Efficacy of lurasidone in first episode psychosis: patient phenotypes, dosage, and recommendations from an expert panel

Vol.:(0123456789) Neurol Ther (2025) 14:85–98 https://doi.org/10.1007/s40120-024-00700-y REVIEW Efficacy ofLurasidone inFirst‑Episode Psychosis: Patient Phenotypes, Dosage, andRecommendations fromanExpert Panel MiquelBernardo · MarinaDíazMarsá · AnaGonzález‑Pinto · ManuelMartínCarrasco · VíctorPérezSola · PilarAlejandraSáiz · EduardVieta · MartaTorrens · CelsoArango · BenedictoCrespo‑Facorro Received: November 7, 2024 / Accepted: December 16, 2024 / Published online: January 6, 2025 © The Author(s) 2025 antipsychotic medication show a clinical and functional benefit over the longer term if they continue low‑dose antipsychotic treatment. Lurasidone is an atypical antipsychotic agent which is approved in Europe for the treatment of schizophrenia in adults and adolescents (13–17 years). The efficacy and tolerability of lurasidone have been demonstrated in both antipsychotic‑ naïve and previously treated patients. Areas Covered: This paper provides a review and commentary regarding the use of lurasidone in patients with FEP. Case studies based on the authors’ clinical experiences with lurasidone in real‑world practice are provided. ABSTRACT Introduction: For patients with psychosis, early, intensive therapeutic intervention is thought to improve long‑term outcomes. Fur‑ thermore, patients with a first‑episode psychosis (FEP) who experience a good early response to Prior Publication: The cases presented by Dr. Pinto were previously submitted to the second edition of the Clinical Cases in Schizophrenia competition, held in 2023 in Spain, and were published in local language eBook format with limited distribution (ISBN: 978‑84‑ 09‑56060‑8) 02/2004. M.Bernardo(*)· E.Vieta Department ofPsychiatry andPsychology, Clínic Barcelona, Institute ofNeuroscience, University ofBarcelona, IDIBAPS, CIBERSAM, Barcelona, Spain e‑mail: [email protected] M.D.Marsá Hospital Clínico San Carlos, Universidad Complutense, CIBERSAM, Madrid, Spain A.González‑Pinto Hospital Universitario de Álava, BIOARABA. UPV/ EHU, CIBERSAM, Vitoria, Spain M.M.Carrasco Clínica Psiquiátrica Padre Menni, Pamplona, FIDMAG Research Foundation, Barcelona, Spain V.P.Sola· M.Torrens Mental Health Institute Hospital del Mar, Barcelona, Hospital del Mar Research Institute, University Pompeu Fabra, University ofVic‑Central Catalunya, RIAPAD, Barcelona, Spain P.A.Sáiz Department ofPsychiatry, Universidad de Oviedo, CIBERSAM, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Neurociencias del Principado de Asturias (INEUROPA), Servicio de Salud del Principado de Asturias (SESPA), Oviedo, Spain C.Arango Department ofChild andAdolescent Psychiatry, Institute ofPsychiatry andMental Health, Hospital General Universitario Gregorio Marañón School ofMedicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain B.Crespo‑Facorro Department ofPsychiatry, Faculty ofMedicine, Mental Health Unit, Virgen del Rocio University Hospital, Translational Psychiatry Group, IBiS‑CSIC, CIBERSAM, University ofSeville, Seville, Spain 86 Neurol Ther (2025) 14:85–98 Expert Opinion: In our experience, lurasidone has shown efficacy in FEP in different patient profiles, including those with psychoses associ‑ ated with substance use disorders. Lurasidone provides clinically relevant benefits, especially in patients with affective symptomatology, and has a good tolerability profile. Keywords: First‑episode psychosis; Treatment; Antipsychotic; Schizophrenia; Tolerability; Lur‑ asidone Key Summary Points Lurasidone is an effective antipsychotic treatment for patients experiencing their first psychotic episode. Lurasidone is effective in various patient populations, including those with psychoses associated with substance use disorders. Lurasidone provides clinically relevant benefits, especially in patients with affective symptoms. Lurasidone is well tolerated in both antipsy‑ chotic‑naïve and previously treated patients. INTRODUCTION Psychotic disorders encompass a wide range of conditions characterized by thought, sensoper‑ ceptive, cognitive, and affective symptoms [1–3]. They are relatively common, with up to 3% of the general population experiencing a first‑epi‑ sode psychosis (FEP) within their lifetime [4], and are associated with a high societal burden [1, 5]. The onset of psychotic disorders typically occurs in adolescence or early adulthood [6], although they can appear throughout life; around 50% of FEPs are associated with the use of cannabis or other substances [7, 8]. Young patients receiving antipsychotic medication may be more sensitive to treatment side effects than adult patients, or may be more likely to discon‑ tinue their medication if they experience sexual dysfunction, excessive sedation, or weight gain, potentially compromising both their recovery and their long‑term prognosis [9, 10]. Lurasidone is an atypical antipsychotic agent which is approved by the European Medicines Agency for the treatment of schizophrenia in adults and adolescents aged 13years and over [11], and by the Food and Drug Administration for the treatment of schizophrenia and depres‑ sive episodes associated with bipolar I disorder [12]. Interest in lurasidone as a treatment for FEP is based on its unique pharmacological profile and potential clinical advantages in FEP. Its high affinity for 5‑HT7 and 5‑HT1A receptors contrib‑ utes to antidepressant and cognitive‑enhanc‑ ing effects, which are particularly relevant for patients with FEP who often experience depres‑ sive symptoms and cognitive deficits [13–15]. In this review, we assess the evidence for the use of lurasidone in FEP. A panel of experts was convened to assess real‑world practice with lur‑ asidone, to describe clinical cases, and to pro‑ pose best practices in the treatment of patients with FEP. HETEROGENEITY AND CLINICAL EVOLUTION OF PSYCHOTIC DISORDERS Patients with FEP may exhibit positive symp‑ toms (e.g., delusions and hallucinations), disor‑ ganization (related to thoughts and behavior), and/or negative symptoms (e.g., anhedonia, apathy, and alogia) [1–3]. Outcome studies have reported that over 50% of people with FEP have a good long‑term outcome [16, 17], although this rate may drop depending on the criteria used to define functional recovery [18]. In addi‑ tion to the clinical heterogeneity of FEPs [1], there is an underlying biological heterogene‑ ity which, if better understood, could help to inform the most appropriate therapy. In recent studies, the relationship between brain mor‑ phology and pathology (i.e., diagnosis, disease stage or symptoms) has been assessed, leading to the identification of neuromorphological 87 Neurol Ther (2025) 14:85–98 subgroups which could potentially be used to stratify patients [11] or to predict differential clinical trajectories [19]. The heterogeneity inherent to this pathology underscores the need for real‑world data and expert recommendations to guide clinicians in effective FEP management. CONSIDERATIONS FOR FEP MANAGEMENT Due to the clinical heterogeneity of psychotic disorders, an individualized assessment is required before establishing the appropriate treatment. The severity of positive and nega‑ tive symptoms should be assessed alongside the characteristics of disease presentation, such as the type of onset, suicidal ideation, neurocog‑ nition, social functioning, concomitant psychi‑ atric conditions, comorbidities, lack of efficacy, poor adherence to previous treatments, and other social factors [20]. FEPs should be treated as soon as the disease is diagnosed, as there is an association between the duration of untreated psychosis and poor clinical outcomes [21, 22]. Patients with an FEP who experience a good early response to antipsychotic medication show a clinical and functional benefit over the longer term if they continue low‑dose antipsychotic treatment [23]. Thus, early, intensive, comprehensive, and sus‑ tained therapeutic interventions from the early phases of the illness may improve long‑term outcomes. In many cases, FEPs occur during adolescence, and there is evidence of differences in cortical gray matter deficits between adolescent‑onset and adult‑onset schizophrenia which may be related to the developmental stages of the brain when an FEP occurs [24]. It is therefore impor‑ tant to understand the efficacy and safety of antipsychotic medications in both the adoles‑ cent and adult populations. Antipsychotic drugs are associated with a diverse range of adverse effects, including agranulocytosis, akathisia, constipation, dys‑ tonia, hyperprolactinemia, myocarditis, seda‑ tion, sexual side effects, tardive dyskinesia, and weight gain [25]. These are specific to each antipsychotic medication and may impact on treatment adherence and efficacy [26]. In adoles‑ cents, specific antipsychotics have been shown to be associated with a higher incidence of weight gain, sedation, and hyperprolactinemia [27]. Management strategies to reduce adverse effects may include lowering the dose, adjust‑ ing the dosing schedule, switching to a different antipsychotic treatment, or using concomitant medications to address the adverse effects [25]. LURASIDONE IN THE TREATMENT OF FEP Lurasidone received marketing approval for the treatment of schizophrenia in Europe in 2014 [11], and is currently the only antipsychotic licensed for use in adolescents aged 13 and over. Its complex pharmacology includes antago‑ nist activity at dopaminergic D2 receptors and 5‑hydroxytryptamine receptors (5‑HT2A and 5‑HT7) and partial agonism at the 5HT‑1A recep‑ tor, which together may contribute to its benefi‑ cial effects in FEP [13]. Notably, lurasidone does not bind to histaminergic or muscarinic recep‑ tors, which may account for a lower incidence of weight gain compared with other antipsychotics [27, 28]. Efficacy of Lurasidone in Patients with Psychotic Disorders Patients with schizophrenia exhibit symptoms across multiple domains, including perception, cognition, mood, and behavior. Lurasidone has demonstrated efficacy across the spectrum of schizophrenia symptoms, including positive symptoms, disorganized thought, hostility/ excitement, and depression/anxiety [29]. Efficacy in Reducing Positive Symptoms The efficacy of lurasidone (37–148 mg/day) in reducing positive symptoms has been demon‑ strated following acute and long‑term treat‑ ment of adults with schizophrenia across a number of clinical studies [30–36]. Two 88 Neurol Ther (2025) 14:85–98 network meta‑analyses have shown similar efficacy between lurasidone and other atypi‑ cal antipsychotics in this regard [37, 38]. The efficacy of lurasidone at 37–74 mg/day has also been demonstrated in adolescent patients with schizophrenia in a 6‑week, double‑blind, placebo‑controlled trial [39]. In a post hoc analysis, the efficacy of lurasidone in reducing Positive and Negative Symptom Scale (PANSS) scores in adolescent patients with schizophre‑ nia was found to be greater in treatment‑naïve patients than in previously treated patients, suggesting the effectiveness of lurasidone in FEP [40]. In Table1, we present the case of a 15‑year‑old male with psychotic symptoms who showed complete remission and unre‑ markable side effects following treatment with lurasidone 37mg/day (Table1, Case 1). Efficacy in Reducing Depressive Symptoms Lurasidone has also demonstrated efficacy in reducing depressive symptoms in patients with schizophrenia [15, 41]. Depression is com‑ mon in FEP and has been shown to predict a lower likelihood of psychosis remission dur‑ ing a 10‑week follow‑up [42]. In addition, sui‑ cide risk is higher in FEP compared with other periods of pyschosis, and depressive symptoms appear to be one of the most important drivers for the increased suicide risk in this population [43]. A recently published case study has reported clinical and functional improvement 3 months after the initiation of lurasidone in a 19‑year‑ old man with FEP and predominant depressive symptoms [44]. Treatment with lurasidone led to disappearance of the depressive symptoms and a dramatic reduction in psychotic symptoms, with good tolerance to treatment. In Table1, we illus‑ trate the case of a 17‑year‑old female with autol‑ ytic ideation and low response to previous antip‑ sychotics who showed a reduction in depressive symptoms with lurasidone 55.5 mg/day (Table1, Case 2). This case suggests that lurasidone is a promising treatment in patients with FEP and depressive symptomatology, in line with recent studies [15, 41, 45]. Efficacy in FEP Associated with Substance Use Substance use is strongly associated with the development of psychotic disorders [46], lead‑ ing to psychoses characterized by increased alterations in consciousness, dissociative states, frequent hallucinations, and often aggressive or disruptive behavior [47]. With its broad phar‑ macological profile, lurasidone has the poten‑ tial to interact with multiple pathways linked to psychotic symptoms in these patients. In a real‑world study of patients with concurrent schizophrenia spectrum disorder and alcohol/ substance use disorder (SUD), lurasidone pro‑ vided a beneficial decrease in psychopathologi‑ cal burden, positive symptoms, and substance craving in participants using cannabis, alcohol, cocaine, or LSD [48]. Similarly, Ricci etal. have published a case series highlighting the utility of lurasidone in patients with substance‑induced FEP [47]. Four patients, aged 20–25 years and presenting with cannabis‑induced psychosis and increasing symptoms, were treated with lurasi‑ done (74–148 mg/day). Despite heterogeneity in the clinical manifestation of cannabis‑induced FEP among the patients, they all showed improvement in the clinical nature of their psychosis, with improvements in positive and negative symptoms and in global functioning over time. In addition, no significant side effects were reported with lurasidone [47]. In Table1, we present the case of a 30‑year‑old male with cannabis use disorder, which highlights the effi‑ cacy of lurasidone in providing good control of psychotic, affective symptomatology, and absti‑ nence to substance use (Table1, Case 3). Lurasidone Safety Profile Acute and long‑term treatment of patients with lurasidone is well tolerated across clinical studies [30–36]. Known adverse effects associated with lurasidone include somnolence and akathisia [49, 50], both of which are manageable. Initial sedation observed with lurasidone may be ben‑ eficial in patients with acute symptoms. In com‑ mon with several other antipsychotic agents, 89 Neurol Ther (2025) 14:85–98 Table 1 Patient case studies highlighting lurasidone treatment for first-episode psychosis Case no. Treating physician Patient Symptoms Initial treatments Lurasidone maximum dose (mg/ day) Follow up 1Dr Arango 15-year-old male Isolation, depressive mood, agitation, self-harm, delusion, hallucinations Treatment-naïve 37 Discharged from hospital after 3 weeks; referred to outpatient clinic (once monthly); back at school with no residual positive symptoms and no side effects from lurasidone 2Dra Pinto 17-year-old female Autolytic ideation, depressed mood with delusional ideas of persecution and insomnia with frequent awakenings Previously treated with aripiprazole, risperidone, and olanzapine, with low response 55.5 Attenuation of delusional symptoms and improvement in mood; disappearance of autolytic ideas 3Dra Pinto 30-year-old male Delusions, hallucinations, hypotimia, anxiety,cannabis use disorder Risperidone, aripiprazole, cariprazine, and clonazepam 111 Good control of psychotic and anxiety symptoms; abstinence to cannabis 4Dr Martin 71-year-old male Delusions, hallucinations, psychotic behavior Risperidone 12 mg/day, clonazepam 4 mg/day, and lormetazepam 2 mg/day Discharged after 2 weeks but presented in outpatient clinic with psychomotor retardation, functional deterioration, and signs of parkinsonism 148 After 2weeks of lurasidone, extrapyramidal symptoms, functionality, and psychotic symptoms improved 90 Neurol Ther (2025) 14:85–98 lurasidone has been associated with hyperpro‑ lactinemia [50], which can lead to sexual side effects. However, increases in prolactin levels with lurasidone are minimal compared with ris‑ peridone and paliperidone [50], and prolactin levels are reduced on switching from risperi‑ done to lurasidone [51]. Lurasidone is associated with a reduced risk of weight gain compared with other atypical antipsychotic medications in both adult and adolescent patients [38, 52, 53]. A network meta‑analysis of randomized controlled trials showed less weight gain with lurasidone compared with other atypical antip‑ sychotic monotherapies in adolescent patients with schizophrenia [38]. Similarly, a real‑world, retrospective analysis of 15,323 adults with schizophrenia indicated a lower risk of clinically relevant weight gain with lurasidone compared with other commonly used antipsychotics [52]. The low risk of weight gain seen with lurasidone probably reflects its lack of binding to histamin‑ ergic and muscarinic receptors [11]. Lurasidone’s manageable safety profile is highlighted by high treatment retention rates. It is associated with better adherence rates and a lower risk of all‑ cause discontinuation compared with other atypical antipsychotic treatments [38, 54]. In an Italian real‑world study, persistence with lurasidone was high, with 78% of patients with schizophrenia still on lurasidone after 6 months of treatment [55]. Importantly, lurasidone has demonstrated long‑term safety in adolescents with schizophrenia, who will likely require treat‑ ment over the long term [56]. Finally, tolerabil‑ ity of lurasidone is demonstrated in all of the patient cases highlighted in Table1, with cases 2 and 3 demonstrating how lurasidone can reverse weight gain caused by previous antipsychotic medications. Long‑Term Treatment in Young Patients Lurasidone has demonstrated sustained efficacy and safety in long‑term treatment settings [37, 52], which is particularly evident in young pop‑ ulations [57]. Correll etal. have shown that lur‑ asidone effectively manages symptoms in ado‑ lescents with schizophrenia over the long term, emphasizing its potential for early intervention Table 1 continued Case no. Treating physician Patient Symptoms Initial treatments Lurasidone maximum dose (mg/ day) Follow up 5 Dra Marsá 35-year-old female Delusions, hallucinations, disorganized thought Paliperidone i.m. due to lack of adherence to oral medication; amenorrhea, galactorrhea and sexual dysfunction appeared 92.5 mg Decrease in hyperprolactinemia symptoms, improved galactorrhea, and recovery of menstrual cycle; improvement in psychotic symptoms (hallucinations, delusions) and in patient’s quality of life 91 Neurol Ther (2025) 14:85–98 [58], while its minimal side effects suggest that it is a practical option for maintenance treatment [56]. A recent pooled analysis of two 12‑month extension studies further supports these find‑ ings, highlighting lurasidone’s balance of effi‑ cacy and tolerability in adolescents and young adults with schizophrenia, and its potential for sustained use across diverse psychiatric condi‑ tions [59]. Dosage Clinicians should ensure that an adequate dos‑ age of lurasidone is administered to patients to maximize clinical benefit [20]. The recom‑ mended starting dose of lurasidone is 37 mg once daily and the maximum daily dose is 74 mg in adolescents and 148 mg in adults [11]. In our experience, lurasidone is frequently adminis‑ tered below the recommended dose, possibly due to a lack of awareness of appropriate dos‑ ing schedules or overcautiousness when using a lesser‑known drug. In either case, the effec‑ tiveness of lurasidone may be compromised. A randomized, controlled trial in patients hospitalized with acute schizophrenia found that increasing the lurasidone dose from 80 to 160mg/day provided significantly greater improvement in schizophrenia symptoms in early non‑responders compared with continu‑ ing the initial dose [60]. Similarly, in a pooled analysis of short‑term placebo‑controlled studies in patients with schizophrenia, the maximum daily dose of lurasidone was the most efficacious across all five domains of PANSS [29]. Notably, a post hoc analysis of pooled data from five short‑term, randomized, controlled trials found that the benefit of higher doses of lurasidone is more apparent in patients with more severe agitation based on PANSS‑Excited Component (PANSS‑EC) scores [61]. In this study, lurasidone significantly reduced agitation from Days 3/4 to Week 6 in patients with an acute exacerbation of schizophrenia and high levels of agitation (often associated with substance use‑related psychotic behavior [47]), and lurasidone 120–160mg/day was particularly effective in patients with more severe agitation at baseline [61]. In Table1, we highlight the case of a 71‑year‑ old male with severe deterioration and a history of side effects with prior antipsychotic medica‑ tion (Table1, Case 4). In this patient, lurasidone at its maximum dose (148 mg/day) was effective in controlling agitation and aiding functional recovery. Comparison with Other Antipsychotic Agents for FEP Compared with other antipsychotics, lurasidone demonstrates similar efficacy in reducing psy‑ chotic symptoms while offering distinct advan‑ tages, such as minimal metabolic side effects, including lower risks of weight gain and dys‑ lipidemia [62]. Additionally, it is less likely to cause extrapyramidal symptoms and has shown promising outcomes in improving both nega‑ tive and depressive symptoms [33]. In compari‑ son with other second‑generation antipsychot‑ ics, lurasidone has shown similar effectiveness, with the exception of clozapine [50, 63]. Com‑ pared with brexpiprazole and cariprazine, lur‑ asidone has shown similar efficacy and safety outcomes, with the 160‑mg dose showing supe‑ riority for changes in PANSS and Clinical Global Impression‑Severity scores [63]. Lurasidone has a favorable side‑effect profile, with significantly less weight gain and metabolic disturbances compared with olanzapine, quetiapine, and ris‑ peridone [38]. Hyperprolactinemia, which is a concern with many antipsychotics, occurs at a lower frequency with lurasidone compared with risperidone and paliperidone [38]. How‑ ever, akathisia has been reported in approxi‑ mately 12.7% of patients treated with lurasi‑ done, which is higher than with some other second‑generation antipsychotics [e.g., asenap‑ ine (6.8%)], although lower than with caripra‑ zine (17.2%) [64]. Akathisia with lurasidone is generally mild and manageable [32]; strategies to manage akathisia include dose reduction, slower titration, or the addition of beta‑blockers or benzodiazepines as needed [20]. Overall, the characteristics of lurasidone help to position it as a potentially valuable treatment option for patients with FEP, and in particular those requir‑ ing long‑term management. 92 Neurol Ther (2025) 14:85–98 Treatment Switching Treatment switching to lurasidone is an option in patients who experience a lack of efficacy or intolerable adverse effects with other antip‑ sychotic treatments. For example, patients switched from olanzapine to lurasidone have shown significant reductions in body weight and improvements in metabolic parameters after 6months of treatment [65]. Similarly, after switching from risperidone to lurasidone, patients with schizophrenia have shown reduc‑ tions in weight, metabolic parameters, and pro‑ lactin levels, while maintaining improvements in PANSS total score [51, 66]. The elderly patient highlighted above (Table1, Case 4) switched to lurasidone due to parkinsonism exhibited with risperidone‑based antipsychotic treat‑ ment. After 2 weeks of treatment with 148 mg/ day lurasidone, he showed an improvement in extrapyramidal effects, functionality, and psy‑ chotic symptoms. We also highlight the case of a 35‑year‑old female who experienced amenor‑ rhea, galactorrhea, and sexual dysfunction asso‑ ciated with hyperprolactinemia while receiving paliperidone for psychotic symptoms (Table1, Case 5). Following a switch to lurasidone, this patient’s hyperprolactinemia and psychotic symptoms both improved. While data to sup‑ port switching of different antipsychotic medi‑ cations are sparse, switching to lurasidone is supported by several studies, as highlighted by a recent systematic review [67]. Contraindications Both lurasidone and its active metabolite are primarily metabolized by CYP3A4. Lurasidone is contraindicated with strong CYP3A4 inhibi‑ tors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazo‑ done, nelfinavir, posaconazole, ritonavir, saqui‑ navir, telaprevir, telithromycin, voriconazole). Coadministration of lurasidone with medicinal products that moderately inhibit CYP3A4 (e.g., diltiazem, erythromycin, fluconazole verapamil) may increase exposure to lurasidone. Lurasidone is also contraindicated with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbi‑ tal, phenytoin, rifampicin, and St John’s wort [Hypericum perforatum]). Coadministration of lurasidone with mild (e.g. armodafinil, ampre‑ navir, aprepitant, prednisone, rufinamide) or moderate (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) inducers of CYP3A4 would be expected to reduce exposure to lurasidone [11]. Limitations To date, the information available on lurasidone in the context of FEP is limited to clinical case reports [47]. The case studies included in this review are intended to complement the existing body of literature in the broader schizophrenia population and to provide real‑world insights into the use of lurasidone in this specific popula‑ tion. However, we acknowledge that case studies are anecdotal and are presented here as part of a broader effort to address the significant gaps in evidence for lurasidone in FEP. In support of this approach, a systematic review has suggested that the effects of antipsychotics in various patient subgroups are generally similar to those observed in the broader population of patients with schizophrenia [68]. Some conclusions in this review are based on retrospective or post hoc analyses, which are inherently subject to selection bias and limited by the lack of control over confounding variables. Unlike prospective, randomized controlled trials, these study designs cannot establish causality and may reflect pre‑ existing patient characteristics or treatment conditions rather than the true effects of the intervention. Additionally, the absence of ran‑ domization and potential for incomplete data further restrict the generalizability of these find‑ ings. There is therefore a need for prospective, controlled studies to validate these observations and to provide a more robust evidence base for the use of lurasidone in FEP. CONCLUSIONS Lurasidone is a new antipsychotic drug which has demonstrated efficacy and tolerability in 93 Neurol Ther (2025) 14:85–98 both the acute phase of schizophrenia and as maintenance treatment to reduce the risk of relapse. As the duration of untreated psychosis is associated with poor clinical outcomes, FEPs should be treated as soon as the disease is diag‑ nosed [21, 22]. Based on its favorable efficacy and safety profile, including minimal metabolic side effects, and its approval for use in adoles‑ cents aged 13years and over, lurasidone repre‑ sents a valuable treatment option for patients with FEP, particularly in populations where tol‑ erability and long‑term safety are critical con‑ siderations. There is a broad experience with lurasidone in clinical practice, both as a first‑ line treatment and after switching from other antipsychotic drugs. Real‑world case studies pre‑ sented here suggest that lurasidone has utility in a range of FEP scenarios, including treatment‑ naïve patients, patients with agitation and/or aggressiveness, those requiring a switch from other antipsychotic medications on account of low efficacy or poor tolerability, and patients with substance‑induced psychosis. Lurasidone may be particularly beneficial in FEP with prom‑ inent affective symptoms. Due to the high variability of conditions and symptoms encompassed in psychosis, there is no homogeneity in the way patients are treated with lurasidone. Selecting the correct dose of lurasidone is key to maximizing efficacy, but, in real‑world settings, the dosage of lurasidone is suboptimal in many cases of FEP. According to the European label [11], lurasidone is effective in a dose range of 37–148mg/day, but the maxi‑ mum daily dose of lurasidone has been shown to be the most effective across all five domains of PANSS [29]. In clinical practice, the maximum doses are reached within 1–5 days of treatment, depending on tolerability [20]. A systematic review and meta‑analysis of data from randomized controlled trials in the general population (including adults, adolescents, and children) suggests that second‑generation antip‑ sychotics differ to a greater extent in their toler‑ ability profiles than in their antipsychotic effi‑ cacy. Thus, lurasidone, with its good tolerability profile, is well positioned among antipsychotics that minimize clinically significant side effects such as metabolic syndrome, hyperprolactine‑ mia, or parkinsonism [68]. In conclusion, our experience indicates that lurasidone has efficacy in FEP in different patient profiles, including those with SUD, and provides clinically relevant benefits with a good tolerability profile. ACKNOWLEDGEMENTS We thank Olga Iglesias Cano and Andrea Flores Ceballos for assistance with patient cases 2 and 4. Medical Writing and Editorial Assistance. Medical writing and editorial assistance were provided by Ian Marshall of WriteMedical Ltd and funded by Angelini Pharma. Author Contributions. Miquel Bernardo designed and created the first draft of the man‑ uscript and collated feedback from the other authors. Miquel Bernardo, Marina Díaz Marsá, Ana González‑Pinto, Manuel Martín Carrasco, Víctor Pérez Sola, Pilar Alejandra Sáiz, Eduard Vieta, Marta Torrens, Celso Arango and Bene‑ dicto Crespo‑Facorro provided feedback for the subsequent drafts and approved the final version of the manuscript. Funding. This paper was funded by unre‑ stricted support from Angelini Pharma, includ‑ ing the study and open‑access fee. The company had no influence on article content. Declarations Conflict of Interest. Miquel Bernardo has received grants and/or served as a consult‑ ant, advisor or speaker for AB‑Biotics, Abar‑ tis Pharma, Adamed, Angelini Pharma, Casen Recordati, Esteve, Janssen‑Cilag, Menarini, Rovi and Takeda. Marina Díaz Marsá has received grants and/or served as a consultant, advisor or speaker for Alter, Angelini, Idorsia, Janssen‑ Cilag, Lundbeck, Novartis, Otsuka, Rovi, Takeda, the Ministry of Science (Carlos III Institute), the Basque Government, and the European Framework Program of Research. Ana González‑ Pinto has received grants and/or served as a