Fagiolini et al. Ann Gen Psychiatry Annals of General Psychiatry (2020) 19:55 https://doi.org/10.1186/s12991-020-00305-3 REVIEW Open Access Treating schizophrenia with cariprazine: from clinical research to clinical practice. Real world experiences and recommendations from an International Panel Andrea Fagiolini1* , José Ángel Alcalá2, Thomas Aubel3, Wojciech Bienkiewicz4, Mats Magnus Knut Bogren5, Joaquim Gago6, Giancarlo Cerveri7, Michael Colla8, Francisco Collazos Sanchez9,10, Alessandro Cuomo1, Frieling Helge11, Eduardo Iacoponi12, Per‑Axel Karlsson13, Pradeep Peddu14, Mauro Pettorruso15, Henrique Jorge Ramos Pereira16, Johan Sahlsten Schölin17 and Ingo Bernd Vernaleken18,19 Abstract Background: Management of schizophrenia is sub-optimal in many patients. Targeting negative symptoms, among the most debilitating aspects of schizophrenia, together with positive symptoms, can result in significant functional benefits and dramatically improve quality of life for patients and their carers. Cariprazine, a partial agonist of the dopamine receptors D2/D3 has demonstrated effectiveness across symptom domains in clinical trials, particularly on negative symptoms. Objective: To obtain a broader insight from clinicians with specific experience with cariprazine, on how it affects patient populations outside the clinical trial setting. Methods: The panel addressed a series of psychopharmacologic topics not comprehensively addressed by the evidence-based literature, including characteristics of patients treated, dosing and switching strategies, duration of therapy, role of concomitant medications and tolerability as well as recommendations on how to individualize cariprazine treatment for patients with schizophrenia. Results: Patients recommended for cariprazine treatment are those with first episodes of psychosis, predominant negative symptoms (maintenance/acute phase) and significant side effects (metabolic side effects, hyperprolactine‑ mia, sedation) with other antipsychotics. When the long-term treatment of a lifetime illness is adequately weighted, cariprazine becomes one of the first-line medications, not only for patients with predominant negative symptoms but also for those with relatively severe positive symptoms, especially if they are at the first episodes and if a specific medi‑ cation is added for symptoms such as agitation or insomnia. For instance, patients with agitation may also benefit from the combination of cariprazine and a benzodiazepine or another sedating agent. Cariprazine may be prescribed as add-on to medications such as clozapine, when that medication alone is ineffective for negative symptoms, and sometimes the first may be discontinued or its dose lowered, after a period of stability, leaving the patient on a better tolerated antipsychotic regimen. *Correspondence: andrea.fagiolini@unisi.it 1 School of Medicine, Department of Molecular Medicine, University of Siena, Siena, Italy Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat​iveco​ mmons​.org/licen​ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/publi​cdoma​in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Fagiolini et al. Ann Gen Psychiatry (2020) 19:55 Page 2 of 11 Conclusions: Based on real-world clinical experience, the panel considered that cariprazine, with its distinct advan‑ tages including pharmacokinetics/pharmacodynamics, good efficacy and tolerability, represents a drug of choice in the long-term management of schizophrenia not only for patients with predominant negative symptoms but also for those with positive symptoms. Keywords: Schizophrenia, Antipsychotics, Cariprazine, Patient subgroups, Recommendations, Negative symptoms Introduction alone to lead to functional recovery, with full functional/ What do King Henry VI and the Nobel laureate John social recovery occurring in 15% or less of patients with Nash have in common? Both were thought to have had schizophrenia, with negative symptoms playing a key role schizophrenia. While the term schizophrenia is less [9]. than 100 years, it was first identified as a discrete men- Despite the complexity and heterogeneity of schizo- tal illness in 1887 and is believed to have accompanied phrenia, the reduction of D2-like receptor mediated mankind through its history [1, 2]. Schizophrenia is a neurotransmission was regarded to be the fundamen- complex heterogenous, stigmatised mental disorder with tal mechanism of antipsychotic action. However, recent multiple domains of presentation and a highly variable studies have proposed that alteration in the glutamate, clinical course that can devastate individuals and fami- GABA, acetylcholine, and serotonin system may play lies. It affects approximately 1% of the general popula- a role in the pathology of schizophrenia and a revised tion with an estimated 20 million cases worldwide [3, dopamine hypothesis suggests a role of both hyperac- 4]. Treatment modalities in schizophrenia have changed tive dopamine transmission in the mesolimbic areas and fundamentally in recent decades and fortunately the days hypoactive dopamine transmission in the prefrontal cor- of people with the disease being confined to treatment in tex [10]. To this end partial agonism as well as the differ- asylums are far behind us. We now have a range of antip- entiated recognition of the D2-like dopamine receptors sychotic agents and rehabilitation strategies with proven provide a promising approach for treatment of schizo- efficacy in treating symptoms and behaviours associated phrenia [11]. Cariprazine, a partial agonist of the dopa- with the disorder [5]. However, there are still treatment mine receptors receptor and—with higher affinity—of gaps—with one source indicating that only about half of the D3-receptor, was approved by the US Food and Drug all patients with schizophrenia receive treatment [6]. Administration and the European Medicines Agency, for For instance, the clinical manifestations of schizophre- the management of schizophrenia based on an extensive nia are heterogeneous and this makes it difficult to estab- clinical trial programme demonstrating its effectiveness lish the effectiveness of specific treatments in a group of particularly on negative symptoms and its safety [12, 13]. patients presenting with quite diverse clinical manifesta- Since its approval the exposure to cariprazine is around tions. Also, more than half of patients with schizophre- 50,000 patient/treatment/year [14]. nia experience negative symptoms, which are connected Cariprazine is pharmacodynamically and pharmacoki- with significant treatment challenges [7]. In fact, nega- netically distinct from other oral antipsychotics in that tive symptoms have been associated to worse treatment it has two active metabolites which contribute to its effi- response and poor functional outcomes compared with cacy and tolerability—the parent drug and the desme- individuals without negative symptoms [8]. thyl cariprazine (DCAR) metabolite are responsible for Domains of presentation in schizophrenia include early efficacy and side effects, while the second metabo- positive, negative and emotional symptoms as well as lite didesmethyl cariprazine (DDCAR) with its extended cognitive and social functional deficits. Generally, antip- half-life is primarily responsible for later efficacy and tol- sychotic agents are most effective in treating the positive erability issues [15–17]. symptoms of schizophrenia and less successful in treating Optimal management requires accurate patient charac- the negative symptoms and cognitive disabilities. Target- terization and the heterogeneity of schizophrenia means ing negative symptoms (apathy, lack of emotion, alogia, that subjects included in clinical trials may not be entirely anhedonia, and poor social functioning) can result in representative of real-world patients [18]. We now know significant functional benefits and dramatically improve that clinical trial data alone may not accurately reflect quality of life of patients and their carers [9]. Indeed, how a drug will behave long-term in a larger, less homog- the evidence underscoring the importance of negative enous patient population. Real-world experience pro- symptoms’ resolution has quickly grown, paralleling the vides a broader insight into the how a product will affect growing interest in functional recovery and the observa- patient populations outside the clinical trial setting. With tion that resolution of positive symptoms is not sufficient this in mind, a group of European psychiatrists (chosen Fagiolini et al. Ann Gen Psychiatry (2020) 19:55 Page 3 of 11 from a range of EU countries, where health systems and for patients with schizophrenia. Each of the thematically prescribing habits vary widely), met in December 2019 defined discussions was supplemented by systematically to present and discuss their clinical experience with evaluations and ratings of the proposed topics. A number cariprazine. of the questions included Likert scales (0–10) and free Our hypothesis was that specific treatment algo- text replies to measure opinions, perceptions, and behav- rithms could be suggested based on the characteristics iours. Clinicians completed questionnaires electronically, of patients treated, for instance to establish dosing and during the in person meeting, and answers were stored switching strategies, duration of therapy, role and type remotely for analysis. All completed answers were elec- of concomitant medications and strategies to improve tronically and anonymously recorded during the meet- tolerability. We also hypothesized that it was possi- ing, and no demographic data were collected. ble to develop a consensus on the recommendations to individualize cariprazine treatment for patients with Results: Data gathering and recommendations schizophrenia. Cariprazine: place in therapy, patient characteristics This statement represents the panel’s collective experi- What are the most frequent clinical conditions for which ence, opinions, evaluation, and rationale for the inclusion you use cariprazine in your clinic? of cariprazine in the management algorithm for medica- The panel members indicated use of cariprazine in tion treatment of schizophrenia. patients with a wide spectrum of presenting symptoms or conditions (Table 1). Cariprazine was most often pre- Methodology scribed for patients presenting with their first episode of This was a descriptive survey of a panel of clinicians and psychosis—in general these tend to be younger patients; researchers with extensive experience in the management sufficient clinical experience with cariprazine in elderly of schizophrenia in general and the use of cariprazine patients (over 65 years) was not reported. The two other in particular. The panel focused on a series of psychop- major groups considered to be ‘first-line candidates’ harmacologic topics not comprehensively addressed by for cariprazine are those with predominantly negative the evidence-based literature but beneficial to clinicians symptoms and those with metabolic syndrome includ- prescribing antipsychotic medications and caring for ing ethnic groups/non-caucasians with diverse metabolic patients with schizophrenia. The process took the form profiles. of the following steps. First, a group of clinicians and clinical researchers practicing in Europe or in the United Most frequently used doses of cariprazine in clinical Kingdom were surveyed about their ability and willing- practice ness to provide clinical experience, scientific background What are the most frequently used doses of caripra- and decision-making authority to supply real-world zine in your clinic? For patients with a first episode of experience with cariprazine. Second, one of the clini- psychosis the general consensus was that the majority cians (AF) drafted a list of clinically relevant topics and of patients can be successfully managed on 1.5–3.0 mg questions pertaining to the treatment of schizophrenia but this depends on several issues, such as severity of with cariprazine in the real world. Third, the panel par- symptoms and setting of treatment (community/in ticipants met in person and were asked to discuss the patients), with more severe symptoms often requiring topics above and offered to add other question or topic higher doses, and other patient characteristics, for exam- that they felt was clinically relevant for real-world treat- ple BMI (higher BMI usually requires longer periods to ment of schizophrenia with cariprazine. The final survey, included the following topics: (1) place in therapy and clinical characteristics of patient populations treated with cariprazine by panel members in their respective clini- Table 1 Spectrum of presenting conditions for which Panel prescribed cariprazine in their practice (in- and out- cal centres (both in- and out-patient facilities); (2) most patients) frequently used doses of cariprazine in their practice; (3) procedures used in switching from other antipsychot- First episode of psychosis ics to cariprazine, up-titration and time to observation Positive symptoms of beneficial effects: acute/maintenance treatment; (4) Negative symptoms use of concomitant medications and duration of therapy Patients with schizophrenia spectrum disorders and agitation (in combi‑ by patient group/setting; (5) combination treatment; (6) nation with a second medication, e.g., a benzodiazepine) nature, incidence and management of adverse events and Patients with schizophrenia spectrum disorders and metabolic syndrome the role of treatment adjustment/withdrawal; and (7) Patients with schizophrenia spectrum disorders and substance use disorder recommendations to individualize cariprazine treatment Fagiolini et al. Ann Gen Psychiatry (2020) 19:55 Page 4 of 11 achieve steady state and hence therapeutical levels and Procedures used in switching from other antipsychotics may require a faster titration schedule or higher initial to cariprazine, up‑titration and time to observation dose, to attain an earlier achievement of the therapeutical of beneficial effects: acute/maintenance treatment blood concentrations). When severe symptoms are pre- The overriding consideration in switching stable patients sent, there is usually a need to quickly achieve a higher who need to change medication because of side effects, dose (4.5/6 mg). The panel judged that patients with agi- or to better deal with residual negative symptoms/cogni- tation who are treated with cariprazine very often need tive disabilities, is to avoid relapse and the panel were in adjunctive treatment with a benzodiazepine or another agreement of the need to ensure that an effective dose of sedating agent (See: “Use of concomitant medication and cariprazine is reached before tapering. In some cases, the duration of therapy by patient group/setting”—patients risk of increased side effects is offset by avoiding relapse, with insomnia or agitation). In those cases, cariprazine is but it is important to obtain a balance. The long-half life usually needed at doses of 4.5–6 mg. If side effects such of cariprazine gave reason to the opinion that it can be as akathisia appear, the dosage should be reduced (See: up-titrated quickly followed by final adjustments of daily “Nature, incidence and management of side effects and dose, while blood levels gradually increase, up to steady the role of treatment adjustment/withdrawal” section). state according to previous pharmacokinetic investiga- When cariprazine is used to treat a patient with schizo- tions. After multiple dose administration mean caripra- phrenia and acute agitation, the advantage is that it can zine and DCAR concentrations reached steady state at be continued long-term thus avoiding the need to start around weeks 1–2 and mean DDCAR levels approached with a sedative antipsychotic drug and then switch treat- steady state at around weeks 4–8, in a 12-week study ment after the acute phase has passed. The majority of [16]. Using the half-life of total cariprazine (the sum of the panel considered that treatment-resistant patients cariprazine and its major active metabolites DCAR, and require the highest dosage (6.0 mg). A large portion of DDCAR) a time marker of 3 weeks for a steady state has physicians reported improvements in symptoms with been estimated. Population pharmacokinetic/pharma- 3.0 mg, in particular favourable long-term effects on neg- codynamic modelling has been used to investigate the ative symptoms with 3.0 mg without the need to increase longitudinal exposure‐response relationship for total the dosage. The possibility of using therapeutic drug cariprazine in patients enrolled in the clinical devel- monitoring (TDM) for dose optimization and to respond opment program. Total cariprazine exposure was sig- to individual differences during the course of therapy nificantly related to reductions in Positive and Negative were mentioned. Figure 1 reports cariprazine dosages Syndrome Scale (PANSS) total scores and typical steady‐ used by Panel to treat schizophrenia in their clinical prac- state plasma concentrations after 3.0 and 4.5 mg/day tice (Fig. 1). were associated with 50% of maximum typical reductions in PANSS scores [17]. Clinicians reported that they usually introduce caripra- zine while slowly reducing other antipsychotics (if Fig. 1 Cariprazine dosages used by Panel (%) to treat schizophrenia in their clinical practice Fagiolini et al. Ann Gen Psychiatry (2020) 19:55 Page 5 of 11 taking). The length of time in switching depends on the and adherence in the long-term (See: “Nature, incidence type of drug(s) the patient has already been prescribed and management of side effects and the role of treatment and TDM may be useful for dose optimization. In the adjustment/withdrawal” section). The time to observe panel’s experience switching from the partial agonist beneficial effects depends on the patient and the dosage aripiprazole can be done in 1 week or less but a longer used: improvements are observed in around 1 month for overlapping time is necessary when switching from med- positive symptoms, but complex negative symptoms take ications such as risperidone or haloperidol. Care must be up to 6 months and longer to improve. taken when down-titrating medications with pronounced antihistaminergic/antimuscarinic effects like olanzap- Use of concomitant medications and duration of therapy ine, quetiapine or clozapine. In stable patients, switching by patient group/setting from risperidone is not usually associated with hista- Patients with insomnia or agitation minergic/muscarinic rebound. However, a dopaminer- A cross section of responders would prescribe a ben- gic rebound is possible and hence an overlap of at least zodiazepine to treat insomnia but for some the use of a 2–3 weeks is usually recommended. If the patient is sta- benzodiazepine depends on the setting and the risk of ble and treated with olanzapine, quetiapine or clozapine, addiction and other side effects, such as paradoxical acti- the switch will be usually performed over a longer time vation, sedation, falls, and withdrawal symptoms if the period (3–4 weeks) owing to the risk of both antihista- medication is discontinued too quickly (Fig. 2a). Antide- minergic/muscarinic and dopaminergic rebound. Over- pressants, such as mirtazapine or trazodone, or sedating lapping ‘plateau’ switch strategies (the effective blood antipsychotics at low doses, may be alternatives to a ben- concentration of the new drug is reached before reduc- zodiazepine. Similarly, to manage concomitant agitation ing/stopping the other one) and transient co-treatment the group were distributed as to add a benzodiazepine with medications, such as benzodiazepines (e.g., loraz- (which had the highest score) or a second sedating antip- epam 1-4 mg/day) are used to overcome the rebound sychotic/antidepressant agent but not at antipsychotic phenomena that can complicate the early switch period. doses, or to avoid using two antipsychotics, i.e., discon- The time employed in up-titration of cariprazine depends tinue cariprazine and change antipsychotic (Fig. 2b). to some extent on the setting and practical issues—in the acute setting it is usually performed faster than in out- Partial response to positive or negative symptoms patient clinics according to the frequency of visitation In patients showing partial responses to positive symp- as well as due to different urgencies of the clinical situ- toms after treatment with cariprazine for a period of ations (Table 2). With outpatients who may be seen less 2–3 weeks, one option is to increase the dose of caripra- frequently, it takes longer to up-titrate/switch with medi- zine to the highest dosage. If this is not adequate another cations with long-half life. A portion of patients, around antipsychotic is added (Fig. 3a). Similarly, if there is a 25%, experience akathisia when switching to cariprazine partial response for negative symptoms—the dose can which decreases the likelihood of a successful switch- be increased and/or add an antidepressant and/or add/ as patients are reluctant to continue. In these cases, the switch to another antipsychotic (Fig. 3b). The role of dosage is increased in a stepwise fashion at longer (e.g., non-pharmacological therapies should, however, not 2-week) intervals. This takes longer but improves efficacy be underestimated—if there is a partial response for Table 2 Up-titration with cariprazine in acute and maintenance settings Fast Slow Acute Maintenance In acute setting up-titrate to 4.5 mg or 6.0 mg in 1 week—increase 1.5 mg Up-titration should be slow in maintenance, whereas fast titration is not every day up to 6.0 mg if no side effects manifest necessary in maintenance Fast titration appropriate for hospital setting due to the need to shorten the Stopping in case of side effects 1 week if replaced with another neu‑ length of stay in the hospital roleptic. Reducing dose in case of beginning of metabolic problems, stop immediately in case of worsening psychotic feature (positive symptoms) Side effects may delay up-titration, but goal is to reach effective dose as soon The slower the better if side effects such as akathisia manifest as possible When used as monotherapy in highly ‘acute’ cases fast up-titration required If body weight is over 120 kg should start with the 3.0 mg dosage Switch 1.5 mg every 3 days is acceptable and usually less likely to produce Vulnerable patients must be titrated much slower akathisia Fagiolini et al. Ann Gen Psychiatry (2020) 19:55 Page 6 of 11 Fig. 2 Medications used by Panel to treat concomitant insomnia (a) and agitation (b) negative symptoms then the patient can be motivated Nature, incidence and management of side effects to start psychotherapies or rehabilitation interventions and the role of treatment adjustment/withdrawal such as cognitive rehabilitation and social skills training, The most common and clinically bothersome adverse which then can have a synergistic/additive effect. event with cariprazine is akathisia (Fig. 5). Increase in body weight, metabolic syndromes and cardiovascular Combination therapy changes are not reported to be particularly problematic. The panel reported that cariprazine monotherapy is In many cases, when cariprazine is discontinued it is indicated for patients with schizophrenia spectrum dis- not due to lack of efficacy but adverse events which are orders. However, for partial responses and patients with patient dependent. In most cases adverse events are suc- comorbidities (schizoaffective disorder, agitation, aggres- cessfully managed by dosage reductions or, in the case of sion, substance abuse) combinations may be necessary acute akathisia, short-term combination with a benzodi- (Fig. 4). It is important to ensure drug interactions do azepine or beta-blocker. not occur to avoid side effects such as dizziness, drowsi- ness, confusion, and difficulty concentrating. Also, it is Recommendations to individualize cariprazine treatment not advisable to use carbamazepine, or another CYP3A4 for patients with schizophrenia inducer, in combination with cariprazine; moreover, cli- Due to the specific pharmacodynamics profile, (partial nicians should evaluate very carefully adding valproic agonist of the dopamine receptors D2/D3, with a ten- acid in females, due to the teratogenic risk. Cariprazine fold affinity for the D3 receptor with partial agonism for can be given in combination with lithium in patients at the serotonin [5-hydroxytryptamine] 5HT1A receptor, risk of suicide. as well as antagonism at 5HT2B and 5HT2A receptors Fagiolini et al. Ann Gen Psychiatry (2020) 19:55 Page 7 of 11 Fig. 3 Strategies employed when there is a partial response for positive symptoms (a) and negative symptoms (b) Fig. 4 Frequency (%) of cariprazine as monotherapy and in combination Fagiolini et al. Ann Gen Psychiatry (2020) 19:55 Page 8 of 11 Fig. 5 Side effects (%) most commonly observed in physicians’ everyday clinical practice and for the histamine H1 receptor), the panel members dangerous effects of closed-angle glaucoma), anti-adren- judge cariprazine to be a drug with important clinical ergic (orthostatic hypotension), antihistaminergic (seda- and pharmacological advantages over other antipsychotic tion, weight gain) and metabolic (weight gain, increased agents [17, 19–21]. The main advantage is assumed in cholesterol, increased triglycerides) as well as a reduced its superior efficacy in treating the negative symptoms risk of arrhythmias [24, 25]. of schizophrenia—representing a major step forward The panel recommended patients with negative symp- for patients, carers and healthcare professionals alike toms—which are among the most debilitating aspects of [22, 23]. The panel noted the evidence on the ability of schizophrenia—as a target group for cariprazine (Fig. 6) cariprazine to reduce troublesome side-effects that fre- [26]. The importance of preparing a long-term treatment quently cause patients to discontinue some of the other plan is sometimes lost sight of, in particular when rele- antipsychotics, including anti-cholinergic (dry mouth, vant acute positive symptoms triggered the initial treat- constipation, urinary retention, exacerbation of the ment decisions. If the initial antipsychotic strategy does Fig. 6 Patients groups the Panel considered would benefit treatment with cariprazine Fagiolini et al. Ann Gen Psychiatry (2020) 19:55 Page 9 of 11 not significantly improve negative symptoms, a medica- place as an add-on therapy (at low dosages) in treatment- tion switch may be necessary once the positive symptoms resistant patients, including those on clozapine or on are treated. In many situations healthcare professionals long acting antipsychotics (LAI). To our knowledge, no concentrate on the acute phase of schizophrenia (psy- randomized controlled trials testing the combination of choses), because it is the most ‘urgent’ but the resolu- cariprazine and clozapine or cariprazine and LAI have tion of negative symptoms or of side effects is just being been conducted to date. Indeed, the results from meta- postponed. Furthermore, sedation is a major issue in the analyses of antipsychotic combinations indicate that data management of schizophrenia—it may be welcomed in are insufficient and that more studies are needed. How- the acute phase but is detrimental in the long-term as ever, a recent paper by Guinart and Correl, evaluated it prevents patients from functioning and focusing on the existing evidence and concluded that ‘evidence for the future and in some cases causes patients to be non- superior efficacy vs antipsychotic monotherapy is scant adherent. Schizophrenia patients with metabolic issues (possibly with the exception of reductions in negative are dying 15 years earlier, inter alia, due to metabolic symptoms when combining a partial D2 agonist and a issues so a drug such as cariprazine with a low level of D2 antagonist)’ [32]. Hence, the combination clozapine– metabolic problems—there has been a recent report of cariprazine or LAI cariprazine is of interest, especially a reversal of the metabolic syndrome with cariprazine— for cases of patients with treatment-resistant schizophre- represents a major advance in the management of this nia that do not respond to more supported treatments patient group [27]. [32–34]. When cariprazine is administered at the outset to first psychotic episode patients (acute/in-patients/in the com- Conclusions munity) to control both positive and negative symptoms, According to the panel’s collective experience and opin- the need for a switch once positive symptoms are con- ions, the ideal cariprazine patients are individuals at their trolled might be lower (Fig. 6). first episodes of psychosis, those with predominant nega- Another patient group in whom the panel considered tive symptoms during the maintenance period or during cariprazine can make a difference is in patients with the acute phase, and those with significant side effects schizophrenia and concomitant substance use disor- (i.e., metabolic side effects, hyperprolactinemia, or seda- der. A large portion of the patients the panel see with tion) from other antipsychotics during periods of stabil- schizophrenia also consume illicit drugs and there are ity. Cariprazine may also be a drug of choice for patients limited treatment choices that can make a difference. If with predominant positive symptoms during the acute a patient continues to, for example, smoke cannabis, is phase, especially when clinicians consider the longer non-adherent or partially adherent and does not want term benefits. When schizophrenia is seen as a life-long to take a depot formulation, the long-half life and non- disorder, characterized by relatively brief periods of exac- sedative action of cariprazine make it the drug of choice. erbation and relatively longer periods of remission, the Cravings are a part of the ongoing cycle of addiction goal of treating acute symptoms remains paramount. and certain agents can prevent cravings (illicit drugs/ However, in these cases, the efficacy in treating negative alcohol) by blocking the receptors (e g., NMDA-, opioid- symptoms and the tolerability profile become as impor- and dopamine receptors) associated with cues that set tant as the need to treat and prevent the positive and off relapse—cariprazine is a partial agonist at dopamine most acute symptoms. When the long-term treatment D2/D3 receptors and as such may have a role in reduc- of a lifetime illness is adequately weighted, cariprazine ing cravings in schizophrenia patients with substance use becomes one of the first-line medications, not only for disorder [28–30]. In an animal study, cariprazine outper- first episode patients, patients with predominant negative formed aripiprazole in decreasing the rewarding effect of symptoms and those with significant side effects from cocaine and avoiding relapse after a period of withdrawal other antipsychotics but also for patients with relatively from cocaine and related cues [31]. Patients with mild or severe positive symptoms. When positive symptoms are moderate agitation may benefit from cariprazine, pro- very severe, adjunctive medications may be necessary, at vided that a second agent (such as lorazepam) is added. least for the acute treatment period. In fact, the favour- The panel considered that cariprazine is not a first choice able effectiveness during the maintenance period may for patients with severe agitation (Fig. 6). drive the choice in the acute phase, even at the price of Combinations of antipsychotics are commonly used using a second medication. For instance, in a patient in refractory schizophrenia when a single agent does with moderate agitation, a clinician looking exclusively at not relieve symptoms adequately, but there is limited the acute phase would likely choose a sedating antipsy- evidence on the benefits of this strategy. Cariprazine chotic, such as olanzapine, that successfully treats all the improves social functioning and as such may have a symptoms discussed above in most patients. However, a Fagiolini et al. Ann Gen Psychiatry (2020) 19:55 Page 10 of 11 clinician that looks at the maintenance treatment as well, presentations fees and travel grants from Casen Recordati, Lundbeck-Otsuka, Janssen; AC is/has been a consultant and/or a speaker for Angelini, Apsen, may rather choose a medication like cariprazine aug- Lundbeck, Otsuka, Pfizer; HF has received speaker and consultant honoraria mented with a benzodiazepine or another medication (last 3 years) from Recordati, Servier, Janssen-Cilag; EI has acted as a consultant that is effective for agitation. In fact, cariprazine is usu- for Recordati; P-A K has given lectures for Eli Lilly, Janssen, Recordati, Lund‑ beck, Astra Zeneca, was involved in conducting safety studies for Janssen, Eli ally better tolerated than olanzapine, primarily in terms Lilly and took part in Advisory boards for Recordati and Eli Lilly; PP has been a of metabolic side effects, and the benzodiazepine can be speaker and/or consultant and/or received grants from Astra Zeneca, Janssen, discontinued afterwards, when the control of agitation is Lundbeck, Recordati, Sunovion, Servier; MP has reported no conflicts of inter‑ est; HJRP has reported no conflicts of interest; JSS has given talks for Recordati no longer necessary. and his employer Sahlgrenska University Hospital Gothenburg; IBV has given The same may be true when a clinician chooses to aug- lectures for Recordati, Janssen, Neuraxpharm and Otsuka. ment clozapine with an antipsychotic such as cariprazine, Author details when a patient is experiencing inefficacy of clozapine 1 School of Medicine, Department of Molecular Medicine, University of Siena, for negative symptoms. In some of these cases, once the Siena, Italy. 2 Clinical Unit of Mental Health, Reina Sofia University Hospital, patient is stabilised, it is then possible to decrease the Cordoba, Spain. 3 Kliniken Essen-Mitte, Klinik für Psychiatrie, Psychotherapie, Psychosomatik und Suchtmedizin, Essen, Germany. 4 GGZ Keizersgracht clozapine dose. In a smaller yet significant number of Outpatient Mental Health Clinic, Amsterdam, The Netherlands. 5 Divsion cases, it may even be possible to completely discontinue of Psychiatry, Department of Clinical Sciences, Lund University Hospital,, Lund, clozapine, after a long enough period of stability, leaving Sweden. 6 Mental Health Department, Nova Medical School, Lisbon, Portugal. 7 Department of Mental Health and Addiction, ASST Lodi, Lodi, Italy. 8 Clinic the patient on a better tolerated antipsychotic. Likewise, and Polyclinic for Psychiatry and Psychotherapy, University of Rostock, Rostock, when a patient experiences psychotic symptoms in the Germany. 9 Department of Psychiatry, Hospital Universitari Vall d’Hebron, CIB‑ acute phase that are partially resistant to cariprazine, a ERSAM, Barcelona, Spain. 10 Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. 11 Department of Psy‑ clinician can choose to use it in combination with clozap- chiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Han‑ ine or risperidone. nover, Germany. 12 Lambeth Early Onset (LEO), South London & Maudsley NHS Based on their real-world clinical experience the panel Foundation Trust and Psychosis Studies Department, Institute of Psychiatry, Psychology and Neurosciences, London, UK. 13 Forensic Services of Norrbotten considered that cariprazine, with its distinct advantages County Council, Öjebyn, Sweden. 14 Psychosis Pathway Coventry and War‑ including pharmacokinetics, pharmacodynamics, efficacy wickshire Partnership NHS Trust and Buckingham Medical School, Rugby, UK. and tolerability, represents one of the drugs of choice in 15 Department of Neuroscience, Imaging and Clinical Sciences, D’Annunzio University of Chieti, Pescara, Italy. 16 Hospital de Magalhães Lemos, Porto, the long-term management of schizophrenia not only for Portugal. 17 Sahlgrenska University Hospital, Gothenburg, Sweden. 18 Depart‑ patients with predominant negative symptoms but also ment of Psychiatry and Psychotherapy, Fliedner Krankenhaus Neunkirchen for those with positive symptoms. When positive symp- Kreuznacher Diakonie, Neunkirchen, Germany. 19 Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany. toms are severe and partially responding to cariprazine, the combination of cariprazine with a second antipsy- Received: 21 July 2020 Accepted: 17 September 2020 chotic may be considered, with the goal to attempt mon- otherapy once the acute phase has solved and the patient progresses to maintenance treatment. References 1. Kraepelin E. Psychiatrie Ein kurzes Lehrbuch für Studierende und Aerzte. Authors’ contributions 2nd ed. Leipzig: Abel; 1887. All authors contributed to the development and writing of the manuscript. 2. History of Schizophrenia. schiz​ophre​nia.com. Accessed 3 June 2020. AF acted as manuscript coordinator. All authors read and approved the final 3. Kahn R, Sommer I, Murray R, et al. Schizophrenia. Nat Rev Dis Primers. manuscript. 2015;1:15067. https​://doi.org/10.1038/np.2015.67. 4. Disease and Injury Incidence and Prevalence Collaborators. Global, Funding regional, and national incidence, prevalence, and years lived with disabil‑ Supported by an unrestricted grant from Recordati. ity for 354 diseases and injuries for 195 countries and territories, 1990– 2017: a systematic analysis for the Global Burden of Disease Study 2017. Data sharing and data accessibility [Published correction appears in Lancet. 2019 Jun 22;393(10190):e44]. Relevant data are available on reasonable request. Lancet. 2018;392(10159):1789–858. https​://doi.org/10.1016/s0140​ -6736(18)32279​-7. Competing interests 5. Haddad PM, Correll CU. The acute efficacy of antipsychotics in schizo‑ AF is/has been a consultant and/or a speaker and/or has received research phrenia: a review of recent meta-analyses. Ther Adv Psychopharmacol. grants from Allergan, Angelini, Apsen, Boheringer Ingelheim, Daiichi Sankyo 2018;8(11):303–18. Brasil Farmacêutica, Doc Generici, FB-Health, Italfarmaco, Janssen, Lundbeck, 6. Lora A, Kohn R, Levav I, McBain R, et al. Service availability and utilization Mylan, Otsuka, Pfizer, Recordati, Sanofi Aventis, Sunovion, Vifor; JAA has been and treatment gap for schizophrenic disorders: a survey in 50 low- and a speaker for Adamed, Angelini, Casen Recordati, Lundbeck, Janssen-Cilag, middle-income countries. Bull World Health Organ. 2012;90(1):47–54. Pfizer and Servier and an advisor to Lundbeck, Janssen-Cilag and Servier; 7. Galderisi S, Mucci A, Buchanan RW, Arango C. Negative symptoms of TA has given lectures and participated in Advisory Boards for Janssen-Cilag, schizophrenia: new developments and unanswered research questions. Otsuka, Recordati, Servier, Lilly; WB has reported no conflicts of interest; MNKB Lancet Psychiatry. 2018;5(8):664–77. has been a consultant and speaker for Lundbeck, Otsuka and Recordati; JG has 8. Bucci P, Galderisi S. Categorizing and assessing negative symptoms. Curr been an occasional speaker for Lundbeck, Janssen, Jaba-Recordati, Angelini; Opin Psychiatry. 2017;30(3):201–8. GC has been a speaker for Recordati, Janssen Cilag, Lundbeck, Doc Generici; 9. Remington G, Foussias G, Fervaha G, et al. Treating Negative Symptoms in MC TBA; FCS has received honoraria from the following companies for Schizophrenia: an Update. Curr Treat Options Psychiatry. 2016;3:133–50. https​://doi.org/10.1007/s4050​1-016-0075-8. Fagiolini et al. Ann Gen Psychiatry (2020) 19:55 Page 11 of 11 10. Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein HG, Steiner J, Bogerts B, data. Schizophr Res. 2019;204:282–8. https​://doi.org/10.1016/j.schre​ Braun K, Jankowski Z, Kumaratilake J, Henneberg M, Gos T. The role of s.2018.08.020. dopamine in schizophrenia from a neurobiological and evolutionary 24. Nasrallah HA, Earley W, Cutler AJ, et al. The safety and tolerability of perspective: old fashioned, but still in vogue. Front Psychiatry. 2014;5:47. cariprazine in long-term treatment of schizophrenia: a post hoc pooled 11. Seeman P. Targeting the dopamine D2 receptor in schizophrenia. Expert analysis. BMC Psychiatry. 2017;17(1):305. https​://doi.org/10.1186/s1288​ Opin Ther Targets. 2006;10(4):515–31. https​://doi.org/10.1517/14728​ 8-017-1459-z. 222.10.4.515. 25. Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 12. Cariprazine Drug FDA, Package; Approval. 2015. http://www.acces​sdata​ antipsychotics on metabolic function in patients with schizophrenia, pre‑ .fda.gov/drugs​atfda​_docs/nda/2015/20437​0Orig​2s000​TOC.cfm. dictors of metabolic dysregulation, and association with psychopathol‑ 13. European Medicines Agency Reagila Assessment Report. 2017. http:// ogy: a systematic review and network meta-analysis. Lancet Psychiatry. www.ema.europ​a.eu/docs/en_GB/docum​ent_libra​ry/EPAR_-_Publi​ 2020;7(1):64–77. https​://doi.org/10.1016/S2215​-0366(19)30416​-X. c_asses​sment​_repor​t/human​/00277​0/WC500​23492​6.pdf ). 26. Citrome L. Unmet needs in the treatment of schizophrenia: new targets 14. European Medicines Agency Pharmacovigilance Risk Assessment Com‑ to help different symptom domains. J Clin Psychiatry. 2014;75(Suppl mittee (PRAC) 28 November 2019, EMA/PRAC/107813/2020. 1):21–6. https​://doi.org/10.4088/JCP.13049​su1c.04. 15. Allergan. VRAYLAR (cariprazine) capsules, for oral use; 2017. https​://www. 27. Halaris A, Wuest J. Metabolic syndrome reversal with cariprazine. J Clin aller​gan.com/asset​s/pdf/vrayl​ar_pi. Psychopharmacol. 2019;39(4):413–6. https​://doi.org/10.1097/JCP.00000​ 16. Nakamura T, Kubota T, Iwakaji A, et al. Clinical pharmacology study of 00000​00107​4. cariprazine (MP-214) in patients with schizophrenia (12-week treatment). 28. Zhan J, Jordan CJ, Bi GH, et al. Genetic deletion of the dopamine D3 Drug Des Devel Ther. 2016;10:327–38. https​://doi.org/10.2147/DDDT. receptor increases vulnerability to heroin in mice. Neuropharmacology. S9510​0. 2018;141:11–20. https​://doi.org/10.1016/j.neuro​pharm​.2018.08.016. 17. Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinet‑ 29. Heidbreder CA, Gardner EL, Xi ZX, et al. The role of central dopamine D3 ics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin receptors in drug addiction: a review of pharmacological evidence. Brain Drug Metab Toxicol. 2013;9(2):193–206. https​://doi.org/10.1517/17425​ Res Brain Res Rev. 2005;49(1):77–105. https​://doi.org/10.1016/j.brain​resre​ 255.2013.75921​1. v.2004.12.033. 18. Tiihonen J, et al. Real-world effectiveness of antipsychotic treatments in a 30. Sokoloff P, Le Foll B. The dopamine D3 receptor, a quarter century later. Nationwide Cohort of 29,823 patients with Schizophrenia. JAMA Psychia‑ Eur J Neurosci. 2017;45:2–19. https​://doi.org/10.1111/ejn.13390​. try. 2017;74(7):686–93. 31. Román V, Gyertyán I, Sághy K, Kiss B, Szombathelyi Z. Cariprazine 19. Fleischhacker W, Galderisi S, Laszlovszky I, et al. The efficacy of cariprazine (RGH-188), a D­ 3-preferring dopamine ­D3/D2 receptor partial agonist in negative symptoms of schizophrenia: post hoc analyses of PANSS antipsychotic candidate demonstrates anti-abuse potential in rats. individual items and PANSS-derived factors. Eur Psychiatry. 2019;58:1–9. Psychopharmacology. 2013;226(2):285–93. https​://doi.org/10.1007/s0021​ https​://doi.org/10.1016/j.eurps​y.2019.01.015. 3-012-2906-7. 20. Gyertyán I, Kiss B, Sághy K, et al. Cariprazine (RGH-188), a potent D3/ 32. Guinart D, Correll CU. Antipsychotic polypharmacy in schizophrenia: why D2 dopamine receptor partial agonist, binds to dopamine D3 receptors not? 3. 2020;81(3):19ac13118. in vivo and shows antipsychotic-like and procognitive effects in rodents. 33. Roerig JL. Clozapine augmentation strategies. Ment Health Clin. Neurochem Int. 2011;59(6):925–35. https​://doi.org/10.1016/j.neuin​ 2019;9(6):336–48. t.2011.07.002. 34. De Berardis D, Rapini G, Olivieri L, et al. Cariprazine add-on in inadequate 21. Kiss B, Horváth A, Némethy Z, et al. Cariprazine (RGH-188), a dopamine clozapine response: a report on two cases. Clinical Psychopharmacology D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial and Neuroscience. 2019. Epub ahead of print, accessed at http://www. agonist antipsychotic candidate: in vitro and neurochemical profile. J cpn.or.kr/journ​al/view.html?uid=1023&vmd=Full. Pharmacol Exp Ther. 2010;333(1):328–40. 22. Németh G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperi‑ done monotherapy for treatment of predominant negative symp‑ Publisher’s Note toms in patients with schizophrenia: a randomised, double-blind, Springer Nature remains neutral with regard to jurisdictional claims in pub‑ controlled trial [published correction appears in Lancet. Lancet. lished maps and institutional affiliations. 2017;389(10074):1103–13. 23. Earley W, Guo H, Daniel D, et al. Efficacy of cariprazine on negative symp‑ toms in patients with acute schizophrenia: a post hoc analysis of pooled Ready to submit your research ? Choose BMC and benefit from: • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations • maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions