0365 Mild severity group (88.4%) - PBO − 1.3; CAR 1.5 mg/d − 1.8, p < 0.0001, and CAR 3 mg/d − 1.5, p = 0.0292 Moderate severity group (66.0%)- PBO − 1.5; CAR − 1.9 mg/d − 1.7, p < 0.0001, and CAR 3 mg/d − 1.5, p = 0.0366 4 8 weeks CAR (N = 135) 1,5mg/d CAR (N = 126) 3 mg/d vs PBO (N = 132) FAST Cognitive subscale LSMD (CAR vs PBO) ITT LSMD (CAR 1,5 mg vs PBO − 1.2; p = 0 .0035) Cognitive impairment group (75,8%) LSMD (CAR 1,5 mg vs PBO − 1.4; p = 0 .0039) Post hoc analysis from 3 randomized, double-blind, controlled trials Bipolar I mania and mixed episodes, N = 1012 18–65 3 weeks CAR (N = 593) 3–12 mg/d vs PBO (N = 419) Meltzer Cognitive Subscale (CAR vs PBO) ITT LSMD (− 0.9, p 50%) LSMD − 1.2, p < .001 LSMD P2: − 0.4, p < 0.0001; N5: − 0.2, p = 0.0127; N7: − 0.1, p = 0.1246; G10: − 0.1, p = 0.0392; G11: − 0.3, p = 0.0002 Moderate severity group (17,2%) LSMD − 2.1, p < .001 LSMD P2: − 0.6, p < .001; N5: − 0.5, p < .01; N7: − 0.3, p 0.05; G11: 0.5, p < .01 4 PANSS, Positive and Negative Syndrome Scale; PPNS, Patients with predominant negative symptoms; Marder Disorganized Thoughts factor (N5, P2, G5, G10, G11, G13, G14); Meltzer Cognitive Subscale (N5, N7, P2, G10, G11); FAST, Functional Assessment Staging Test; CAR, cariprazine; RIS, risperidone; ARI, aripiprazole; PBO, placebo; ITT, intention to treat total population; PoA, power of attention; CoA, continuity of attention; LS, least squares; LSMD, least squares mean difference; LSMC: least squares mean change; ES, effect size; M, media; SD, standard deviation. * Quality of clinical trials according to the Jadad scale. Overall, the studies reviewed were of good to excellent quality of evidence (Table 1 ). Thus, the total strength of recommendations of this review according to the National Health and Medical Research Council (NHMRC) (2009) is good to excellent. Synthesis of results Up to 5 post hoc analysis conducted on data from different pivotal phase II/III double blinded randomized controlled trials carried out in adults with the aim of analyzing the efficacy, safety and tolerability of different doses of cariprazine (CAR) compared to placebo (PBO), aripiprazole (ARI) and risperidone (RIS) in patients with schizophrenia, bipolar I mania and bipolar I depression were reviewed. Studies performed in schizophrenia patients A total of four of the reviewed reports addressed cognition in patients with schizophrenia. Schizophrenia RCTs included 3 short 6-week follow up (NCT00694707 [RGH-MD-16], NCT01104766 [RGH-MD-04] and NCT01104779 [RGH-MD-05]), and 1 long-term 26-week follow up studies (EudraCT 2012-005485-36 [RGH-188-005]). The first study ( 22 ), based on data from the prospective pivotal study RGH-MD-188-005 was designed to explore the effectiveness of cariprazine compared to risperidone in patients with a DSM IV TR diagnosis of schizophrenia and predominant negative symptoms (PNNS) defined as the presence of PPNS for ≥ 6 months, Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS) ( 27 , 28 ) score ≥ 24, and a score ≥ 4 on at least 2 of 3 negative symptoms item, after a 26 week follow up period. The cognition measures used in this study were Improvement in the Marder’s disorganized thoughts factor of the PANSS (items N5, P2, G5, G10, G11, G13, G14) ( 27 ), the Meltzer cognition subscale of the PANSS (items N5, N7, P2, G10, G11) ( 29 ) and the difficulty in abstract thinking item of the PANSS (N5) ( 30 ). Differences in mean change from baseline at week 26 in favor of cariprazine 4.5 mg/d compared to risperidone 4 mg/d were statistically significant in the Marder’s Disorganized Thoughts factor (LSMC, CAR − 4.16 vs RIS − 3.53; p < 0.05), the Meltzer Cognitive Subscale (LSMC, CAR − 3.13 vs RIS − 2.60, p < 0.05) and the individual item difficulty in abstract thinking, N5 of the PANSS (LSMC, CAR − 0.89 vs RIS − 0.72, p < 0.05). The second study published by Marder ( 23 ), based on data pooled from 3 similarly designed, pivotal positive, 6-week, double-blind, placebo-controlled, phase II/III trials [RGH-MD-16 ( 31 ), RGH-MD-04 ( 32 ), and RGH-MD-05 ( 33 )] was designed to explore the efficacy of cariprazine across different symptom domains in DSM IV TR diagnosis of schizophrenia. Acute patients were defined as those with a Clinical Global Impressions-Severity of Illness (CGI-S) ( 34 ) score ≥ 4, a PANSS ( 30 ) total score ≥ 80 and ≤ 120 and, a score ≥ 4 in at least 2 of the PANSS positive symptoms. Differences in mean change from baseline at week 6 in favor of all doses of cariprazine versus placebo were statistically significant in the Marder Disorganized Thought factor (LSMC, CAR − 4.5 vs PBO − 2.5; p < 0.0001). In addition, a slightly larger treatment effect was found with higher doses of cariprazine (4.5 -6 mg/d) than with lower doses (1.5 and 3 mg/d) in the Marder Disorganized Thought factor. The third post hoc analysis performed with DSM IV TR diagnosis of schizophrenia patients was published by Falkai ( 24 ) based on data from the same previous 3 phase II/III 6-week, randomized, double-blind, placebo-controlled trials [RGH-MD-16 ( 31 ), RGH-MD-04 ( 32 ), and RGH-MD-05 ( 33 )]. This study was developed to compare the efficacy and safety of cariprazine against placebo, risperidone and aripiprazole in two subgroups of patients, patients in early stage (≤ 5 years from diagnosis) and in late stage (≥ 15 years from diagnosis) of schizophrenia, all in an acute exacerbation phase, defined as a CGI-S ( 34 ) score ≥ 4, PANSS ( 30 ) total score ≥ 80 and ≤ 120 and, a score ≥ 4 in at least 2 of the PANSS positive symptoms. Differences in mean change from baseline at week 6 in favor of cariprazine compared to placebo were statistically significant in the Marder Disorganized Thoughts factor in both population subgroups [early stage (LSMC, CAR − 3.3 vs PBO − 2.1, p < 0.0001); late stage (LSMC, CAR − 2.7 vs – 1.4, p < 0.01]. Moreover, the mean changes from baseline in the Marder Disorganized Thoughts factor score were similar in both subgroups. The last study performed with schizophrenia patients conducted by McIntyre ( 25 ) was a post hoc analysis based on data from 3 phase II/III, randomized, double-blind, placebo-controlled, parallel-group, multi-center clinical trials assessing cariprazine´s cognitive efficacy. This study evaluates the cognitive response in 3 different samples of patients: 1) schizophrenia, 2) bipolar I depression ( 35 – 37 ) and, 3) bipolar I mania ( 38 – 40 ). In the schizophrenia subset of patients, data was pooled from the RGH-MD-04 pivotal study ( 32 ). Participants were required to have a CGI-S score ≥ 4, a PANSS total score ≥ 80 and ≤ 120, and a score ≥ 4 in at least 2 of the PANSS positive symptoms. Performance based outcomes from the Cognitive Drug Research (CDR) system attention battery ( 41 ), were presented as power of attention (PoA) and continuity of attention (CoA). Overall, the median change from baseline to week 6 in PoA was statistically significant for cariprazine 3 mg/d, but not for cariprazine 6 mg/d or aripiprazole 10 mg/d compared to placebo [M (SD), PBO 27.3 (597.5); CAR 3 mg/d 59 (595), p = 0.0036; CAR 6 mg/d 5.7 (781.8), p = 0.1272 and ARI 10 mg/d 44.2 (828.1), p = 0.4104]. Differences in PoA change were also statistically significant for both doses of cariprazine compared to aripiprazole (CAR 3 mg/d, p = 0.0006; CAR 6 mg/d, p = 0.0260). Besides, a subset of patients with high cognitive impairment defined as those with a PoA time above or equal to the median (≥ 1545.1 ms) at baseline was specifically analyzed. The median change from baseline to week 6 in PoA in this group was statistically significant in favor of cariprazine 3 mg/d vs placebo ( p = 0.0080) and vs aripiprazole ( p = 0.0064). However, difference vs placebo was not significant for cariprazine 6 mg/d ( p = 0 .2974) or aripiprazole (p = 0.4443). Furthermore, overall, the median change from baseline to week 6 in CoA was statistically significant for cariprazine 3 mg/d and cariprazine 6 mg/d but not for aripiprazole compared to placebo [M (SD), PBO 0 (11.7); CAR 3 mg/d 2 (10.5), p = 0.0005; CAR 6 mg/d 1 (14.1), p = 0.0168 and; ARI 10 mg/d 0 (13.9), p = 0.1685]. Besides, a subset with high cognitive impairment defined as patients with a CoA score below or equal to the median CoA score (≤ 88) at baseline showed a median change from baseline to week 6 significantly higher, indicating improvement in all treatment groups compared to placebo (CAR 3 mg/d, p = 0.0012; CAR 6 mg/d, p = 0.0073; ARI, p = 0.0160). Studies performed in bipolar I manic or mixed patients The study presented by McIntyre ( 25 ) also explored a subset of adult patients with a DSM 5 diagnosis of bipolar I manic or mixed episodes. Data were pooled from all 3 pivotal 3-week double-blind, placebo-controlled, flexible-dose randomized clinical trials (NCT00488618 [RGH-MD-31] ( 38 – 40 ), NCT01058096 [RGH-MD-32] ( 39 ) and NCT01058668 [RGH-MD-33] ( 40 ). A post hoc analysis conducted to analyze cognitive symptoms evaluated changes from baseline to week 3 in the Meltzer cognition subscale of the PANSS as well as in each of the Meltzer cognition subscale individual item score. Participants scoring ≥ 20 in the Young Mania Rating Scale (YMRS) total score ( 42 ), a score ≥ 4 on at least 2 of 4 YMRS items (irritability, speech, content, and disruptive/aggressive behavior) and a score ≤ 18.45 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score ( 43 ) were included. Cariprazine doses ranged from 3 mg/d to 12 mg/d. Overall, mean change from baseline to week 3 in the Meltzer cognition subscale score was statistically significant in favor of cariprazine versus placebo (LSMC, CAR 2.2 vs PBO 1.3; p < 0.0001). In addition, 2 subgroups of patients were created based on baseline cognitive performance. A first group composed of patients with greater cognitive impairment defined as a Meltzer cognition subscale score ≥ 15 (moderate severity) and a second less restrictive group made up of patients with a baseline Meltzer cognition subscale score greater than or equal to the median (median = 11) (mild severity). Mean change from baseline to week 3 in the Meltzer cognition subscale score was statistically significant in favor of cariprazine vs placebo in both subset of patients [Meltzer cognition subscale score ≥ 15 (LSMC, CAR − 4.1 vs PBO − 2.0, p < 0.0001) and Meltzer cognition subscale score ≥ Median (LSMC, CAR − 3.1 vs PBO − 1.9, p < 0.001)] as well as in 4/5 individual items. However, a qualitative difference was observed between these two groups. In the first group, those with a worse baseline cognitive performance, differences were statistically significant for all items except disorientation (P2), although in the second group differences were statistically significant for all items but stereotyped thinking (N7). Studies performed in bipolar I major depression Furthermore, the study presented by McIntyre ( 25 ) also explored a third clinical subset made of adult patients with a DSM IV TR diagnosis of bipolar I depression, defined as a Hamilton Depression Rating Scale (HAMD17) total score ( 44 ) ≥ 20, an item 1 from HAMD (depressed mood) score ≥ 2 and, CGI-S score ≥ 4. Data were pooled from 3 pivotal double-blind, placebo-controlled, flexible-dose randomized clinical trials, the first 2 with a 6-week treatment period (NCT02670538 [RGH-MD-53], NCT02670551 [RGH-MD-54]) and a third one with a 8 week follow up (NCT01396447 [RGH-MD-56]) designed with the aim of assessing efficacy, safety and tolerability of cariprazine in patients with bipolar depression. Two different assessments regarding cognitive performance have been carried out in two different population samples. The first part of the study ( 25 ) was carried out in the total bipolar I depression sample and a single item "Concentration Difficulties" (representing difficulties in collecting one's thoughts mounting to incapacitating lack of concentration) was chosen as a cognition measure. Least squares mean changes from baseline to week 6 in favor of all doses of cariprazine compared to placebo were statistically significant in MADRS concentration difficulties score (Item 6) [LSMC, PBO (− 1.2); CAR 1.5 mg/d (-1.6; p < 0.0001) and CAR 3 mg/d (– 1.4; p = 0.0365)]. In addition, 2 patient subgroups with greater levels of cognitive impairment were analyzed. First, patients with at least mild cognitive symptoms (item 6 score ≥ 3) and second, patients with at least moderate cognitive symptoms (item 6 score ≥ 4). Both subset of patients showed a statistically significant mean change from baseline to week 6 compared to placebo [mild cognitive symptoms group (LSMC, PBO − 1.3; CAR 1.5 mg/d − 1.8, p < .0001, and CAR 3 mg/d − 1.5, p = .0292); moderate cognitive symptoms group (LSMC, PBO − 1.5; CAR − 1.9 mg/d − 1.7, p < .0001, and CAR 3 mg/d − 1.5, p = .0366)]. Moreover, the second part of the study ( 25 ) carried out in a different subset of bipolar I depression patients pooled from the RGH-MD-56 pivotal trial, chose the cognitive subscale score of the Functioning Assessment Short Test (FAST) ( 45 ) at week 8 as assessment measure. This scale evaluates functioning in patients with mental disorders. The different domains are based on grouping of the 24 individual items: autonomy (4 items), occupational functioning (5 items), cognitive functioning (5 items), financial issues (2 items), interpersonal relationships (6 items) and leisure time (2 items). The items that make up the cognitive subscale are Ability to Concentrate on a Book/Film, Make Mental Calculations, Solve a Problem Adequately, Remember Newly Learned Names, and Learn New Information concentration. The scores for each item range from 0 to 3. The higher the score, the greater the difficulty. Overall, the difference in change from baseline to week 8 in the FAST Cognitive subscale score was statistically significant in favor of cariprazine 1.5 mg/d vs placebo (LSMD, -1.2, p = 0.0035); but not for cariprazine 3 mg/d vs placebo (LSMD, − 0.5, p > 0.05). Besides, a subgroup composed by patients with baseline cognitive symptoms defined as FAST cognitive score of ≥ 2 on at least 2 of the 5 items was specifically assessed, and a statistically significant difference in change from baseline in FAST cognitive subscale score was found in favor of cariprazine 1.5 mg/d vs placebo (LSMD, − 1.4; p = 0.0039); but not for cariprazine 3 mg/d vs placebo (LSMD, − 0.6, p > 0.05). In addition, changes from baseline were significantly different in favor of cariprazine 1.5 mg/d vs placebo on all individual symptom items included in the FAST Cognitive subscale but on the “memory for a new name” item. No statistically significant difference in favor of cariprazine 3 mg/d was found on any individual item. Finally, the fifth study reviewed was reported by the group of Vieta ( 26 ) who presented a post hoc analysis pooled from a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group fixed dose study (NCT01396447 [RGH-MD-56]) performed on bipolar I major depression patients developed with the aim to evaluate the efficacy of different doses of cariprazine (1.5 mg/d and 3 mg d) compared to placebo on the cognitive subscale score of the Functioning Assessment Short Test (FAST) ( 45 ). Bipolar depression patients were defined as those with a HAMD ( 44 ) total score ≥ 20, an item 1 (depressed mood) from HAMD score ≥ 2 and, CGI-S score ≥ 4. Mean change from baseline at week 8 in favor of cariprazine 1.5 mg/d versus placebo was statistically significant in the cognitive subscale FAST score for 1.5 mg/d (LSMC, CAR − 3.6 vs PBO – 2.4; p < 0.01) but not for the higher dose ( p = 0.0575). A systematic summary of the results presented can be seen in Table 1 . Discussion We have performed a systematic review of all RCT-based studies published to date addressing the cognitive efficacy of cariprazine in schizophrenia and bipolar disorder. We have explored this area of interest based on two different but complementary aspects. First, the unique receptor profile of cariprazine, that is, its binding for the D3 receptor ( 15 ), resulting in full D3 receptor occupancy at clinically relevant doses ( 16 ) that may enhance cognitive performance in people with mental disorders, including improvements in attention, working memory, and executive function as clinical studies have suggested ( 46 , 47 ). And second, the promising results that attribute pro cognitive effect to cariprazine D3 receptor blockade collected from basic research on animal models ( 17 , 18 , 48 ). The 5 reports reviewed examined the efficacy of different doses of cariprazine on the cognitive performance of patients with schizophrenia, bipolar I mania and bipolar I depression ( 22 – 26 ). Regarding patients with schizophrenia, studies with a short follow-up period of 6 weeks, carried out with patients presenting an acute exacerbation have shown that, overall, cariprazine is superior to placebo in all cognitive outcomes and therefore may have a pro cognitive effect. In addition, the cognitive improvement observed with cariprazine compared to placebo is present both in patients in the initial stages of the disease and in those more chronic ones. Also, benefits were observed in the overall population assessed but also in those with a higher cognitive impairment. Moreover, the results presented are coincident despite the application of different measurement instruments and continue to show cognitive benefits attributed to cariprazine in spite of whether different cognitive factors of the PANSS, single PANSS items or a specific battery have been applied. Furthermore, one of the studies reviewed regarding patients with schizophrenia chose another D2 partial agonist, aripiprazole, in addition to placebo as a comparator of the cognitive efficacy. The results from the application of the Cognitive Drug Research (CDR) system attention battery ( 41 ), showed different outcomes depending on whether power of attention (PoA) or continuity of attention (CoA) were assessed. On the one hand, differences in overall PoA change were significant for both doses of cariprazine compared to aripiprazole, however, in those patients with greater cognitive impairment, only low doses of cariprazine (3 mg/d) have shown to be more effective than aripiprazole and placebo. On the other hand, when CoA is addressed, overall performance was significantly better for all doses of cariprazine (3 mg/d and 6 mg/d) but not for aripiprazole compared to placebo. However, in those with higher cognitive impairment an improvement in CoA for all treatment groups was found compared to placebo. Notwithstanding, a discrepancy in relation to the doses of cariprazine associated with a better cognitive improvement has been observed in the studies presented. Marder and colleagues ( 23 ), reported a slightly larger treatment effect with higher doses of cariprazine (4.5 -6 mg/d) compared to lower doses (1.5 and 3 mg/d) on the Marder Disorganized Thought. In the opposite direction, the group of McIntyre ( 25 ) found, both in the total population evaluated as well as in those with higher baseline cognitive impairment, a better cognitive response to cariprazine compared to placebo when low doses (3 mg) but not high doses (6 mg/d) are used in power of attention (PoA) performance. These discrepancies in the cognitive benefit of different doses of cariprazine may be due to both methodological aspects, since some studies use direct measurements of specific cognitive features such as PoA, while others base their results on indirect measurements (Marder Disorganized Thought factor). But also due to pharmacodynamic aspects, since the selectivity for D3 can decrease as the dose is increased ( 49 ). The study by Fleischhacker ( 22 ) with the longest follow up period, supports the cognitive benefit of cariprazine compared to a D2 antagonist, risperidone, in patients with schizophrenia and predominant negative symptoms. Data presented showed a better cognitive performance in all cognitive measures explored (the Marder Disorganized Thought factor, the Meltzer cognition subscale and the difficulty in abstract thinking item) in favor of cariprazine compared to risperidone. The only study addressing the cognitive efficacy of cariprazine in bipolar I manic and mixed patients ( 25 ) also showed the ability of this drug to improve the cognitive functioning compared to placebo in the Meltzer cognition subscale total score and in practically all the individual subscale items explored. This cognitive advantage was significantly presented both in the overall population as well as in patients with moderate and mild cognitive severity. With respect to bipolar I depression patients, 3 population subgroups from 2 different studies showed concordant results in favor of cariprazine versus placebo. The cognitive benefit provided by cariprazine is observed in the entire group of patients with depression, but also in subpopulations with greater baseline cognitive impairment. These favorable results for the drug reviewed remained positive despite of the two different measure systems used to assess cognition in bipolar I depression patients (MADRS concentration difficulties item and FAST cognition subscale). To end, data unanimously showed that this cognitive improvement is predominantly observed with low doses of cariprazine, since cariprazine has greater preference for occupying dopamine D3 receptors vs D2 receptors at lower doses, and, as a consequence, the greater effects on cognitive symptoms described in our current analyses both in bipolar depression and schizophrenia are consistent with its pharmacologic profile suggesting that low doses with greater D3 selectivity could have a more pro cognitive effect ( 49 ). As with all systematic reviews, this review has limitations and strengths. The main limitation is perhaps, that most of the cognitive measures used are not direct cognitive assessments, but indirect ones, that is, obtained from clinical evaluation instruments such as the PANSS in the case of schizophrenia and bipolar I mania or the FAST and the MADRS in the case of bipolar I depression patients. However, although these measures are not direct cognitive variables, they represent an acceptable approximation in the absence of direct a cognitive assessment ( 50 ). As main strength, the quality of the reviewed studies according to Jadad's recommendations and guidelines have been rated and we have found it to be of good to excellent ( 21 ). Overall, the data collected by this review allow us to conclude that the use of cariprazine in patients with schizophrenia and bipolar disorder is presented as an interesting option to address the cognitive deficits that these patients present, which today continue to be an unmet therapeutic need. In addition, the use of cariprazine in patients with schizophrenia, bipolar I mania and bipolar I depression has proven to improve performance on cognitive measures compared to placebo, especially in patients with greater baseline impairment and when low doses are used. Furthermore, the use of cariprazine in patients with schizophrenia could become a more effective therapeutic option to enhance cognition compared to some of the current antipsychotics available. For all the above, and given the lack of treatment options available to improve cognition, it would be advisable to expand research on the potential of cariprazine as a pro cognitive strategy by designing specific studies with the objective of evaluating all affected domains using standardized instruments to measure cognitive performance, that allow us to know the real magnitude of the pro-cognitive effect in patients with schizophrenia, bipolar disorder and other mental disorders. Declarations Declarations Ethics approval and consent to participate Not applicable. Consent for publication Consent for publication was received from all authors. Competing interests Dr. R. Rodriguez-Jimenez has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/ BMD-2422 AGES; S2017/BMD-3740; P2022/BMD-7216), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen-Recordati, Angelini, Rovi. Authors' information Authors and Affiliations Lorena García-Fernández Clinical Medicine Department. Universidad Miguel Hernández, Alicante, Spain. Psychiatry Department, Hospital Universitario de San Juan, Alicante, Spain. CIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain 0000-0001-5523-9762 [email protected] Verónica Romero CIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain. Universidad Europea de Madrid, Madrid, Spain. Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. 0000-0003-3211-1744 [email protected] Inmaculada Peñuelas-Calvo Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. Complutense University of Madrid (UCM), Madrid, Spain. 0000-0003-4093-1312 [email protected] Miguel Ángel Álvarez de Mon Department of Medicine and Medical Specialities. University of Alcalá, Alcalá de Henares, Spain. Department of Psychiatry and Mental Health. Hospital Universitario Infanta Leonor, Madrid, Spain. Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain 0000-0002-1987-0394 [email protected] Mauro Scala Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy 0000-0002-7428-2835 [email protected] Carmen Romero Ferreiro Faculty of Health Sciences, Universidad Francisco de Vitoria, Madrid, Spain. CIBERESP/ISCIII (Biomedical Research Networking Centre for Epidemiology and PublicHealth/Carlos III Health Institute), Spain. 0000-0002-9125-2275 [email protected] Estela Jiménez López CIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain. Center for Social and Health Research, University of Castilla-La Mancha, Cuenca, Spain. Department of Psychiatry, Virgen de La Luz Hospital, Cuenca, Spain. 0000-0001-8553-7701 [email protected] José Luis Santos CIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain. Department of Psychiatry, Virgen de La Luz Hospital, Cuenca, Spain. Neurobiological Research Group. Technological Institute, University of Castilla-La Mancha, Cuenca, Spain 0000-0002-4692-1310 [email protected] Roberto Rodríguez-Jiménez CIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain. Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. Complutense University of Madrid (UCM), Madrid, Spain. 0000-0003-2251-7249 [email protected] Funding This research was supported in part by the Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), and by CIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors' contributions RRJ is the guarantor of this review. LGF, VR and RRJ defined the research question. LGF and VR developed the search strategy and determined inclusion and exclusion criteria. Methodological support was provided by VR. LGF and RRJ created the first draft of this manuscript, and all authors reviewed and approved the final draft Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia-An Overview. JAMA Psychiatry. 2020;77(2):201–210. 10.1001/jamapsychiatry . 2019;3360. Gebreegziabhere Y, Habatmu K, Mihretu A, Cella M, Alem A. Cognitive impairment in people with schizophrenia: an umbrella review. Eur Arch Psychiatry Clin Neurosci. 2022;272(7):1139–55. 10.1007/s00406-022-01416-6 . Horan WP, Catalano LT, Green MF. An Update on Treatment of Cognitive Impairment Associated with Schizophrenia. Curr Top Behav Neurosci. 2023;63:407–36. 10.1007/7854_2022_382 . Rodriguez-Jimenez R, Santos JL, Dompablo M et al. MCCB cognitive profile in Spanish first episode schizophrenia patients. Schizophr Res. 2019;211:88–92. 10.1016/j.schres. 2019; 211:88–92. Targum SD, Keefe RS. Cognition and schizophrenia: is there a role for cognitive assessments in diagnosis and treatment? Psychiatry (Edgmont). 2008;5(12):55–9. Franck N. Réhabilitation psychosociale dans la schizophrénie [Psychiatric rehabilitation in schizophrenia]. Rev Prat. 2021;71(1):52–7. Maric NP, Jovicic MJ, Mihaljevic M, Miljevic C. Improving Current Treatments for Schizophrenia. Drug Dev Res. 2016;77(7):357–67. https://doi.org/10.1002/ddr.21337 . Fitapelli B, Lindenmayer JP. Advances in cognitive remediation training in schizophrenia: a review. Brain Sci. 2022;12. 10.3390/brainsci12020129 . Cella M, Price T, Corboy H, Onwumere J, Shergill S, Preti A. Cognitive remediation for inpatients with psychosis: a systematic review and meta-analysis. Psychol Med. 2020;50:1062–76. 10.1017/S0033291720000872 . Rauly-Lestienne I, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Cussac D. Differential profile of typical, atypical and third generation antipsychotics at human 5-HT7a receptors coupled to adenylyl cyclase: detection of agonist and inverse agonist properties. Naunyn Schmiedebergs Arch Pharmacol. 2007;376(1–2):93–105. Lieberman JA. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs. 2004;18(4):251–67. Hirose T, Kikuchi T. Aripiprazole, a novel antipsychotic agent: dopamine D2 receptor partial agonist. J Med Invest. 2005;52:284–90. 10.2152/jmi.52.284 . Laszlovszky I, Barabássy Á, Németh G, Cariprazine. A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety. Adv Ther. 2021;38(7):3652–73. 10.1007/s12325-021-01797-5 . Johnson DE, McIntyre RS, Mansur RB, Rosenblat JD. An update on potential pharmacotherapies for cognitive impairment in bipolar disorder. Expert Opin Pharmacother. 2023;24(5):641–54. https://doi.org/10.1080/14656566.2023.2194488 . Calabrese F, Tarazi FI, Racagni G, Riva MA. The role of dopamine D3 receptors in the mechanism of action of cariprazine. CNS Spectr. 2020;25(3):343–51. Stahl SM. Mechanism of action of cariprazine. CNS Spectr. 2016;21(2):123–7. Zimnisky R, Chang G, Gyertyán I, Kiss B, Adham N, Schmauss C. 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. 2013;226(1):91–100. 10.1007/s00213-012-2896-5 . Watson DJG, King MV, Gyertyán I, Kiss B, Adham N, Fone KCF. The dopamine D₃-preferring D₂/D₃ dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia. Eur Neuropsychopharmacol. 2016;26(2):208–24. Olivola M, Bassetti N, Parente S, Arienti V, Civardi SC, Topa PA, Brondino N. Cognitive Effects of Lurasidone and Cariprazine: A Mini Systematic Review. Curr Neuropharmacol. 2023;21(12):2431–46. https://doi.org/10.2174/1570159X21666230727140843 . Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann T, Mulrow CD, Shamseer L, Tetzlaff J, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. https://doi.org/10.1136/bmj.n71 . Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12. 10.1016/0197-2456(95)00134-4 . Fleischhacker W, Galderisi S, Laszlovszky I, et al. The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors. Eur Psychiatry. 2019;58:1–9. 10.1016/j.eurpsy.2019.01.015 . Marder S, Fleischhacker WW, Earley W, Lu K, Zhong Y, Németh G, Laszlovszky I, Szalai E, Durgam S. Efficacy of cariprazine across symptom domains in patients with acute exacerbation of schizophrenia: Pooled analyses from 3 phase II/III studies. Eur Neuropsychopharmacol. 2019;29(1):127–36. 10.1016/j.euroneuro.2018.10.008 . Falkai P, Dombi ZB, Acsai K, Barabássy Á, Schmitt A, Németh G. The efficacy and safety of cariprazine in the early and late stage of schizophrenia: a post hoc analysis of three randomized, placebo-controlled trials. CNS Spectr. 2023;28(1):104–11. 10.1017/S1092852921000997 . McIntyre RS, Daniel DG, Vieta E, Laszlovszky I, Goetghebeur PJ, Earley WR, Patel MD. The efficacy of cariprazine on cognition: a post hoc analysis from phase II/III clinical trials in bipolar mania, bipolar depression, and schizophrenia. CNS Spectr. 2023;28(3):319–30. 10.1017/S109285292200013X . Vieta E, Calabrese JR, Whelan J, Tohen M, Earley WR. The efficacy of cariprazine on function in patients with bipolar depression: a post hoc analysis of a randomized controlled trial. Curr Med Res Opin. 2021;37(9):1635–43. 10.1080/03007995.2021.1932446 . Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry. 1997;58:538–46. White L, Harvey PD, Opler L, Lindenmayer JP. Empirical assessment of the factorial structure of clinical symptoms in schizophrenia. A multisite, multimodel evaluation of the factorial structure of the Positive and Negative Syndrome Scale. The PANSS Study Group. Psychopathology. 1997;30:263–74. Meltzer HY, Cucchiaro J, Silva R, Ogasa M, Phillips D, Xu J, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry. 2011;168:957–67. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–76. 10.1093/schbul/13.2.261 . Durgam S, Starace A, Li D, et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res. 2014;152(2–3):450–7. Durgam S, Cutler AJ, Lu K, et al. Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind,placebo- and active-controlled trial. J Clin Psychiatry. 2015;76(12):e1574–82. Kane JM, Zukin S, Wang Y, et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: results from an International. Phase III clinical trial. J Clin Psychopharmacol. 2015;35(4):367–73. Guy W. Clinical global impressions scale. Psychiatry; 1976. Durgam S, Earley W, Guo H, Li D, Németh G, Laszlovszky I, et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: Results from an international, phase III clinical trial. J Clin Psychopharmacol. 2015;35(4):367–73. Earley W, Burgess MV, Rekeda L, et al. Cariprazine treatment of bipolar depression: a randomized double-blind placebo-controlled phase 3 study. Am J Psychiatry. 2019;176(6):439–48. Earley WR, Burgess MV, Khan B, et al. Efficacy and safety of cariprazine in bipolar I depression: a double-blind, placebo-controlled phase 3 study. Bipolar Disord. 2020;22(4):372. Calabrese JR, Keck PE Jr, Starace A, et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2015;76(3):284–92. Durgam S, Starace A, Li D, et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial. Bipolar Disord. 2015;17(1):63–75. Sachs GS, Greenberg WM, Starace A, et al. Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, phaseIII trial. J Affect Disord. 2015;174:296–302. Simpson PM, Surmon DJ, Wesnes KA, Wilcock GK. The cognitive drug research computerized assessment system for demented patients: a validation study. Int J Geriatr Psychiatry. 1991;6(2):95–102. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–35. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–9. 10.1192/bjp.134.4.382 . Hamilton M. Rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62. Rosa AR, Sánchez-Moreno J, Martínez-Aran A, Salamero M, Torrent C, Reinares M, Comes M, Colom F, Van Riel W, Ayuso-Mateos JL, Kapczinski F, Vieta E. Validity and reliability of the Functioning Assessment Short Test (FAST) in bipolar disorder. Clin Pract Epidemiol Ment Health. 2007;3:5. https://doi.org/10.1186/1745-0179-3-5 . Citrome L. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013;30(2):114–26. 10.1007/s12325-013-0006-7 . Sokoloff P, Le Foll B. The dopamine D3 receptor, a quarter century later. Eur J Neurosci. 2017;45(1):2–19. 10.1111/ejn.13390 . Heidbreder CA, Newman AH. Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders. Ann N Y Acad Sci. 2010;1187:4–34. 10.1111/j.1749-6632.2009.05149.x . Girgis RR, Slifstein M, D’Souza D, et al. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(þ)-PHNO. Psychopharmacology. 2016;233(19–20):3503–12. Bagney A, Dompablo M, Santabárbara J, Moreno-Ortega M, Lobo A, Jimenez-Arriero MA, Palomo T, Rodriguez-Jimenez R. Are negative symptoms really related to cognition in schizophrenia? Psychiatry Res. 2015;230(2):377 – 82. doi: 10.1016/j.psychres.2015.09.022. Epub 2015 Sep 14. PMID: 26454405. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3857313","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":283956284,"identity":"44542d3f-6d1d-44cd-a6c0-dfc8c38641da","order_by":0,"name":"LORENA Garcia-Fernandez","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYBACPmTOAQYbGwYGCQJa2FC1pKWRqIWBIe0wEVrYex8+LqhhsOufffjhgR8J5xPXzm5gfPgDnxae48bGM44xJM84l2ZwsCfhduK2OweYjXnwaZFIY5PmYWNIZjjDw3CA9wdQy40ENmm8DpNIY//N848hWR6o5eCfhHMgLew/8ToMaAszbxuDnQFQy2GehANgWxjwOoznGLM0b59EguEZNoPDMgnJxttuJDZL49PCz97G+Jnnm4293Bnmxx/fJNjJbruRfPAjPodBgURiA4LD2IBLGQqwJ0rVKBgFo2AUjEwAAGorSlC9eP7hAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-5523-9762","institution":"Universidad Miguel Hernandez de Elche","correspondingAuthor":true,"prefix":"","firstName":"LORENA","middleName":"","lastName":"Garcia-Fernandez","suffix":""},{"id":283956285,"identity":"5d9809d8-52b6-44ad-9ed2-a427b6e9e27f","order_by":1,"name":"Veronica Romero","email":"","orcid":"","institution":"Universidad Europea: Universidad Europea de Madrid SLU","correspondingAuthor":false,"prefix":"","firstName":"Veronica","middleName":"","lastName":"Romero","suffix":""},{"id":283956286,"identity":"bbb5354c-0ac9-4d40-bb22-eecedf3946a4","order_by":2,"name":"Inmaculada Peñuelas-Calvo","email":"","orcid":"","institution":"Complutense University of Madrid: Universidad Complutense de Madrid","correspondingAuthor":false,"prefix":"","firstName":"Inmaculada","middleName":"","lastName":"Peñuelas-Calvo","suffix":""},{"id":283956287,"identity":"1749f89d-56df-4cbc-ac08-a35366f47ed3","order_by":3,"name":"Miguel Angel Álvarez de Mon","email":"","orcid":"","institution":"Universidad de Alcala","correspondingAuthor":false,"prefix":"","firstName":"Miguel","middleName":"Angel Álvarez","lastName":"de Mon","suffix":""},{"id":283956288,"identity":"2eccae77-8a5b-42c5-b3c7-001bd581fe3f","order_by":4,"name":"Mauro Scala","email":"","orcid":"","institution":"Università di Bologna: Universita di Bologna","correspondingAuthor":false,"prefix":"","firstName":"Mauro","middleName":"","lastName":"Scala","suffix":""},{"id":283956289,"identity":"06fca86d-e465-4d27-b8c4-f7bf8aa871c0","order_by":5,"name":"Carmen Romero Ferreiro","email":"","orcid":"","institution":"Francisco de Vitoria University: Universidad Francisco de Vitoria","correspondingAuthor":false,"prefix":"","firstName":"Carmen","middleName":"Romero","lastName":"Ferreiro","suffix":""},{"id":283956290,"identity":"d5041d35-7bbf-492a-9c0b-8b5d1897c30c","order_by":6,"name":"Estela Jiménez López","email":"","orcid":"","institution":"University of Castilla-La Mancha: Universidad de Castilla-La Mancha","correspondingAuthor":false,"prefix":"","firstName":"Estela","middleName":"Jiménez","lastName":"López","suffix":""},{"id":283956291,"identity":"47ee2f5a-9e3c-4a1b-ad02-2ce9b48c51bf","order_by":7,"name":"Jose Luis Santos","email":"","orcid":"","institution":"Virgen de la Luz Hospital: Hospital Virgen de la Luz","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"Luis","lastName":"Santos","suffix":""},{"id":283956292,"identity":"2d45cfdf-37a5-4ef6-bdd5-9ebd4916bc09","order_by":8,"name":"Roberto Rodriguez-Jimenez","email":"","orcid":"","institution":"Complutense University of Madrid: Universidad Complutense de Madrid","correspondingAuthor":false,"prefix":"","firstName":"Roberto","middleName":"","lastName":"Rodriguez-Jimenez","suffix":""}],"badges":[],"createdAt":"2024-01-12 14:46:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3857313/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3857313/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53751229,"identity":"b5aa3869-1a0a-4060-964c-860fb5a37a67","added_by":"auto","created_at":"2024-03-29 18:44:28","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":534542,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flowchart and results of our database search, including reasons for exclusion and studies selected.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3857313/v1/d865c7d79e3029700d7362e0.jpeg"},{"id":56483862,"identity":"1c94370c-6ca1-4384-be4c-c721bf3bbb11","added_by":"auto","created_at":"2024-05-14 19:25:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":880130,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3857313/v1/bb06ff41-add5-4656-b734-56dd2f1a63e4.pdf"}],"financialInterests":"","formattedTitle":"Cariprazine and cognition in patients with schizophrenia and bipolar disorder: A systematic review","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePsychotic disorders and, specifically schizophrenia, constitute a group of diseases that affect different symptomatic domains known as positive, negative, affective and cognitive symptoms. All those domains have shown to be related but they are considered independent features (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) and therefore, require a differentiated therapeutic approach.\u003c/p\u003e \u003cp\u003eCognition has been identified as a core feature of schizophrenia (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Cognitive deficits have been observed in the initial stages of the disease as well as in chronic patients, in patients in remission, in naive patients and even in high-risk mental states or in first-degree relatives of people affected by the disease (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Moreover, cognitive deficits have been identified in practically all affected people presenting a heterogeneous and diffuse impairment that affects almost all cognitive domains performing between 1\u0026ndash;2 standard deviations (SD) below the average in healthy people (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCognition has also been postulated as one of the main domains of schizophrenia and bipolar disorder, especially affecting important areas of life such as community functioning, problems coping, successful employment and independent living (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In addition, cognitive performance has also been associated with the ability to successfully benefit from the different psychotherapeutic remediation programs available (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Though, despite the cognitive advances achieved in pharmacological (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and non-pharmacological approaches (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) for people with schizophrenia, cognitive improvement remains an unmet therapeutic target.\u003c/p\u003e \u003cp\u003eNonetheless, to date, current antipsychotic medications have shown little potential to improve cognition in schizophrenia and bipolar disorder patients, but the appearance of the so-called third generation antipsychotics has allowed the scientific community to hypothesize about the pro cognitive effects of these drugs (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Those agents act as partial agonists with a lower intrinsic receptor activity that enables them to act as either functional agonists or antagonists depending on the surrounding neurotransmitter environment (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Therefore, a D2 receptor partial agonist behaves as an antagonist in a hyperdopaminergic environment, and as an agonist when hypodopaminergia predominates (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). This interesting mechanism of action gives this group of antipsychotics the ability to address the positive symptoms generated by states of hyperdopaminergia in the mesolimbic circuit and, also the negative and cognitive ones, related to mesocortical hypodopaminergia (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Research has shown incipient results that, although promising, are still inconclusive and without the desirable clinical relevance (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Furthermore, the appearance of cariprazine is of special interest. Cariprazine is a partial agonist at the dopamine D2 and D3 receptors and serotonin 5-HT1A receptors, and antagonist at the 5-HT2B receptors (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). It differs from the rest of the drugs belonging to this group in its specific binding for the D3 receptor, mainly expressed in the mesolimbic pathway, higher than dopamine itself, resulting in full D3 receptor occupancy at clinically relevant doses (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCariprazine, especially through the D3 receptor partial agonist effect, has already demonstrated pro cognitive activity in phencyclidine animal models (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In vitro studies have also emphasized the pro cognitive properties of cariprazine observed in D3 Knockout mice, which has not been found in the wild ones (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Therefore, the role of the D3 receptor has been postulated as crucial in addressing cognitive impairment in people with schizophrenia and bipolar disorder and, as a consequence, cariprazine, due to its specific D3 receptor profile, might improve the cognitive deficits inherent to the disease.\u003c/p\u003e \u003cp\u003eRecently, several studies have been published on the pro cognitive effects of cariprazine in patients with schizophrenia and bipolar disorder, although a systematic review has not yet been carried out with the exception of a minireview that only included 2 clinical studies publish before 2021 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Therefore, we ought to systematically review all available studies regarding the effectiveness of cariprazine in the cognitive impairments suffered by people with psychotic symptoms, especially patients with schizophrenia and bipolar disorder.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSelection criteria and search strategy\u003c/h2\u003e \u003cp\u003eWe carried out a systematic review regarding cariprazine and cognition in people with schizophrenia and bipolar disorder, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines 2020 version (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Search Methods and Results are highlighted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The protocol was registered on PROSPERO (registration number: CRD42023485028).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePatients with a mental disorder of any age in any stage of the disease have been included. Studies in populations receiving treatment with cariprazine in all flexible doses have also been included.\u003c/p\u003e \u003cp\u003eStudies included in this review were limited to English-language and studies published before December 2023. Articles in languages other than English have been excluded. Search was limited to human studies and included randomized controlled trials (RCTs). Narrative reviews, case reports, conference abstracts, letters or editorials have been excluded. Any follow-up period length has been included.\u003c/p\u003e \u003cp\u003ePubMed (medline), Web of Science, Scopus and the Cochrane database were searched for articles related to the effectiveness of cariprazine on cognitive functioning. The search terms used were (CARIPRAZINE AND COGNIT*) using \u0026lsquo;humans\u0026rsquo; as filter. In addition, a manual search of the reference lists of the included studies was performed for additional eligible studies. The electronic search was conducted until December 31st, 2023. The Participant (patients with schizophrenia, bipolar I mania and bipolar I depression), Intervention (cariprazine), Comparator (placebo or any other antipsychotic agent), and Outcome (cognitive improvement) (PICO) framework was used to define the inclusion criteria.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection and risk of bias assessment\u003c/h2\u003e \u003cp\u003eTwo reviewers (LGF, VRF) independently screened the titles and abstracts of potentially eligible articles, reviewed full text articles, and checked inclusion criteria. Differences were discussed and in case of doubt the study methodology was carefully analyzed. A senior reviewer (RRJ) was consulted if consensus was not achieved.\u003c/p\u003e \u003cp\u003eThe methodological quality of the RCTs was addressed using the Jadad scale (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) which evaluates the quality of each trial on a five-domain scale (randomization and allocation, methodology to generate randomization, blinding, methodology of blinding and, withdrawals and dropouts), able to affect the global quality of the report. Each study included in the review has been assigned a numerical value that ranges from 0 (high risk of bias) to 5 (low risk of bias). To evaluate the quality of the post hoc studies, the original pivotal studies from which the sample has been selected have been taken as a reference.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measures\u003c/h2\u003e \u003cp\u003eTo describe the results, the comparison statistics presented by each of the reviewed studies have been used.\u003c/p\u003e \u003cp\u003eResults obtained have been reflected as the mean change from baseline to the end of the follow up period, pooled in the intention to treat (ITT) population and also in specific population subgroups created based on the degree of cognitive impairment. Median (M) and standard deviation (SD) change from baseline, Least squares mean change (LSMC), Least squares mean difference (LSMD), and effect sizes (ES) for the change from baseline to end of follow up have been used to present the data.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStudies selection\u003c/h2\u003e \u003cp\u003eThe electronic search initially identified 136 papers in the screened database, including full-text articles, case reports and congress communications. Up to 5 additional records were selected through the searched report\u0026acute;s references and other sources. Next, 37 records were removed as they were duplicates. Of the 104 pooled articles retrieved on the basis of their titles and abstracts, 85 were excluded due to different reasons that are described in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. At this point, a total of 19 articles were screened on the basis of full texts and finally, according to study inclusion criteria, 5 studies with post hoc analysis of positive phases II/III double blinded randomized controlled trials were included in this systematic review (\u003cspan additionalcitationids=\"CR23 CR24 CR25\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the search process according to the PRISMA flow-chart.\u003c/p\u003e \u003cp\u003eRegarding the different mental disorders, up to 3 studies assessed the cognitive improvement in people with schizophrenia, one of them in a population with predominance of negative symptoms (PPNS); a fourth study explored the cognitive performance in 3 samples of patients with different diagnoses: schizophrenia, bipolar I major depression and bipolar I mania and mixed episodes and, lastly, 1 final trial evaluated the cognitive benefit in patients with bipolar I major depression. The details of each study are reported in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of the reviewed studies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst author, and date\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePopulation, N\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDuration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eComparison (n), doses\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eQuality*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFleischhacker et al, 2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePost hoc analysis from 1 randomized, double-blind, controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSchizophrenia,\u003c/p\u003e \u003cp\u003e(negative symptoms),\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u0026ndash;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;227) 3\u0026ndash;6 mg/d\u003c/p\u003e \u003cp\u003evs RIS (N\u0026thinsp;=\u0026thinsp;229) 3\u0026ndash;6 mg/d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMarder Disorganized Thoughts factor LSMD (CAR vs RIS \u0026minus;\u0026thinsp;0.63, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/p\u003e \u003cp\u003eMeltzer Cognitive Subscale LSMD (CAR vs RIS \u0026minus;\u0026thinsp;0.53, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/p\u003e \u003cp\u003eDifficulty in Abstract Thinking item LSMD (CAR vs RIS \u0026minus;\u0026thinsp;0.17, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarder et al, 2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePost hoc analysis from 3 randomized, double-blind,\u003c/p\u003e \u003cp\u003econtrolled trials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSchizophrenia\u003c/p\u003e \u003cp\u003e(acute exacerbation),\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;1466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u0026ndash;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;1024) 1,5\u003cb\u003e\u0026ndash;\u003c/b\u003e9 mg/d vs PBO (N\u0026thinsp;=\u0026thinsp;442)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMarder Disorganized Thoughts factor LSMD (CAR vs PBO \u0026minus;\u0026thinsp;2, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003cp\u003eMarder Disorganized Thoughts factor ES (CAR vs PBO 0.47, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003cp\u003eTreatment effects CAR 4.5-6 mg/d\u0026thinsp;\u0026gt;\u0026thinsp;CAR 1.5-3 mg/d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVieta et al, 2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePost hoc analysis from 1 randomized, double-blind, controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBipolar I\u003c/p\u003e \u003cp\u003e(major depression),\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;393\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u0026ndash;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;135) 1,5 mg/d\u003c/p\u003e \u003cp\u003evs CAR (N\u0026thinsp;=\u0026thinsp;126) 3 mg/d\u003c/p\u003e \u003cp\u003evs PBO (N\u0026thinsp;=\u0026thinsp;132)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFAST Cognitive subscale LSMD (CAR 1.5 mg/d vs PBO \u0026minus;\u0026thinsp;1.2, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFalkai et al, 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePost hoc analysis from 3 randomized, double-blind, controlled trials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSchizophrenia\u003c/p\u003e \u003cp\u003e(acute exacerbation),\u003c/p\u003e \u003cp\u003eEarly stage, N\u0026thinsp;=\u0026thinsp;460\u003c/p\u003e \u003cp\u003eLate stage, N\u0026thinsp;=\u0026thinsp;414\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u0026ndash;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEarly stage patients\u003c/p\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;302) vs PBO (N\u0026thinsp;=\u0026thinsp;140)\u003c/p\u003e \u003cp\u003eLate stage patients\u003c/p\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;271) vs PBO (N\u0026thinsp;=\u0026thinsp;125)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMarder Disorganized Thoughts factor\u003c/p\u003e \u003cp\u003eEarly stage\u003c/p\u003e \u003cp\u003eLSMD (CAR vs PBO \u0026minus;\u0026thinsp;1.2; ES 0.39, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001)\u003c/p\u003e \u003cp\u003eLate stage\u003c/p\u003e \u003cp\u003eLSMD (CAR vs PBO \u0026minus;\u0026thinsp;1.3, ES 0.39, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMcIntyre et al, 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePost hoc analysis from 3 randomized, double-blind, controlled trials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSchizophrenia,\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;520\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u0026ndash;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePoA\u003c/p\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;124) 3 mg/d\u003c/p\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;137) 6 mg/d\u003c/p\u003e \u003cp\u003eARI (N\u0026thinsp;=\u0026thinsp;130) 10 mg/d\u003c/p\u003e \u003cp\u003evs PBO (N\u0026thinsp;=\u0026thinsp;129)\u003c/p\u003e \u003cp\u003eCoA\u003c/p\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;122) 3 mg/d\u003c/p\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;135) 6 mg/d\u003c/p\u003e \u003cp\u003eARI (N\u0026thinsp;=\u0026thinsp;130) 10 mg/d\u003c/p\u003e \u003cp\u003evs PBO (N\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePoA (ms) Median (SD) change from baseline\u003c/p\u003e \u003cp\u003eITT - PBO 27.3 (597.5); CAR 3 mg/d 59 (595) p\u0026thinsp;=\u0026thinsp;0.0036; CAR 6 mg/d 5.7 (781.8), p\u0026thinsp;=\u0026thinsp;0.1272; ARI 10 mg/d 44.2 (828.1), p\u0026thinsp;=\u0026thinsp;0.4104\u003c/p\u003e \u003cp\u003eDifferences in PoA median change from baseline (CAR vs ARI)\u003c/p\u003e \u003cp\u003eITT - CAR 3 mg/d, p\u0026thinsp;=\u0026thinsp;0.0006; CAR 6 mg/d, p\u0026thinsp;=\u0026thinsp;0.0260\u003c/p\u003e \u003cp\u003eDifferences in PoA in high cognitive impairment group (49,8%)\u003c/p\u003e \u003cp\u003eCAR 3 mg/d vs PBO LSMC \u0026minus;\u0026thinsp;240, p\u0026thinsp;=\u0026thinsp;0.0080\u003c/p\u003e \u003cp\u003eCAR 3 mg/d vs ARI LSMC \u0026minus;\u0026thinsp;210, p\u0026thinsp;=\u0026thinsp;0.0064\u003c/p\u003e \u003cp\u003eCoA Median (SD) change from baseline\u003c/p\u003e \u003cp\u003eITT - PBO 0 (11.7); CAR 3 mg/d 2 (10.5), p\u0026thinsp;=\u0026thinsp;0.0005); CAR 6 mg/d 1 (14.1), p\u0026thinsp;=\u0026thinsp;0.0168; ARI 10 mg/d 0 (13.9), p\u0026thinsp;=\u0026thinsp;0.1685\u003c/p\u003e \u003cp\u003eDifferences in CoA in high cognitive impairment group (54,4%)\u003c/p\u003e \u003cp\u003eCAR 3 mg/d vs PBO LSMC 4.9, p\u0026thinsp;=\u0026thinsp;0.0012\u003c/p\u003e \u003cp\u003eCAR 6 mg/d vs PBO LSMC 4.0, p\u0026thinsp;=\u0026thinsp;0.0073\u003c/p\u003e \u003cp\u003eARI 10 mg/d vs PBO LSMC 4.0, p\u0026thinsp;=\u0026thinsp;0.0160\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePost hoc analysis from 3 randomized, double-blind,\u003c/p\u003e \u003cp\u003econtrolled trials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBipolar I major depression,\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;1383\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e18\u0026ndash;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;461) 1,5 mg/d\u003c/p\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;462) 3 mg/d\u003c/p\u003e \u003cp\u003evs PBO (N\u0026thinsp;=\u0026thinsp;460)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMADRS Concentration Difficulties item LSMC (CAR vs PBO)\u003c/p\u003e \u003cp\u003eITT - PBO (\u0026minus;\u0026thinsp;1.2); CAR 1.5 mg/d -1.6; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 and CAR 3 mg/d \u0026ndash; 1.4; p 0.0365\u003c/p\u003e \u003cp\u003eMild severity group (88.4%) - PBO \u0026minus;\u0026thinsp;1.3; CAR 1.5 mg/d \u0026minus;\u0026thinsp;1.8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, and CAR 3 mg/d \u0026minus;\u0026thinsp;1.5, p\u0026thinsp;=\u0026thinsp;0.0292\u003c/p\u003e \u003cp\u003eModerate severity group (66.0%)- PBO \u0026minus;\u0026thinsp;1.5; CAR \u0026minus;\u0026thinsp;1.9 mg/d \u0026minus;\u0026thinsp;1.7, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, and CAR 3 mg/d \u0026minus;\u0026thinsp;1.5, p\u0026thinsp;=\u0026thinsp;0.0366\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;135) 1,5mg/d\u003c/p\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;126) 3 mg/d\u003c/p\u003e \u003cp\u003evs PBO (N\u0026thinsp;=\u0026thinsp;132)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFAST Cognitive subscale LSMD (CAR vs PBO)\u003c/p\u003e \u003cp\u003eITT LSMD (CAR 1,5 mg vs PBO \u0026minus;\u0026thinsp;1.2; p\u0026thinsp;=\u0026thinsp;0 .0035)\u003c/p\u003e \u003cp\u003eCognitive impairment group (75,8%) LSMD (CAR 1,5 mg vs PBO \u0026minus;\u0026thinsp;1.4; p\u0026thinsp;=\u0026thinsp;0 .0039)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePost hoc analysis from 3 randomized, double-blind, controlled trials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBipolar I mania and mixed episodes,\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;1012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u0026ndash;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCAR (N\u0026thinsp;=\u0026thinsp;593) 3\u0026ndash;12 mg/d\u003c/p\u003e \u003cp\u003evs PBO (N\u0026thinsp;=\u0026thinsp;419)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMeltzer Cognitive Subscale (CAR vs PBO)\u003c/p\u003e \u003cp\u003eITT LSMD (\u0026minus;\u0026thinsp;0.9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003cp\u003eMild severity group (\u0026gt;\u0026thinsp;50%) LSMD \u0026minus;\u0026thinsp;1.2, p\u0026thinsp;\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003cp\u003eLSMD P2: \u0026minus;\u0026thinsp;0.4, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; N5: \u0026minus;\u0026thinsp;0.2, p\u0026thinsp;=\u0026thinsp;0.0127; N7: \u0026minus;\u0026thinsp;0.1, p\u0026thinsp;=\u0026thinsp;0.1246; G10: \u0026minus;\u0026thinsp;0.1, p\u0026thinsp;=\u0026thinsp;0.0392; G11: \u0026minus;\u0026thinsp;0.3, p\u0026thinsp;=\u0026thinsp;0.0002\u003c/p\u003e \u003cp\u003eModerate severity group (17,2%) LSMD \u0026minus;\u0026thinsp;2.1, p\u0026thinsp;\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003cp\u003eLSMD P2: \u0026minus;\u0026thinsp;0.6, p\u0026thinsp;\u0026lt;\u0026thinsp;.001; N5: \u0026minus;\u0026thinsp;0.5, p\u0026thinsp;\u0026lt;\u0026thinsp;.01; N7: \u0026minus;\u0026thinsp;0.3, p\u0026thinsp;\u0026lt;\u0026thinsp;.05; G 10: \u0026minus;\u0026thinsp;0.2, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05; G11: 0.5, p\u0026thinsp;\u0026lt;\u0026thinsp;.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003ePANSS, Positive and Negative Syndrome Scale; PPNS, Patients with predominant negative symptoms; Marder Disorganized Thoughts factor (N5, P2, G5, G10, G11, G13, G14); Meltzer Cognitive Subscale (N5, N7, P2, G10, G11); FAST, Functional Assessment Staging Test; CAR, cariprazine; RIS, risperidone; ARI, aripiprazole; PBO, placebo; ITT, intention to treat total population; PoA, power of attention; CoA, continuity of attention; LS, least squares; LSMD, least squares mean difference; LSMC: least squares mean change; ES, effect size; M, media; SD, standard deviation. * Quality of clinical trials according to the Jadad scale.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOverall, the studies reviewed were of good to excellent quality of evidence (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Thus, the total strength of recommendations of this review according to the National Health and Medical Research Council (NHMRC) (2009) is good to excellent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSynthesis of results\u003c/h2\u003e \u003cp\u003eUp to 5 post hoc analysis conducted on data from different pivotal phase II/III double blinded randomized controlled trials carried out in adults with the aim of analyzing the efficacy, safety and tolerability of different doses of cariprazine (CAR) compared to placebo (PBO), aripiprazole (ARI) and risperidone (RIS) in patients with schizophrenia, bipolar I mania and bipolar I depression were reviewed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStudies performed in schizophrenia patients\u003c/h2\u003e \u003cp\u003eA total of four of the reviewed reports addressed cognition in patients with schizophrenia. Schizophrenia RCTs included 3 short 6-week follow up (NCT00694707 [RGH-MD-16], NCT01104766 [RGH-MD-04] and NCT01104779 [RGH-MD-05]), and 1 long-term 26-week follow up studies (EudraCT 2012-005485-36 [RGH-188-005]).\u003c/p\u003e \u003cp\u003eThe first study (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), based on data from the prospective pivotal study RGH-MD-188-005 was designed to explore the effectiveness of cariprazine compared to risperidone in patients with a DSM IV TR diagnosis of schizophrenia and predominant negative symptoms (PNNS) defined as the presence of PPNS for \u0026ge;\u0026thinsp;6 months, Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) score\u0026thinsp;\u0026ge;\u0026thinsp;24, and a score\u0026thinsp;\u0026ge;\u0026thinsp;4 on at least 2 of 3 negative symptoms item, after a 26 week follow up period. The cognition measures used in this study were Improvement in the Marder\u0026rsquo;s disorganized thoughts factor of the PANSS (items N5, P2, G5, G10, G11, G13, G14) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), the Meltzer cognition subscale of the PANSS (items N5, N7, P2, G10, G11) (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) and the difficulty in abstract thinking item of the PANSS (N5) (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Differences in mean change from baseline at week 26 in favor of cariprazine 4.5 mg/d compared to risperidone 4 mg/d were statistically significant in the Marder\u0026rsquo;s Disorganized Thoughts factor (LSMC, CAR \u0026minus;\u0026thinsp;4.16 vs RIS \u0026minus;\u0026thinsp;3.53; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), the Meltzer Cognitive Subscale (LSMC, CAR \u0026minus;\u0026thinsp;3.13 vs RIS \u0026minus;\u0026thinsp;2.60, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and the individual item difficulty in abstract thinking, N5 of the PANSS (LSMC, CAR \u0026minus;\u0026thinsp;0.89 vs RIS \u0026minus;\u0026thinsp;0.72, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eThe second study published by Marder (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), based on data pooled from 3 similarly designed, pivotal positive, 6-week, double-blind, placebo-controlled, phase II/III trials [RGH-MD-16 (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), RGH-MD-04 (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), and RGH-MD-05 (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e)] was designed to explore the efficacy of cariprazine across different symptom domains in DSM IV TR diagnosis of schizophrenia. Acute patients were defined as those with a Clinical Global Impressions-Severity of Illness (CGI-S) (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) score\u0026thinsp;\u0026ge;\u0026thinsp;4, a PANSS (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) total score\u0026thinsp;\u0026ge;\u0026thinsp;80 and \u0026le;\u0026thinsp;120 and, a score\u0026thinsp;\u0026ge;\u0026thinsp;4 in at least 2 of the PANSS positive symptoms. Differences in mean change from baseline at week 6 in favor of all doses of cariprazine versus placebo were statistically significant in the Marder Disorganized Thought factor (LSMC, CAR \u0026minus;\u0026thinsp;4.5 vs PBO \u0026minus;\u0026thinsp;2.5; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). In addition, a slightly larger treatment effect was found with higher doses of cariprazine (4.5 -6 mg/d) than with lower doses (1.5 and 3 mg/d) in the Marder Disorganized Thought factor.\u003c/p\u003e \u003cp\u003eThe third post hoc analysis performed with DSM IV TR diagnosis of schizophrenia patients was published by Falkai (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) based on data from the same previous 3 phase II/III 6-week, randomized, double-blind, placebo-controlled trials [RGH-MD-16 (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), RGH-MD-04 (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), and RGH-MD-05 (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e)]. This study was developed to compare the efficacy and safety of cariprazine against placebo, risperidone and aripiprazole in two subgroups of patients, patients in early stage (\u0026le;\u0026thinsp;5 years from diagnosis) and in late stage (\u0026ge;\u0026thinsp;15 years from diagnosis) of schizophrenia, all in an acute exacerbation phase, defined as a CGI-S (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) score\u0026thinsp;\u0026ge;\u0026thinsp;4, PANSS (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) total score\u0026thinsp;\u0026ge;\u0026thinsp;80 and \u0026le;\u0026thinsp;120 and, a score\u0026thinsp;\u0026ge;\u0026thinsp;4 in at least 2 of the PANSS positive symptoms. Differences in mean change from baseline at week 6 in favor of cariprazine compared to placebo were statistically significant in the Marder Disorganized Thoughts factor in both population subgroups [early stage (LSMC, CAR \u0026minus;\u0026thinsp;3.3 vs PBO \u0026minus;\u0026thinsp;2.1, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001); late stage (LSMC, CAR \u0026minus;\u0026thinsp;2.7 vs \u0026ndash; 1.4, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01]. Moreover, the mean changes from baseline in the Marder Disorganized Thoughts factor score were similar in both subgroups.\u003c/p\u003e \u003cp\u003eThe last study performed with schizophrenia patients conducted by McIntyre (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) was a post hoc analysis based on data from 3 phase II/III, randomized, double-blind, placebo-controlled, parallel-group, multi-center clinical trials assessing cariprazine\u0026acute;s cognitive efficacy. This study evaluates the cognitive response in 3 different samples of patients: 1) schizophrenia, 2) bipolar I depression (\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) and, 3) bipolar I mania (\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). In the schizophrenia subset of patients, data was pooled from the RGH-MD-04 pivotal study (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Participants were required to have a CGI-S score\u0026thinsp;\u0026ge;\u0026thinsp;4, a PANSS total score\u0026thinsp;\u0026ge;\u0026thinsp;80 and \u0026le;\u0026thinsp;120, and a score\u0026thinsp;\u0026ge;\u0026thinsp;4 in at least 2 of the PANSS positive symptoms. Performance based outcomes from the Cognitive Drug Research (CDR) system attention battery (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e), were presented as power of attention (PoA) and continuity of attention (CoA).\u003c/p\u003e \u003cp\u003eOverall, the median change from baseline to week 6 in PoA was statistically significant for cariprazine 3 mg/d, but not for cariprazine 6 mg/d or aripiprazole 10 mg/d compared to placebo [M (SD), PBO 27.3 (597.5); CAR 3 mg/d 59 (595), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0036; CAR 6 mg/d 5.7 (781.8), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1272 and ARI 10 mg/d 44.2 (828.1), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.4104]. Differences in PoA change were also statistically significant for both doses of cariprazine compared to aripiprazole (CAR 3 mg/d, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0006; CAR 6 mg/d, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0260). Besides, a subset of patients with high cognitive impairment defined as those with a PoA time above or equal to the median (\u0026ge;\u0026thinsp;1545.1 ms) at baseline was specifically analyzed. The median change from baseline to week 6 in PoA in this group was statistically significant in favor of cariprazine 3 mg/d vs placebo (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0080) and vs aripiprazole (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0064). However, difference vs placebo was not significant for cariprazine 6 mg/d (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0 .2974) or aripiprazole (p\u0026thinsp;=\u0026thinsp;0.4443).\u003c/p\u003e \u003cp\u003eFurthermore, overall, the median change from baseline to week 6 in CoA was statistically significant for cariprazine 3 mg/d and cariprazine 6 mg/d but not for aripiprazole compared to placebo [M (SD), PBO 0 (11.7); CAR 3 mg/d 2 (10.5), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0005; CAR 6 mg/d 1 (14.1), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0168 and; ARI 10 mg/d 0 (13.9), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1685]. Besides, a subset with high cognitive impairment defined as patients with a CoA score below or equal to the median CoA score (\u0026le;\u0026thinsp;88) at baseline showed a median change from baseline to week 6 significantly higher, indicating improvement in all treatment groups compared to placebo (CAR 3 mg/d, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0012; CAR 6 mg/d, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0073; ARI, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0160).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudies performed in bipolar I manic or mixed patients\u003c/h3\u003e\n\u003cp\u003eThe study presented by McIntyre (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) also explored a subset of adult patients with a DSM 5 diagnosis of bipolar I manic or mixed episodes. Data were pooled from all 3 pivotal 3-week double-blind, placebo-controlled, flexible-dose randomized clinical trials (NCT00488618 [RGH-MD-31] (\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e), NCT01058096 [RGH-MD-32] (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) and NCT01058668 [RGH-MD-33] (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). A post hoc analysis conducted to analyze cognitive symptoms evaluated changes from baseline to week 3 in the Meltzer cognition subscale of the PANSS as well as in each of the Meltzer cognition subscale individual item score. Participants scoring\u0026thinsp;\u0026ge;\u0026thinsp;20 in the Young Mania Rating Scale (YMRS) total score (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e), a score\u0026thinsp;\u0026ge;\u0026thinsp;4 on at least 2 of 4 YMRS items (irritability, speech, content, and disruptive/aggressive behavior) and a score\u0026thinsp;\u0026le;\u0026thinsp;18.45 in the Montgomery-\u0026Aring;sberg Depression Rating Scale (MADRS) total score (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e) were included. Cariprazine doses ranged from 3 mg/d to 12 mg/d.\u003c/p\u003e \u003cp\u003eOverall, mean change from baseline to week 3 in the Meltzer cognition subscale score was statistically significant in favor of cariprazine versus placebo (LSMC, CAR 2.2 vs PBO 1.3; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). In addition, 2 subgroups of patients were created based on baseline cognitive performance. A first group composed of patients with greater cognitive impairment defined as a Meltzer cognition subscale score\u0026thinsp;\u0026ge;\u0026thinsp;15 (moderate severity) and a second less restrictive group made up of patients with a baseline Meltzer cognition subscale score greater than or equal to the median (median\u0026thinsp;=\u0026thinsp;11) (mild severity). Mean change from baseline to week 3 in the Meltzer cognition subscale score was statistically significant in favor of cariprazine vs placebo in both subset of patients [Meltzer cognition subscale score\u0026thinsp;\u0026ge;\u0026thinsp;15 (LSMC, CAR \u0026minus;\u0026thinsp;4.1 vs PBO \u0026minus;\u0026thinsp;2.0, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and Meltzer cognition subscale score\u0026thinsp;\u0026ge;\u0026thinsp;Median (LSMC, CAR \u0026minus;\u0026thinsp;3.1 vs PBO \u0026minus;\u0026thinsp;1.9, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001)] as well as in 4/5 individual items. However, a qualitative difference was observed between these two groups. In the first group, those with a worse baseline cognitive performance, differences were statistically significant for all items except disorientation (P2), although in the second group differences were statistically significant for all items but stereotyped thinking (N7).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudies performed in bipolar I major depression\u003c/h2\u003e \u003cp\u003eFurthermore, the study presented by McIntyre (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) also explored a third clinical subset made of adult patients with a DSM IV TR diagnosis of bipolar I depression, defined as a Hamilton Depression Rating Scale (HAMD17) total score (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e)\u0026thinsp;\u0026ge;\u0026thinsp;20, an item 1 from HAMD (depressed mood) score\u0026thinsp;\u0026ge;\u0026thinsp;2 and, CGI-S score\u0026thinsp;\u0026ge;\u0026thinsp;4. Data were pooled from 3 pivotal double-blind, placebo-controlled, flexible-dose randomized clinical trials, the first 2 with a 6-week treatment period (NCT02670538 [RGH-MD-53], NCT02670551 [RGH-MD-54]) and a third one with a 8 week follow up (NCT01396447 [RGH-MD-56]) designed with the aim of assessing efficacy, safety and tolerability of cariprazine in patients with bipolar depression. Two different assessments regarding cognitive performance have been carried out in two different population samples.\u003c/p\u003e \u003cp\u003eThe first part of the study (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) was carried out in the total bipolar I depression sample and a single item \"Concentration Difficulties\" (representing difficulties in collecting one's thoughts mounting to incapacitating lack of concentration) was chosen as a cognition measure. Least squares mean changes from baseline to week 6 in favor of all doses of cariprazine compared to placebo were statistically significant in MADRS concentration difficulties score (Item 6) [LSMC, PBO (\u0026minus;\u0026thinsp;1.2); CAR 1.5 mg/d (-1.6; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and CAR 3 mg/d (\u0026ndash; 1.4; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0365)]. In addition, 2 patient subgroups with greater levels of cognitive impairment were analyzed. First, patients with at least mild cognitive symptoms (item 6 score\u0026thinsp;\u0026ge;\u0026thinsp;3) and second, patients with at least moderate cognitive symptoms (item 6 score\u0026thinsp;\u0026ge;\u0026thinsp;4). Both subset of patients showed a statistically significant mean change from baseline to week 6 compared to placebo [mild cognitive symptoms group (LSMC, PBO \u0026minus;\u0026thinsp;1.3; CAR 1.5 mg/d \u0026minus;\u0026thinsp;1.8, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.0001, and CAR 3 mg/d \u0026minus;\u0026thinsp;1.5, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.0292); moderate cognitive symptoms group (LSMC, PBO \u0026minus;\u0026thinsp;1.5; CAR \u0026minus;\u0026thinsp;1.9 mg/d \u0026minus;\u0026thinsp;1.7, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.0001, and CAR 3 mg/d \u0026minus;\u0026thinsp;1.5, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.0366)].\u003c/p\u003e \u003cp\u003eMoreover, the second part of the study (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) carried out in a different subset of bipolar I depression patients pooled from the RGH-MD-56 pivotal trial, chose the cognitive subscale score of the Functioning Assessment Short Test (FAST) (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e) at week 8 as assessment measure. This scale evaluates functioning in patients with mental disorders. The different domains are based on grouping of the 24 individual items: autonomy (4 items), occupational functioning (5 items), cognitive functioning (5 items), financial issues (2 items), interpersonal relationships (6 items) and leisure time (2 items). The items that make up the cognitive subscale are Ability to Concentrate on a Book/Film, Make Mental Calculations, Solve a Problem Adequately, Remember Newly Learned Names, and Learn New Information concentration. The scores for each item range from 0 to 3. The higher the score, the greater the difficulty. Overall, the difference in change from baseline to week 8 in the FAST Cognitive subscale score was statistically significant in favor of cariprazine 1.5 mg/d vs placebo (LSMD, -1.2, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0035); but not for cariprazine 3 mg/d vs placebo (LSMD, \u0026minus;\u0026thinsp;0.5, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Besides, a subgroup composed by patients with baseline cognitive symptoms defined as FAST cognitive score of \u0026ge;\u0026thinsp;2 on at least 2 of the 5 items was specifically assessed, and a statistically significant difference in change from baseline in FAST cognitive subscale score was found in favor of cariprazine 1.5 mg/d vs placebo (LSMD, \u0026minus;\u0026thinsp;1.4; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0039); but not for cariprazine 3 mg/d vs placebo (LSMD, \u0026minus;\u0026thinsp;0.6, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). In addition, changes from baseline were significantly different in favor of cariprazine 1.5 mg/d vs placebo on all individual symptom items included in the FAST Cognitive subscale but on the \u0026ldquo;memory for a new name\u0026rdquo; item. No statistically significant difference in favor of cariprazine 3 mg/d was found on any individual item.\u003c/p\u003e \u003cp\u003eFinally, the fifth study reviewed was reported by the group of Vieta (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) who presented a post hoc analysis pooled from a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group fixed dose study (NCT01396447 [RGH-MD-56]) performed on bipolar I major depression patients developed with the aim to evaluate the efficacy of different doses of cariprazine (1.5 mg/d and 3 mg d) compared to placebo on the cognitive subscale score of the Functioning Assessment Short Test (FAST) (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Bipolar depression patients were defined as those with a HAMD (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e) total score\u0026thinsp;\u0026ge;\u0026thinsp;20, an item 1 (depressed mood) from HAMD score\u0026thinsp;\u0026ge;\u0026thinsp;2 and, CGI-S score\u0026thinsp;\u0026ge;\u0026thinsp;4. Mean change from baseline at week 8 in favor of cariprazine 1.5 mg/d versus placebo was statistically significant in the cognitive subscale FAST score for 1.5 mg/d (LSMC, CAR \u0026minus;\u0026thinsp;3.6 vs PBO \u0026ndash; 2.4; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) but not for the higher dose (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0575).\u003c/p\u003e \u003cp\u003eA systematic summary of the results presented can be seen in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe have performed a systematic review of all RCT-based studies published to date addressing the cognitive efficacy of cariprazine in schizophrenia and bipolar disorder. We have explored this area of interest based on two different but complementary aspects. First, the unique receptor profile of cariprazine, that is, its binding for the D3 receptor (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), resulting in full D3 receptor occupancy at clinically relevant doses (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) that may enhance cognitive performance in people with mental disorders, including improvements in attention, working memory, and executive function as clinical studies have suggested (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). And second, the promising results that attribute pro cognitive effect to cariprazine D3 receptor blockade collected from basic research on animal models (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe 5 reports reviewed examined the efficacy of different doses of cariprazine on the cognitive performance of patients with schizophrenia, bipolar I mania and bipolar I depression (\u003cspan additionalcitationids=\"CR23 CR24 CR25\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding patients with schizophrenia, studies with a short follow-up period of 6 weeks, carried out with patients presenting an acute exacerbation have shown that, overall, cariprazine is superior to placebo in all cognitive outcomes and therefore may have a pro cognitive effect. In addition, the cognitive improvement observed with cariprazine compared to placebo is present both in patients in the initial stages of the disease and in those more chronic ones. Also, benefits were observed in the overall population assessed but also in those with a higher cognitive impairment. Moreover, the results presented are coincident despite the application of different measurement instruments and continue to show cognitive benefits attributed to cariprazine in spite of whether different cognitive factors of the PANSS, single PANSS items or a specific battery have been applied.\u003c/p\u003e \u003cp\u003eFurthermore, one of the studies reviewed regarding patients with schizophrenia chose another D2 partial agonist, aripiprazole, in addition to placebo as a comparator of the cognitive efficacy. The results from the application of the Cognitive Drug Research (CDR) system attention battery (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e), showed different outcomes depending on whether power of attention (PoA) or continuity of attention (CoA) were assessed. On the one hand, differences in overall PoA change were significant for both doses of cariprazine compared to aripiprazole, however, in those patients with greater cognitive impairment, only low doses of cariprazine (3 mg/d) have shown to be more effective than aripiprazole and placebo. On the other hand, when CoA is addressed, overall performance was significantly better for all doses of cariprazine (3 mg/d and 6 mg/d) but not for aripiprazole compared to placebo. However, in those with higher cognitive impairment an improvement in CoA for all treatment groups was found compared to placebo.\u003c/p\u003e \u003cp\u003eNotwithstanding, a discrepancy in relation to the doses of cariprazine associated with a better cognitive improvement has been observed in the studies presented. Marder and colleagues (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), reported a slightly larger treatment effect with higher doses of cariprazine (4.5 -6 mg/d) compared to lower doses (1.5 and 3 mg/d) on the Marder Disorganized Thought. In the opposite direction, the group of McIntyre (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) found, both in the total population evaluated as well as in those with higher baseline cognitive impairment, a better cognitive response to cariprazine compared to placebo when low doses (3 mg) but not high doses (6 mg/d) are used in power of attention (PoA) performance.\u003c/p\u003e \u003cp\u003eThese discrepancies in the cognitive benefit of different doses of cariprazine may be due to both methodological aspects, since some studies use direct measurements of specific cognitive features such as PoA, while others base their results on indirect measurements (Marder Disorganized Thought factor). But also due to pharmacodynamic aspects, since the selectivity for D3 can decrease as the dose is increased (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe study by Fleischhacker (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) with the longest follow up period, supports the cognitive benefit of cariprazine compared to a D2 antagonist, risperidone, in patients with schizophrenia and predominant negative symptoms. Data presented showed a better cognitive performance in all cognitive measures explored (the Marder Disorganized Thought factor, the Meltzer cognition subscale and the difficulty in abstract thinking item) in favor of cariprazine compared to risperidone.\u003c/p\u003e \u003cp\u003eThe only study addressing the cognitive efficacy of cariprazine in bipolar I manic and mixed patients (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) also showed the ability of this drug to improve the cognitive functioning compared to placebo in the Meltzer cognition subscale total score and in practically all the individual subscale items explored. This cognitive advantage was significantly presented both in the overall population as well as in patients with moderate and mild cognitive severity.\u003c/p\u003e \u003cp\u003eWith respect to bipolar I depression patients, 3 population subgroups from 2 different studies showed concordant results in favor of cariprazine versus placebo. The cognitive benefit provided by cariprazine is observed in the entire group of patients with depression, but also in subpopulations with greater baseline cognitive impairment. These favorable results for the drug reviewed remained positive despite of the two different measure systems used to assess cognition in bipolar I depression patients (MADRS concentration difficulties item and FAST cognition subscale). To end, data unanimously showed that this cognitive improvement is predominantly observed with low doses of cariprazine, since cariprazine has greater preference for occupying dopamine D3 receptors vs D2 receptors at lower doses, and, as a consequence, the greater effects on cognitive symptoms described in our current analyses both in bipolar depression and schizophrenia are consistent with its pharmacologic profile suggesting that low doses with greater D3 selectivity could have a more pro cognitive effect (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs with all systematic reviews, this review has limitations and strengths. The main limitation is perhaps, that most of the cognitive measures used are not direct cognitive assessments, but indirect ones, that is, obtained from clinical evaluation instruments such as the PANSS in the case of schizophrenia and bipolar I mania or the FAST and the MADRS in the case of bipolar I depression patients. However, although these measures are not direct cognitive variables, they represent an acceptable approximation in the absence of direct a cognitive assessment (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). As main strength, the quality of the reviewed studies according to Jadad's recommendations and guidelines have been rated and we have found it to be of good to excellent (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOverall, the data collected by this review allow us to conclude that the use of cariprazine in patients with schizophrenia and bipolar disorder is presented as an interesting option to address the cognitive deficits that these patients present, which today continue to be an unmet therapeutic need. In addition, the use of cariprazine in patients with schizophrenia, bipolar I mania and bipolar I depression has proven to improve performance on cognitive measures compared to placebo, especially in patients with greater baseline impairment and when low doses are used. Furthermore, the use of cariprazine in patients with schizophrenia could become a more effective therapeutic option to enhance cognition compared to some of the current antipsychotics available. For all the above, and given the lack of treatment options available to improve cognition, it would be advisable to expand research on the potential of cariprazine as a pro cognitive strategy by designing specific studies with the objective of evaluating all affected domains using standardized instruments to measure cognitive performance, that allow us to know the real magnitude of the pro-cognitive effect in patients with schizophrenia, bipolar disorder and other mental disorders.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eDeclarations\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eConsent for publication was received from all authors.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eDr. R. Rodriguez-Jimenez has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigaci\u0026oacute;n Sanitaria (FIS), Centro de Investigaci\u0026oacute;n Biom\u0026eacute;dica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/ BMD-2422 AGES; S2017/BMD-3740; P2022/BMD-7216), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen-Recordati, Angelini, Rovi.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eAuthors' information\u003c/h2\u003e \u003cp\u003eAuthors and Affiliations\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eLorena Garc\u0026iacute;a-Fern\u0026aacute;ndez\u003c/strong\u003e \u003cp\u003eClinical Medicine Department. Universidad Miguel Hern\u0026aacute;ndez, Alicante, Spain.\u003c/p\u003e \u003cp\u003ePsychiatry Department, Hospital Universitario de San Juan, Alicante, Spain.\u003c/p\u003e \u003cp\u003eCIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain\u003c/p\u003e \u003cp\u003e0000-0001-5523-9762\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\[email protected]\u003c/span\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eVer\u0026oacute;nica Romero\u003c/strong\u003e \u003cp\u003eCIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain.\u003c/p\u003e \u003cp\u003eUniversidad Europea de Madrid, Madrid, Spain.\u003c/p\u003e \u003cp\u003eInstituto de Investigaci\u0026oacute;n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.\u003c/p\u003e \u003cp\u003e0000-0003-3211-1744\u003c/p\u003e \u003cp\[email protected]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eInmaculada Pe\u0026ntilde;uelas-Calvo\u003c/strong\u003e \u003cp\u003eInstituto de Investigaci\u0026oacute;n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.\u003c/p\u003e \u003cp\u003eComplutense University of Madrid (UCM), Madrid, Spain.\u003c/p\u003e \u003cp\u003e0000-0003-4093-1312\u003c/p\u003e \u003cp\[email protected]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eMiguel \u0026Aacute;ngel \u0026Aacute;lvarez de Mon\u003c/strong\u003e \u003cp\u003eDepartment of Medicine and Medical Specialities. University of Alcal\u0026aacute;, Alcal\u0026aacute; de Henares, Spain.\u003c/p\u003e \u003cp\u003eDepartment of Psychiatry and Mental Health. Hospital Universitario Infanta Leonor, Madrid, Spain.\u003c/p\u003e \u003cp\u003eRam\u0026oacute;n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain\u003c/p\u003e \u003cp\u003e0000-0002-1987-0394\u003c/p\u003e \u003cp\[email protected]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eMauro Scala\u003c/strong\u003e \u003cp\u003eDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy\u003c/p\u003e \u003cp\u003e0000-0002-7428-2835\u003c/p\u003e \u003cp\[email protected]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCarmen Romero Ferreiro\u003c/strong\u003e \u003cp\u003eFaculty of Health Sciences, Universidad Francisco de Vitoria, Madrid, Spain.\u003c/p\u003e \u003cp\u003eCIBERESP/ISCIII (Biomedical Research Networking Centre for Epidemiology and PublicHealth/Carlos III Health Institute), Spain.\u003c/p\u003e \u003cp\u003e0000-0002-9125-2275\u003c/p\u003e \u003cp\[email protected]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEstela Jim\u0026eacute;nez L\u0026oacute;pez\u003c/strong\u003e \u003cp\u003eCIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain.\u003c/p\u003e \u003cp\u003eCenter for Social and Health Research, University of Castilla-La Mancha, Cuenca, Spain.\u003c/p\u003e \u003cp\u003eDepartment of Psychiatry, Virgen de La Luz Hospital, Cuenca, Spain.\u003c/p\u003e \u003cp\u003e0000-0001-8553-7701\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\[email protected]\u003c/span\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eJos\u0026eacute; Luis Santos\u003c/strong\u003e \u003cp\u003eCIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain.\u003c/p\u003e \u003cp\u003eDepartment of Psychiatry, Virgen de La Luz Hospital, Cuenca, Spain.\u003c/p\u003e \u003cp\u003eNeurobiological Research Group. Technological Institute, University of Castilla-La Mancha, Cuenca, Spain\u003c/p\u003e \u003cp\u003e0000-0002-4692-1310\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\[email protected]\u003c/span\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eRoberto Rodr\u0026iacute;guez-Jim\u0026eacute;nez\u003c/strong\u003e \u003cp\u003eCIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain.\u003c/p\u003e \u003cp\u003eInstituto de Investigaci\u0026oacute;n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.\u003c/p\u003e \u003cp\u003eComplutense University of Madrid (UCM), Madrid, Spain.\u003c/p\u003e \u003cp\u003e0000-0003-2251-7249\u003c/p\u003e \u003cp\[email protected]\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research was supported in part by the Instituto de Investigaci\u0026oacute;n Sanitaria Hospital 12 de Octubre (imas12), and by CIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\u003ch2\u003eAuthors' contributions\u003c/h2\u003e \u003cp\u003eRRJ is the guarantor of this review. LGF, VR and RRJ defined the research question. LGF and VR developed the search strategy and determined inclusion and exclusion criteria. Methodological support was provided by VR. LGF and RRJ created the first draft of this manuscript, and all authors reviewed and approved the final draft\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMcCutcheon RA, Reis Marques T, Howes OD. Schizophrenia-An Overview. JAMA Psychiatry. 2020;77(2):201\u0026ndash;210. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamapsychiatry\u003c/span\u003e\u003cspan address=\"10.1001/jamapsychiatry\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 2019;3360.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGebreegziabhere Y, Habatmu K, Mihretu A, Cella M, Alem A. Cognitive impairment in people with schizophrenia: an umbrella review. Eur Arch Psychiatry Clin Neurosci. 2022;272(7):1139\u0026ndash;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00406-022-01416-6\u003c/span\u003e\u003cspan address=\"10.1007/s00406-022-01416-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoran WP, Catalano LT, Green MF. An Update on Treatment of Cognitive Impairment Associated with Schizophrenia. Curr Top Behav Neurosci. 2023;63:407\u0026ndash;36. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/7854_2022_382\u003c/span\u003e\u003cspan address=\"10.1007/7854_2022_382\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRodriguez-Jimenez R, Santos JL, Dompablo M et al. MCCB cognitive profile in Spanish first episode schizophrenia patients. Schizophr Res. 2019;211:88\u0026ndash;92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.schres.\u003c/span\u003e\u003cspan address=\"10.1016/j.schres.\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e2019; 211:88\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTargum SD, Keefe RS. Cognition and schizophrenia: is there a role for cognitive assessments in diagnosis and treatment? Psychiatry (Edgmont). 2008;5(12):55\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFranck N. R\u0026eacute;habilitation psychosociale dans la schizophr\u0026eacute;nie [Psychiatric rehabilitation in schizophrenia]. Rev Prat. 2021;71(1):52\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaric NP, Jovicic MJ, Mihaljevic M, Miljevic C. Improving Current Treatments for Schizophrenia. Drug Dev Res. 2016;77(7):357\u0026ndash;67. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/ddr.21337\u003c/span\u003e\u003cspan address=\"10.1002/ddr.21337\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFitapelli B, Lindenmayer JP. Advances in cognitive remediation training in schizophrenia: a review. Brain Sci. 2022;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/brainsci12020129\u003c/span\u003e\u003cspan address=\"10.3390/brainsci12020129\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCella M, Price T, Corboy H, Onwumere J, Shergill S, Preti A. Cognitive remediation for inpatients with psychosis: a systematic review and meta-analysis. Psychol Med. 2020;50:1062\u0026ndash;76. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1017/S0033291720000872\u003c/span\u003e\u003cspan address=\"10.1017/S0033291720000872\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRauly-Lestienne I, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Cussac D. Differential profile of typical, atypical and third generation antipsychotics at human 5-HT7a receptors coupled to adenylyl cyclase: detection of agonist and inverse agonist properties. Naunyn Schmiedebergs Arch Pharmacol. 2007;376(1\u0026ndash;2):93\u0026ndash;105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLieberman JA. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs. 2004;18(4):251\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirose T, Kikuchi T. Aripiprazole, a novel antipsychotic agent: dopamine D2 receptor partial agonist. J Med Invest. 2005;52:284\u0026ndash;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2152/jmi.52.284\u003c/span\u003e\u003cspan address=\"10.2152/jmi.52.284\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaszlovszky I, Barab\u0026aacute;ssy \u0026Aacute;, N\u0026eacute;meth G, Cariprazine. A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety. Adv Ther. 2021;38(7):3652\u0026ndash;73. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12325-021-01797-5\u003c/span\u003e\u003cspan address=\"10.1007/s12325-021-01797-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnson DE, McIntyre RS, Mansur RB, Rosenblat JD. An update on potential pharmacotherapies for cognitive impairment in bipolar disorder. Expert Opin Pharmacother. 2023;24(5):641\u0026ndash;54. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/14656566.2023.2194488\u003c/span\u003e\u003cspan address=\"10.1080/14656566.2023.2194488\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCalabrese F, Tarazi FI, Racagni G, Riva MA. The role of dopamine D3 receptors in the mechanism of action of cariprazine. CNS Spectr. 2020;25(3):343\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStahl SM. Mechanism of action of cariprazine. CNS Spectr. 2016;21(2):123\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZimnisky R, Chang G, Gyerty\u0026aacute;n I, Kiss B, Adham N, Schmauss C. 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. 2013;226(1):91\u0026ndash;100. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00213-012-2896-5\u003c/span\u003e\u003cspan address=\"10.1007/s00213-012-2896-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatson DJG, King MV, Gyerty\u0026aacute;n I, Kiss B, Adham N, Fone KCF. The dopamine D₃-preferring D₂/D₃ dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia. Eur Neuropsychopharmacol. 2016;26(2):208\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlivola M, Bassetti N, Parente S, Arienti V, Civardi SC, Topa PA, Brondino N. Cognitive Effects of Lurasidone and Cariprazine: A Mini Systematic Review. Curr Neuropharmacol. 2023;21(12):2431\u0026ndash;46. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2174/1570159X21666230727140843\u003c/span\u003e\u003cspan address=\"10.2174/1570159X21666230727140843\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann T, Mulrow CD, Shamseer L, Tetzlaff J, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hr\u0026oacute;bjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/bmj.n71\u003c/span\u003e\u003cspan address=\"10.1136/bmj.n71\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/0197-2456(95)00134-4\u003c/span\u003e\u003cspan address=\"10.1016/0197-2456(95)00134-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFleischhacker W, Galderisi S, Laszlovszky I, et al. The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors. Eur Psychiatry. 2019;58:1\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.eurpsy.2019.01.015\u003c/span\u003e\u003cspan address=\"10.1016/j.eurpsy.2019.01.015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarder S, Fleischhacker WW, Earley W, Lu K, Zhong Y, N\u0026eacute;meth G, Laszlovszky I, Szalai E, Durgam S. Efficacy of cariprazine across symptom domains in patients with acute exacerbation of schizophrenia: Pooled analyses from 3 phase II/III studies. Eur Neuropsychopharmacol. 2019;29(1):127\u0026ndash;36. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.euroneuro.2018.10.008\u003c/span\u003e\u003cspan address=\"10.1016/j.euroneuro.2018.10.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFalkai P, Dombi ZB, Acsai K, Barab\u0026aacute;ssy \u0026Aacute;, Schmitt A, N\u0026eacute;meth G. The efficacy and safety of cariprazine in the early and late stage of schizophrenia: a post hoc analysis of three randomized, placebo-controlled trials. CNS Spectr. 2023;28(1):104\u0026ndash;11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1017/S1092852921000997\u003c/span\u003e\u003cspan address=\"10.1017/S1092852921000997\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcIntyre RS, Daniel DG, Vieta E, Laszlovszky I, Goetghebeur PJ, Earley WR, Patel MD. The efficacy of cariprazine on cognition: a post hoc analysis from phase II/III clinical trials in bipolar mania, bipolar depression, and schizophrenia. CNS Spectr. 2023;28(3):319\u0026ndash;30. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1017/S109285292200013X\u003c/span\u003e\u003cspan address=\"10.1017/S109285292200013X\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVieta E, Calabrese JR, Whelan J, Tohen M, Earley WR. The efficacy of cariprazine on function in patients with bipolar depression: a post hoc analysis of a randomized controlled trial. Curr Med Res Opin. 2021;37(9):1635\u0026ndash;43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/03007995.2021.1932446\u003c/span\u003e\u003cspan address=\"10.1080/03007995.2021.1932446\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry. 1997;58:538\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhite L, Harvey PD, Opler L, Lindenmayer JP. Empirical assessment of the factorial structure of clinical symptoms in schizophrenia. A multisite, multimodel evaluation of the factorial structure of the Positive and Negative Syndrome Scale. The PANSS Study Group. Psychopathology. 1997;30:263\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeltzer HY, Cucchiaro J, Silva R, Ogasa M, Phillips D, Xu J, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry. 2011;168:957\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261\u0026ndash;76. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/schbul/13.2.261\u003c/span\u003e\u003cspan address=\"10.1093/schbul/13.2.261\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDurgam S, Starace A, Li D, et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res. 2014;152(2\u0026ndash;3):450\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDurgam S, Cutler AJ, Lu K, et al. Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind,placebo- and active-controlled trial. J Clin Psychiatry. 2015;76(12):e1574\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKane JM, Zukin S, Wang Y, et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: results from an International. Phase III clinical trial. J Clin Psychopharmacol. 2015;35(4):367\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuy W. Clinical global impressions scale. Psychiatry; 1976.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDurgam S, Earley W, Guo H, Li D, N\u0026eacute;meth G, Laszlovszky I, et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: Results from an international, phase III clinical trial. J Clin Psychopharmacol. 2015;35(4):367\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEarley W, Burgess MV, Rekeda L, et al. Cariprazine treatment of bipolar depression: a randomized double-blind placebo-controlled phase 3 study. Am J Psychiatry. 2019;176(6):439\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEarley WR, Burgess MV, Khan B, et al. Efficacy and safety of cariprazine in bipolar I depression: a double-blind, placebo-controlled phase 3 study. Bipolar Disord. 2020;22(4):372.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCalabrese JR, Keck PE Jr, Starace A, et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2015;76(3):284\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDurgam S, Starace A, Li D, et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial. Bipolar Disord. 2015;17(1):63\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSachs GS, Greenberg WM, Starace A, et al. Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, phaseIII trial. J Affect Disord. 2015;174:296\u0026ndash;302.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimpson PM, Surmon DJ, Wesnes KA, Wilcock GK. The cognitive drug research computerized assessment system for demented patients: a validation study. Int J Geriatr Psychiatry. 1991;6(2):95\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoung RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMontgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1192/bjp.134.4.382\u003c/span\u003e\u003cspan address=\"10.1192/bjp.134.4.382\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHamilton M. Rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosa AR, S\u0026aacute;nchez-Moreno J, Mart\u0026iacute;nez-Aran A, Salamero M, Torrent C, Reinares M, Comes M, Colom F, Van Riel W, Ayuso-Mateos JL, Kapczinski F, Vieta E. Validity and reliability of the Functioning Assessment Short Test (FAST) in bipolar disorder. Clin Pract Epidemiol Ment Health. 2007;3:5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/1745-0179-3-5\u003c/span\u003e\u003cspan address=\"10.1186/1745-0179-3-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCitrome L. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013;30(2):114\u0026ndash;26. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12325-013-0006-7\u003c/span\u003e\u003cspan address=\"10.1007/s12325-013-0006-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSokoloff P, Le Foll B. The dopamine D3 receptor, a quarter century later. Eur J Neurosci. 2017;45(1):2\u0026ndash;19. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/ejn.13390\u003c/span\u003e\u003cspan address=\"10.1111/ejn.13390\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeidbreder CA, Newman AH. Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders. Ann N Y Acad Sci. 2010;1187:4\u0026ndash;34. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1749-6632.2009.05149.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1749-6632.2009.05149.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGirgis RR, Slifstein M, D\u0026rsquo;Souza D, et al. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(\u0026thorn;)-PHNO. Psychopharmacology. 2016;233(19\u0026ndash;20):3503\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBagney A, Dompablo M, Santab\u0026aacute;rbara J, Moreno-Ortega M, Lobo A, Jimenez-Arriero MA, Palomo T, Rodriguez-Jimenez R. Are negative symptoms really related to cognition in schizophrenia? Psychiatry Res. 2015;230(2):377\u0026thinsp;\u0026ndash;\u0026thinsp;82. doi: 10.1016/j.psychres.2015.09.022. Epub 2015 Sep 14. PMID: 26454405.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cariprazine, cognition, schizophrenia, bipolar mania, bipolar depression, systematic review","lastPublishedDoi":"10.21203/rs.3.rs-3857313/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3857313/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCariprazine is a recently incorporated drug whose differential characteristic is its partial agonism for the D3 receptor, with great affinity for it, higher than dopamine itself. Preclinical studies with animal models have shown a manifest pro cognitive effect. The objective of this study is to conduct a systematic review examining the effects of cariprazine on cognitive measures in patients with schizophrenia and bipolar disorder.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eTwo independent reviewers searched PubMed, Web of Science, Scopus, and Cochrane Library databases to December 31st 2023 following the PRISM guideline. Additional studies were identified through hand-searching of references of the included studies. Eligible studies were those randomized controlled trials published in English evaluating the effects of the use of cariprazine on cognitive outcomes in patients with mental disorders. Quality assessment followed the Jadad scale recommendations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFrom a total of 136 initial reports, up to 5 studies comprising 6104 patients with schizophrenia, bipolar I mania and bipolar I depression were included in the systematic review. In patients with schizophrenia, the use of cariprazine showed better cognitive outcomes compared to placebo in both early and late stages. Furthermore, cariprazine showed cognitive advantages over risperidone in patients with a predominance of negative symptoms and over aripiprazole when the variables power and continuity of attention were measured. In patients with bipolar disorder, cariprazine showed cognitive improvements compared to placebo. Most studies seem to find a greater pro cognitive effect with low doses of cariprazine (1.5-3 mg/d).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOverall, cariprazine improved cognitive measures compared to placebo, especially in patients with greater baseline impairment and when low doses are used. Thus, the use of cariprazine in patients with schizophrenia and bipolar disorder could become an effective therapeutic option to enhance cognition as well as other inherent symptoms of both disorders.\u003c/p\u003e\u003ch2\u003eSystematic review registration\u003c/h2\u003e \u003cp\u003ePROSPERO CRD42023485028.\u003c/p\u003e","manuscriptTitle":"Cariprazine and cognition in patients with schizophrenia and bipolar disorder: A systematic review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-29 18:44:18","doi":"10.21203/rs.3.rs-3857313/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"878338c9-0045-48d1-a792-859ca27b458c","owner":[],"postedDate":"March 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-14T19:17:44+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-29 18:44:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3857313","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3857313","identity":"rs-3857313","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}