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Background: Although second-generation antipsychotics (SGAs) have proven to be effective therapeutic options for patients with schizophrenia, there is a notable lack of evidence on patients' subjective perspectives regarding their well-being, quality of life, and satisfaction with these medications. This study aimed to evaluate the treatment satisfaction and effectiveness of lurasidone on quality of life and functioning in adult patients with schizophrenia in real-world Italian clinical practice. Methods: This was a multicentre, national, non-interventional, single-arm, 3-month prospective study. Patients who were naive to lurasidone treatment and whose treating physician had decided to start them on this medication were enrolled and evaluated over a 3-month period. Eligible patients were adults (≥ 18 years of age) with a primary diagnosis of schizophrenia who were being treated with lurasidone (for the first time [i.e., they were lurasidone naive]) as part of routine clinical practice. Efficacy endpoints were changes in patient/caregiver treatment satisfaction (seven-point Likert scale from the Treatment Satisfaction Questionnaire for Medication), patient quality of life and functioning (QLS), investigator-rated global assessment of functioning (CGI-S, IAQ) after 6 weeks and 3 months of lurasidone, and number of relapses and hospitalizations. Results: Sixty-one patients were enrolled and 59 completed the study. The median dosage of lurasidone at baseline was 37.00 mg/day. The median duration of titration was 86.0 days (Min 28; Max 115 days); the median number of dosage changes was 1.0. At the end of 3-month observation period, the median dose of lurasidone was 74.00 mg/day. QoL and Functioning Score showed a trend of improvement over time, reaching a mean change from baseline of 9.8 at the end of the study. According to the CGI-S, the percentage of patients who were "markedly or severely ill" showed a continuous decrease from baseline to 3 months, from 62.29% to 8.20%. Patient satisfaction increased over time, with 80.32% of patients reporting that they were somewhat, fairly, or very satisfied (including 63.93% who were completely or very satisfied) at the end of the study. No relapses/hospitalizations for psychiatric reasons were reported. Lurasidone was well tolerated with no safety concerns or discontinuations due to AEs. Conclusions: Lurasidone represents a valid option for the treatment of schizophrenia and positively affects subjective well-being, quality of life and satisfaction. Trial registration: NCT06527885 retrospectively registered (01/08/2024). [ABSTRACT FROM AUTHOR]

Introduction Lurasidone (LUR) was compared with quetiapine extended release (QUE-ER) regarding 1-year discontinuation in patients with bipolar depression (n=317). Methods This is a retrospective cohort study. Results Although the time to all-cause discontinuation was estimated using the Kaplan–Meier survival curve with log-rank tests to compare treatment groups, no difference was found (p=0.317). The Cox proportional hazard model revealed that only the presence of adverse events (AEs) is associated with increased treatment discontinuation (p<0.0001). The most common AEs were akathisia for LUR (17.7%) and somnolence for QUE-ER (34.7%). In other Cox models divided by LUR or QUE-ER, the presence of akathisia or somnolence was associated with increased LUR (p=0.0205) or QUE-ER (p<0.0001) discontinuation, respectively. Discussion The acceptability of both antipsychotics to bipolar depression in clinical practice may be similar. However, specific AEs for each antipsychotic (LUR: akathisia and QUE-ER: somnolence) were associated with high treatment discontinuation. [ABSTRACT FROM AUTHOR]

A relevant approach based on the attractive inherited merits of fluorescence spectroscopy has been established for quantitative estimation of a newly approved second‐generation atypical antipsychotic lurasidone (LUR) in its raw materials and pharmaceutical dosage forms. This study brings to light the strong native fluorescence of LUR at 400 nm in water after excitation at 316 nm. Different experimental parameters that may compromise the fluorescence of the drug were carefully investigated and optimized. A linear response was established between the relative fluorescence intensity and concentration over the concentration range of 50–650 ng/mL with excellent correlation (r = 0.9998). The validity of the method was evidenced in accordance with International Council for Harmonization guidelines, with minimal detection and quantification limits of 2.88 and 8.73 ng/mL, respectively. The method was effectively applied for the estimation of LUR in spiked human plasma and urine samples with acceptable recoveries. The biopharmaceutical significance of the method was heightened by its successful applications for both content uniformity and in vitro dissolution testing. Three different tools accredited the greenness character of the presented study. Eco‐friendliness, effortlessness, and cost effectiveness are crucial hallmarks of our study. The presented study demonstrates potential applicability in quality control laboratories with limited resources. [ABSTRACT FROM AUTHOR]

Latuda® is a novel antipsychotic drug for schizophrenia and bipolar depression. A bioequivalence trial was performed to investigate the bioequivalence of Latuda® and its generic drug lurasidone. Two independent trials were carried out, each involving 28 subjects. In the fasting trial, subjects were randomly assigned to two groups (1:1 ratio), receiving either 40 mg of generic lurasidone or Latuda®. After a 7-day washout period, subjects entered the second period with a crossover administration of 40 mg of generic lurasidone or Latuda®. The postprandial study design was similar to that of the fasting study. In the fasting study, the pharmacokinetic (PK) parameter values of generic lurasidone and Latuda® were as follows: the Cmax was 28.84 ± 19.34 ng/ml and 28.22 ± 21.19 ng/ml, respectively; the AUC0-t was 121.39 ± 58.47 h*ng/ml and 118.35 ± 52.24 h*ng/ml, respectively; and the AUC0-∞ was 129.63 ± 63.26 h*ng/ml and 126.59 ± 57.99 h*ng/ml, respectively. The primary pharmacokinetic parameter, Cmax, was assessed for equivalence using reference-scaled average bioequivalence (RSABE), while other parameters (AUC0-t, AUC0-∞) were evaluated using average bioequivalence (ABE). The results indicate that both Cmax and AUC meet the equivalence criteria. In the postprandial study, the PK values of generic lurasidone and Latuda® were as follows: the Cmax was 74.89 ± 32.06 ng/ml and 83.51 ± 33.52 ng/ml, respectively; the AUC0-t was 274.77 ± 103.05 h*ng/ml and 289.26 ± 95.25 h*ng/ml, respectively; and the AUC0-∞ was 302.44 ± 121.60 h*ng/ml and 316.32 ± 109.04 h*ng/ml, respectively. The primary pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞) were assessed for equivalence using ABE, and both met the equivalence criteria. In the study, lurasidone and Latuda® both exhibited acceptable safety and tolerability. The results displayed that lurasidone and Latuda® were bioequivalent and safe in healthy Chinese participants. Clinical Trial Registry: This trial is registered at chinadrugtrials.org.cn (no.: CTR20191717, date: 2019.08.29). [ABSTRACT FROM AUTHOR]

Abstract Background Although second-generation antipsychotics (SGAs) have proven to be effective therapeutic options for patients with schizophrenia, there is a notable lack of evidence on patients’ subjective perspectives regarding their well-being, quality of life, and satisfaction with these medications. This study aimed to evaluate the treatment satisfaction and effectiveness of lurasidone on quality of life and functioning in adult patients with schizophrenia in real-world Italian clinical practice. Methods This was a multicentre, national, non-interventional, single-arm, 3-month prospective study. Patients who were naive to lurasidone treatment and whose treating physician had decided to start them on this medication were enrolled and evaluated over a 3-month period. Eligible patients were adults (≥ 18 years of age) with a primary diagnosis of schizophrenia who were being treated with lurasidone (for the first time [i.e., they were lurasidone naive]) as part of routine clinical practice. Efficacy endpoints were changes in patient/caregiver treatment satisfaction (seven-point Likert scale from the Treatment Satisfaction Questionnaire for Medication), patient quality of life and functioning (QLS), investigator-rated global assessment of functioning (CGI-S, IAQ) after 6 weeks and 3 months of lurasidone, and number of relapses and hospitalizations. Results Sixty-one patients were enrolled and 59 completed the study. The median dosage of lurasidone at baseline was 37.00 mg/day. The median duration of titration was 86.0 days (Min 28; Max 115 days); the median number of dosage changes was 1.0. At the end of 3-month observation period, the median dose of lurasidone was 74.00 mg/day. QoL and Functioning Score showed a trend of improvement over time, reaching a mean change from baseline of 9.8 at the end of the study. According to the CGI-S, the percentage of patients who were “markedly or severely ill” showed a continuous decrease from baseline to 3 months, from 62.29% to 8.20%. Patient satisfaction increased over time, with 80.32% of patients reporting that they were somewhat, fairly, or very satisfied (including 63.93% who were completely or very satisfied) at the end of the study. No relapses/hospitalizations for psychiatric reasons were reported. Lurasidone was well tolerated with no safety concerns or discontinuations due to AEs. Conclusions Lurasidone represents a valid option for the treatment of schizophrenia and positively affects subjective well-being, quality of life and satisfaction. Trial registration NCT06527885 retrospectively registered (01/08/2024).

The management of schizophrenia necessitates a comprehensive treatment paradigm that considers individual patient nuances and the efficacy of lurasidone in addressing schizophrenia symptoms, particularly at elevated dosages. Numerous randomized trials have affirmed the efficacy of lurasidone across various dimensions of schizophrenia, demonstrating marked enhancements in positive, negative and cognitive symptoms compared to a placebo. In addition, lurasidone exhibits potential in ameliorating agitation amongst acutely ill patients, showcasing greater efficacy at higher doses. However, despite the favourable outcomes observed with higher lurasidone doses, routine clinical practice often opts for lower doses, potentially limiting its maximal therapeutic impact. Furthermore, lurasidone also shows efficacy in reducing post-psychotic depression in dual psychosis. Moreover, practical insights into lurasidone usage encompass swift dose escalation within a 1–5-day span and recommended combination strategies with other medications such as benzodiazepines for insomnia or agitation, beta-blockers for akathisia, and antihistamines or antimuscarinic drugs for patients transitioning rapidly from antipsychotics with substantial antihistamine and/or anticholinergic effects. Finally, a series of clinical cases is presented, highlighting benefits of lurasidone in terms of cognitive function, functional recovery and other therapeutic aspects for the management of schizophrenia.

Hidenori Maruyama,1 Fumiya Sano,2 Reiko Sakaguchi,3 Keisuke Okamoto,4 Itaru Miura5 1Medical Science, Sumitomo Pharma Co., Ltd, Osaka, Japan; 2Department of Data Science, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 3Department of Clinical Research, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 4Department of Clinical Operation, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 5Department of Neuropsychiatry, Fukushima Medical University, Fukushima, JapanCorrespondence: Hidenori Maruyama, Tel +81-80-4368-2576, Fax +81-6-6203-5733, Email hidenori.maruyama@sumitomo-pharma.co.jpPurpose: To evaluate the effect of lurasidone on a new, patient Life Engagement scale in schizophrenia.Patients and Methods: This post-hoc analysis included participants (ages 18 to 74) diagnosed with schizophrenia who were randomized to lurasidone (40 mg/day) or placebo in a 6-week double-blind efficacy study and those who continued in a subsequent 12-week open-label extension study during which patients received either 40 or 80/mg day lurasidone (flexibly dosed). Change in life engagement was measured using the Positive and Negative Syndrome Scale (PANSS) 11-item Life Engagement subscale score, and individual subscale items, at week 6 during the double-blind phase and extension phase week 12 during the open-label extension phase.Results: Analysis focused on 478 subjects randomized to lurasidone or placebo during the 6-week trial, and 146 who received lurasidone during the extension phase. During the 6-week trial, there was a significantly greater change on the PANSS11 Life Engagement subscale score from baseline to week 6 in the lurasidone group compared to the placebo group (mean changes of − 6.4 and − 4.8, respectively, p = 0.006; effect size = 0.27). Further improvement was evident during the extension phase for patients who received lurasidone in both phases, with a mean change from double-blind baseline to week 12 of the open-label treatment phase of − 10.1 on in PANSS11 Life Engagement subscale.Conclusion: This post-hoc analysis suggests that lurasidone may improve life engagement in patients with schizophrenia, a meaningful outcome from patients’ perspective. Further studies are needed to confirm this effect.Eudract Number: Trial registration: EudraCT Numbers: 2016-000060-42; 2016-000061-23.Keywords: lurasidone, schizophrenia, antipsychotic agents, life engagement, efficacy

Abstract Background and Objectives The aim of this analysis was to evaluate the long-term safety and effectiveness of lurasidone in the treatment of schizophrenia in adolescents and young adults (13–25). Methods The 2 pooled studies used similar designs and outcome measures. Patients (13–25) with schizophrenia completed an initial double-blind 6-week trial of lurasidone (40 and 80 mg/day) in the adolescent trial and (80 and 160 mg/day) in the young adult trial. In open-label long-term trials, adolescent patients were treated with 20–80 mg/day lurasidone, and adults were treated with 40–160 mg/day lurasidone. Efficacy was evaluated based on the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity Scale (CGI-S). Results The safety population consisted of 306 patients (mean age, 16.2 years; 208 patients (68.0%) who completed 12 months of treatment; 8.2% who discontinued treatment by 12 months due to an adverse event). The mean (SD) changes in the PANSS total score from the extension baseline to months 6 and 12 were − 11.8 (13.9) and – 15.3 (15.0), respectively (OC), and the mean (SD) changes in the CGI-S score were − 0.8 (1.0) and − 1.0 (1.1), respectively (OC). The most frequent adverse events were headache (17.6%), anxiety (11.4%), schizophrenia (9.8%), and nausea (9.8%). No clinically meaningful changes were observed in weight, metabolic parameters, or prolactin. Conclusions In adolescents and young adults with schizophrenia, treatment with lurasidone was generally well tolerated and effective. Long-term treatment was associated with a continued reduction in symptoms of schizophrenia. Long-term treatment was associated with minimal effects on weight, metabolic parameters, and prolactin. Clinicaltrials.gov identifiers D1050234, D1050302.

Abstract Background Rash is one of common adverse drug reaction and which have been reported in typical and atypical antipsychotics. Reports of lurasidone induced skin reactions are sparse. In this study, we report a case of rash caused by lurasidone. Case presentation A 63-year-old man with bipolar disorder (BD) who is treated by lurasidone. However, the patient presents a rash all over after lurasidone dose increasing from 40 mg/day to 60 mg/day. With the diagnosis of drug induced rash, lurasidone was discontinued, and the rash complete disappears within 2 weeks. In addition, all case reports about antipsychotics associated rash were reviewed by searching English and Chinese database including Pubmed, Embase, Cochrane Library, CNKI and Wanfang database. A total of 139 articles contained 172 patients were included in our study. The literature review and our case suggest that the cutaneous adverse events caused by antipsychotic drugs should not be ignored, particularly for the patient who was first use or at dose increasing of antipsychotic. Conclusions In conclusion, we report a case of lurasidone related rash and review rash caused by antipsychotics. Psychiatrists should be alert to the possibility of the rash caused by antipsychotics, especially the patient was first use of antipsychotics or the antipsychotic dose was increasing.

Background and Objectives: The aim of this analysis was to evaluate the long-term safety and effectiveness of lurasidone in the treatment of schizophrenia in adolescents and young adults (13–25). Methods: The 2 pooled studies used similar designs and outcome measures. Patients (13–25) with schizophrenia completed an initial double-blind 6-week trial of lurasidone (40 and 80 mg/day) in the adolescent trial and (80 and 160 mg/day) in the young adult trial. In open-label long-term trials, adolescent patients were treated with 20–80 mg/day lurasidone, and adults were treated with 40–160 mg/day lurasidone. Efficacy was evaluated based on the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity Scale (CGI-S). Results: The safety population consisted of 306 patients (mean age, 16.2 years; 208 patients (68.0%) who completed 12 months of treatment; 8.2% who discontinued treatment by 12 months due to an adverse event). The mean (SD) changes in the PANSS total score from the extension baseline to months 6 and 12 were − 11.8 (13.9) and – 15.3 (15.0), respectively (OC), and the mean (SD) changes in the CGI-S score were − 0.8 (1.0) and − 1.0 (1.1), respectively (OC). The most frequent adverse events were headache (17.6%), anxiety (11.4%), schizophrenia (9.8%), and nausea (9.8%). No clinically meaningful changes were observed in weight, metabolic parameters, or prolactin. Conclusions: In adolescents and young adults with schizophrenia, treatment with lurasidone was generally well tolerated and effective. Long-term treatment was associated with a continued reduction in symptoms of schizophrenia. Long-term treatment was associated with minimal effects on weight, metabolic parameters, and prolactin. Clinicaltrials.gov identifiers D1050234, D1050302. [ABSTRACT FROM AUTHOR]

Background: Rash is one of common adverse drug reaction and which have been reported in typical and atypical antipsychotics. Reports of lurasidone induced skin reactions are sparse. In this study, we report a case of rash caused by lurasidone. Case presentation: A 63-year-old man with bipolar disorder (BD) who is treated by lurasidone. However, the patient presents a rash all over after lurasidone dose increasing from 40 mg/day to 60 mg/day. With the diagnosis of drug induced rash, lurasidone was discontinued, and the rash complete disappears within 2 weeks. In addition, all case reports about antipsychotics associated rash were reviewed by searching English and Chinese database including Pubmed, Embase, Cochrane Library, CNKI and Wanfang database. A total of 139 articles contained 172 patients were included in our study. The literature review and our case suggest that the cutaneous adverse events caused by antipsychotic drugs should not be ignored, particularly for the patient who was first use or at dose increasing of antipsychotic. Conclusions: In conclusion, we report a case of lurasidone related rash and review rash caused by antipsychotics. Psychiatrists should be alert to the possibility of the rash caused by antipsychotics, especially the patient was first use of antipsychotics or the antipsychotic dose was increasing. [ABSTRACT FROM AUTHOR]

A recently developed antipsychotic drug, lurasidone, was determined using a simple, sensitive, and eco‐friendly spectrofluorimetric approach. The suggested approach was based on the quantifiable quenching impact of lurasidone on the inherent fluorescence of erythrosine B in an acidic environment employing a Teorell–Stenhagen buffer (pH 4). Following excitation at 530 nm, the quenching of erythrosine B fluorescence was monitored at 552 nm. The system variables were systematically optimized to enhance the formation of the lurasidone‐erythrosine B ion pair for analytical purposes. A linear calibration graph was built in the range of 20–600 ng mL−1 with 0.9998 as a coefficient of correlation. The quantitation and detection limits were 13.5 and 4.5 ng/mL, respectively. The analytical validity of the designed approach was assessed with respect to International Council on Harmonization (ICH) guiding principles. The proposed methodology was employed with high recoveries for assessing lurasidone in bulk powder and its therapeutic tablet dosage form. Additionally, the uniformity of tablet formulations was tested using the developed approach. Finally, the established approach was assessed for its greenness using various tools. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a severe mental disorder characterized by positive, negative, affective, and cognitive symptoms. Affective symptoms in patients with schizophrenia have traditionally been overlooked or even neglected because they are not considered as fundamental as positive and negative symptoms in the choice of medication. Methods: This paper aims to systematically evaluate the efficacy and safety of lurasidone in the treatment of depressive symptoms of schizophrenia. Results: Lurasidone appears to be particularly effective on the depressive symptomatology of schizophrenia while also alleviating the positive and negative symptoms associated with the illness. Conclusions: The efficacy of lurasidone in treating patients with first-episode psychosis who present with predominant depressive symptoms suggests that this medication may be a valuable treatment option not only for established cases of schizophrenia but also for individuals in the early stages of the illness. The good tolerability of lurasidone is an important factor that may positively influence treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment, a core feature of schizophrenia, is associated with poor outcomes. Pharmacotherapy and psychosocial treatment, when used alone, have inadequate effect sizes for cognitive impairment, leading to recent interest in combination interventions. A previous study examined the additive effect of cognitive remediation on lurasidone in patients with schizophrenia, which was negative. Although improvement in cognitive function was suggested for lurasidone, it was inconclusive because there was no antipsychotic control in the study. To clarify whether lurasidone has a meaningful impact on cognitive function in combination with cognitive remediation, we use paliperidone as a control antipsychotic in this study. We hypothesize that combination with lurasidone will improve cognitive and social function to a greater extent than paliperidone. Methods: The valuable interaction with cognitive remediation and optimal antipsychotics for recovery in schizophrenia study is a multicenter, interventional, open-label, rater-blind, randomized comparison study, comparing the effect of lurasidone plus cognitive remediation with that of paliperidone plus cognitive remediation in patients with schizophrenia. The Neuropsychological Educational Approach to Remediation (NEAR) is used for cognitive remediation. Eligible patients will be randomized 1:1 to receive lurasidone or paliperidone combined with NEAR (6 weeks antipsychotic alone followed by 24 weeks combination antipsychotic plus NEAR). The primary endpoint is the change from baseline in the tablet-based Brief Assessment of Cognition in Schizophrenia composite T-score at the end of the NEAR combination treatment period. Secondary endpoints will include change from baseline in social function, schizophrenia symptoms, and quality of life at the end of the NEAR combination treatment period. Furthermore, change from baseline to the end of the pharmacotherapy period and change from the end of the pharmacotherapy period to the end of the NEAR combination treatment period will be assessed for all endpoints. Safety will also be evaluated. Discussion: Achievement of adequate cognitive function is central to supporting social function, which is a key treatment goal for patients with schizophrenia. We think this study will fill in the gaps of the previous study and provide useful information regarding treatment decisions for patients with schizophrenia. [ABSTRACT FROM AUTHOR]

This narrative review explores the efficacy and tolerability of third-generation antipsychotics (TGAs)—aripiprazole, cariprazine, brexpiprazole, and lurasidone—for the management of substance-induced psychosis (SIP). SIP is a psychiatric condition triggered by substance misuse or withdrawal, characterized by unique features distinct from those of primary psychotic disorders. These distinctive features include a heightened prevalence of positive symptoms, such as hallucinations and delusions, in addition to a spectrum of mood and cognitive disturbances. This review comprehensively investigates various substances, such as cannabinoids, cocaine, amphetamines, and LSD, which exhibit a greater propensity for inducing psychosis. TGAs exhibit substantial promise in addressing both psychotic symptoms and issues related to substance misuse. This review elucidates the distinctive pharmacological properties of each TGA, their intricate interactions with neurotransmitters, and their potential utility in the treatment of SIP. We advocate for further research to delineate the long-term effects of TGAs in this context and underscore the necessity for adopting an integrated approach that combines pharmacological and psychological interventions. Our findings underscore the intricate and multifaceted nature of treating SIP, highlighting the potential role of TGAs within therapeutic strategies. [ABSTRACT FROM AUTHOR]

A bioanalytical method was developed and validated for determining lurasidone (LUR) in rat plasma. The analyte and internal standard were extracted from rat plasma using a liquid–liquid extraction method. The mobile phase consisted of methanol, acetonitrile and water, with an ion pairing agent, 0.1% heptafluorobutyric acid, added to minimise the matrix effect. The detection was achieved using a tandem mass spectrometer (API 2000) in positive ion multiple reaction monitoring mode. All parameters were validated, including selectivity, specificity, carry‐over effect, linearity, precision, accuracy, matrix effect, sensitivity and stability. The linearity range was from 5.0 to 1200.0 ng/mL with a correlation coefficient of >0.99. The accuracy ranged from 100.00% to 110.22% across the quality control range. The mean absolute recovery from matrix samples for LUR and the internal standard was found to be 68.46% and 67.25%, respectively, and the relative recovery was found to be 73.89% and 77.44%, respectively. This method can determine LUR concentrations in rat plasma samples up to 12 h after oral administration, aiding in LUR pharmacokinetic (PK) investigations in rats. The method's reproducibility on a conventional LC–MS/MS system and a shorter run time of 3.0 min make it an appealing bioanalytical method for quantifying LUR in PK studies. [ABSTRACT FROM AUTHOR]

Introduction: Adverse event (AE) data in randomized controlled trials (RCTs) allow quantification of a drug's safety risk relative to placebo and comparison across medications. The standard US label for Food and Drug Administration-approved drugs typically lists AEs by MedDRA Preferred Term that occur at ≥ 2% in drug and with greater incidence than in placebo. We suggest that the drug label can be more informative for both patients and physicians if it includes, in addition to AE incidence (percent of subjects who reported the AE out of the total subjects in treatment), the absolute prevalence (percent of subject-days spent with an AE out of the total subject-days spent in treatment) and expected duration (days required for AE incidence to be reduced by half). We also propose a new method to analyze AEs in RCTs using drug-placebo difference in AE prevalence to improve safety signal detection. Methods: AE data from six RCTs in schizophrenia were analyzed (five RCTs of the dopamine D2 receptor-based antipsychotic lurasidone and one RCT of the novel trace amine-associated receptor 1 [TAAR1] agonist ulotaront). We determined incidence, absolute prevalence, and expected duration of AEs for lurasidone and ulotaront vs respective placebo. We also calculated areas under the curve of drug-placebo difference in AE prevalence and mean percent contribution of each AE to this difference. Results: A number of AEs with the same incidence had different absolute prevalence and expected duration. When accounting for these two parameters, AEs that did not appear in the 2% incidence tables of the drug label turned out to contribute substantially to drug tolerability. The percent contribution of a drug-related AE to the overall side effect burden increased the drug-placebo difference in AE prevalence, whereas the percent contribution of a placebo-related AE decreased such difference, revealing a continuum of risk between drug and placebo. AE prevalence curves for drug were generally greater than those for placebo. Ulotaront exhibited a small drug-placebo difference in AE prevalence curves due to a relatively low incidence and short duration of AEs in the ulotaront treatment arm as well as the emergence of disease-related AEs in the placebo arm. Conclusion: Reporting AE absolute prevalence and expected duration for each RCT and incorporating them in the drug label is possible, is clinically relevant, and allows standardized comparison of medications. Our new metric, the drug-placebo difference in AE prevalence, facilitates signal detection in RCTs. We piloted this metric in RCTs of several neuropsychiatric indications and drugs, offering a new way to compare AE burden and tolerability among treatments using existing clinical trial information. [ABSTRACT FROM AUTHOR]

Lurasidone is a novel atypical antipsychotic drug acting on dopaminergic, serotonergic and noradrenergic receptors; it is applied for the long-term treatment of schizophrenia and depression in patients with bipolar disorders. We aimed at performing a comparative study on the influence of chronic treatment with lurasidone on the expression of cytochrome P450 enzymes in the liver and in peripheral blood lymphocytes, and to evaluate the relationship between changes in the expression of CYP enzymes in the two experimental models. The obtained results show a fairly similar expression pattern of the main CYP enzymes in the rat livers and lymphocytes, and they indicate that in the liver, lurasidone exerts an inhibitory effect on the activity, protein and mRNA levels of CYP2B1/2 (not CYP2B2 mRNA), CYP2C11 and CYP2E1, while in the case of CYP3A1 and CYP3A2, it causes enzyme induction. At the same time, lurasidone decreases the expression of CYP2B, CYP2C11 (CYP2C11 protein only) and CYP2E1 but increases that of CYP3A2 (not CYP3A1) in lymphocyte cells. In conclusion, chronic treatment with lurasidone simultaneously and in the same way influences the expression and activity of CYP2B, CYP2C11, CYP2E1 and CYP3A2 in the liver and peripheral blood lymphocytes of rats. Thus, the lymphocyte cytochrome P450 profile may be utilized as an indicator of the hepatic cytochrome P450 profile in further clinical studies with lurasidone, and lymphocytes may serve as easily available surrogates for examining the impact of new drugs and chronic in vivo treatments on CYP enzyme expression, as well as to estimate drug–drug interactions and toxicity risk. [ABSTRACT FROM AUTHOR]

Itaru Miura,1 Sho Horikoshi,1,2 Mizue Ichinose,1,3 Yuhei Suzuki,1 Kenya Watanabe4 1Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Neuropsychiatry, Horikoshi Psychosomatic Clinic, Fukushima, Japan; 3Department of Neuropsychiatry, Hoshigaoka Hospital, Koriyama, Japan; 4Department of Pharmacy, Fukushima Medical University Hospital, Fukushima, JapanCorrespondence: Itaru Miura, Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima, 960-1295, Tel +81-24-547-1331, Fax +81-24-548-6735, Email itaru@fmu.ac.jpAbstract: This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D2, 5-hydroxytryptamine (5-HT)2A, and 5-HT7 receptors and a partial agonistic effect on the 5-HT1A receptor with low affinities for muscarinic M1, histamine H1, and a1 adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT7 and 5-HT1A receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.Keywords: schizophrenia, lurasidone, serotonin-dopamine antagonist, antipsychotics

Drug trials for negative symptoms in schizophrenia select patients based on the severity and stability of negative symptoms, using criteria that are not suitable for trials of acute exacerbation of schizophrenia. Here we present a method to prognostically enrich subjects having a predefined factor structure in PANSS and apply it to the measurement of negative symptoms specifically in trials of acute schizophrenia. A vector of 1335 elements based on between- and within-item variances, covariances, and differences of PANSS items was created to calculate an index of heterogeneity and to enrich for a predetermined symptom construct in PANSS. Using prerandomization PANSS scores across N = 4876 subjects in 13 trials of acute schizophrenia, we demonstrate an ability to select for a subpopulation having the greatest amount of variance explained across the 7-items of the Marder PANSS negative symptom (MPNS) construct. Network analyses on subjects enriched for MPNS construct confirm that negative symptoms were most influential in overall psychopathology, distinct from subjects without the MPNS construct. As expected for D2 antagonists, drug-placebo differences on negative symptoms with lurasidone were not specific to the subpopulation having the MPNS construct. In contrast, the novel TAAR1 agonist ulotaront demonstrated specific improvements in negative symptoms which were greatest in the MPNS subpopulation. These results demonstrate the utility of a novel prognostic enrichment strategy that can address heterogeneity in clinical trials, where patients can be selected on the basis of a greater likelihood of having the measured symptom construct (negative symptoms) related to the disorder (schizophrenia). ClinicalTrials.gov Identifiers: NCT0296938, NCT00088634, NCT00549718, NCT00615433, NCT00790192.

Biological view of the development of mental disorders was described back in the days of Hippocrates in his humoral theory considering the brain as a place of origin of all emotions and therefore rejecting the earlier theories suggesting that psychic phenomena resulted from divine intervention. Later his ideas transformed to produce, inter alia, the Kraepelin’s allegation. Kraepelin described mental disorder as a “natural biological process” and suggested to divide mental disorders into two large groups, dementia praecox and la folie circulaire, based on this allegation. Differentiation was based on intellectual impairment that was more severe in patients with schizophrenia than in patients with bipolar disorder. Current research has revealed considerable clinical and genetic similarity of two disorders. However, in contrast to schizophrenia, the data of patients with bipolar disorder indicate no intellectual impairment. Furthermore, the risk of bipolar disorder is associated with higher premorbid IQ. Can we suppose that the genes that determine such cognitive differences are just genes and their mutations that determine lower IQ in the general population, but not the disease-associated genes? High efficacy of antipsychotics against both disorders is the other common phenomenon revealed in modern times. Modern antipsychotics that will be discussed in this paper show higher efficacy and safety.

The aim of this study was to investigate the impacts of 24 variants of recombinant human CYP3A4 and drug interactions on the metabolism of lurasidone. In vitro, enzymatic reaction incubation system of CYP3A4 was established to determine the kinetic parameters of lurasidone catalyzed by 24 CYP3A4 variants. Then, we constructed rat liver microsomes (RLM) and human liver microsomes (HLM) incubation system to screen potential anti–tumor drugs that could interact with lurasidone and studied its inhibitory mechanism. In vivo, Sprague–Dawley (SD) rats were applied to study the interaction between lurasidone and olmutinib. The concentrations of the analytes were detected by ultra–performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). As the results, we found that compared with the wild-type CYP3A4, the relative intrinsic clearances vary from 355.77 % in CYP3A4.15 to 14.11 % in CYP3A4.12. A series of drugs were screened based on the incubation system, and compared to without olmutinib, the amount of ID–14283 (the metabolite of lurasidone) in RLM and HLM were reduced to 7.22 % and 7.59 %, and its IC50 were 18.83 ± 1.06 μM and 16.15 ± 0.81 μM, respectively. At the same time, it exerted inhibitory effects both through a mixed mechanism. When co-administration of lurasidone with olmutinib in rats, the AUC(0−t) and AUC(0-∞) of lurasidone were significantly increased by 73.52 % and 69.68 %, respectively, while CLz/F was observably decreased by 43.83 %. In conclusion, CYP3A4 genetic polymorphism and olmutinib can remarkably affect the metabolism of lurasidone.

The efficacy and safety of lurasidone monotherapy in patients with bipolar I depression with or without rapid cycling has not been previously investigated. We performed subgroup analysis (rapid cycling/non-rapid cycling) of pooled data from two 6-week, randomized, double-blind, placebo-controlled trials of lurasidone monotherapy (20–60 mg/day or 80–120 mg/day). Analyses included mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Safety assessments included the number of treatment-emergent adverse events (TEAEs) and laboratory assessments. Of 1024 patients randomized, 85 were rapid cycling. Mean change in MADRS total score in patients with non-rapid cycling and rapid cycling, respectively, was −14.8 (effect size = 0.47) and − 12.8 (effect size = 0.04) in the lurasidone 20–60 mg/day group, −14.3 (effect size = 0.41) and − 13.0 (effect size = 0.02) in the lurasidone 80–120 mg/day group and −10.6 and −13.3 in the placebo group. The most common TEAE in each subgroup was akathisia in both lurasidone groups. Treatment-emergent mania was reported only in a small number of rapid cycling and non-rapid cycling patients. This was a post-hoc analysis of a short-term study that excluded patients with ≥8 cycles in the past year. In patients with non-rapid cycling bipolar depression, lurasidone monotherapy significantly improved depressive symptoms relative to placebo at both the 20–60 mg/day and 80–120 mg/day doses. In patients with rapid cycling, both doses of lurasidone displayed depressive symptom score reduction from baseline, but significant improvement was not observed likely due to high levels of improvement on placebo and small sample size. • Monotherapy with lurasidone was highly efficacious for non-rapid cycling patients with bipolar depression. • In rapid cycling, lurasidone reduced depressive symptoms but not significantly due to high levels of improvement on placebo. • On both lurasidone and placebo, akathisia occurred more frequently in rapid-cycling than in non-rapid-cycling patients. • Treatment-emergent mania was reported only in a small number of rapid cycling and non-rapid cycling patients. [ABSTRACT FROM AUTHOR]

Agents that act at the N-methyl-D-aspartate receptor (NMDAR), such as ketamine, have gained increasing attention as rapid-acting antidepressants; however, their use has been limited by potential neurotoxicity. Recent FDA guidance requires a demonstration of safety on histologic parameters prior to the initiation of human studies. D-cycloserine (DCS) is a partial NMDA agonist that, along with lurasidone, is being investigated as a treatment for depression. The current study was designed to investigate the neurologic safety profile of DCS. To this end, female Sprague Dawley rats (n = 106) were randomly divided into 8 study groups. Ketamine was administered via tail vein infusion. DCS and lurasidone were administered via oral gavage in escalating doses to a maximum of 2000 mg/kg DCS. To ascertain toxicity, dose escalation with 3 different doses of D-cycloserine/lurasidone was given in combination with ketamine. MK-801, a known neurotoxic NMDA antagonist, was administered as a positive control. Brain tissue was sectioned and stained with H&E, silver, and Fluoro-Jade B stains. No fatalities were observed in any group. No microscopic abnormalities were found in the brain of animal subjects given ketamine, ketamine followed by DCS/lurasidone, or DCS/lurasidone alone. Neuronal necrosis, as expected, was seen in the MK-801 (positive control) group. We conclude that NRX-101, a fixed-dose combination of DCS/lurasidone, when administered with or without prior infusion of IV ketamine was tolerated and did not induce neurotoxicity, even at supratherapeutic doses of DCS. [ABSTRACT FROM AUTHOR]

Abstract Introduction Kato et al. reported results of a 6‐week, double‐blind, randomized, placebo‐controlled trial of lurasidone in adults with bipolar depression (BDep). Aim We performed a post hoc analysis using data from the lurasidone trial to predict later responses from early improvements. Methods An early improvement was defined as a ≥20% reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) total score at Week 2; response was defined as a ≥50% reduction in MADRS total score at Week 6; symptomatic remission were defined as a score of ≤8 on MADRS total score at Week 6. Results Both sensitivity and negative predictive value (NPV) were higher for the remission outcome than for the response outcome. The interpretation of sensitivity and NPV in the lurasidone group when remission is an outcome is as follows. It means (1) that, from all remitters at Week 6, 80.6% was identified as such at Week 2 on the basis of their early improvement and (2) that a patient showing non‐improvement at 2 weeks had 93.5% probability of being a non‐remitters at Week 6. However, the values of specificity for both response and remission in the lurasidone group were not high. Conclusion Patients who did not show an early response at Week 2 cannot be predicted with a high probability to also show poor improvement at Week 6. In fact, some patients who did not show early response at 2 weeks might have marked improvement at 6 weeks.

Purpose: Lurasidon is a relatively new, second-generation antipsychotic drug with an interesting receptor profile. It is considered to be safe and has a low risk of side effects. It is a substance with a multi-receptor mechanism of action: it mainly blocks dopaminergic D2 and serotonergic 5-HT2A receptors. According to the Summary of Product Characteristics, the adverse reaction of neutropenia was too rare to enable the estimation of its frequency. Case description: A case of 39-year-old patient is presented in the article, diagnosed with paranoid schizophrenia, who developed neutropenia as a result of treatment with lurasidone. After the discontinuation of lurasidone and recommended supplementation, the blood test results gradually improved and finally reached the normal range. Comment: This case report shows the need for regular monitoring of blood cell parameters in patients treated with second-generation antipsychotics, as there is a risk of neutrocytopenia or even agranulocitosis. [ABSTRACT FROM AUTHOR]

Schizophrenia usually begins with prodromal symptoms in adolescence. In 39% of patients, onset of psychotic symptoms occurs prior to age 19. Advances in the treatment of psychosis with medications over the last decade are reviewed in this paper. Understanding how to prescribe antipsychotics early in schizophrenia requires an understanding of the pathophysiology of the disease. The current structure of the dopamine hypothesis is reviewed. Risperidone, paliperidone, olanzapine, quetiapine, and aripiprazole have become established treatments prior to 2012. Since 2012, lurasidone (2017) and brexpiprazole (2022) have also been approved. Lurasidone was approved based on placebo-controlled studies, but brexpiprazole has been approved on the bases of open safety trials. In comparative trials, aripiprazole was better tolerated and less likely to cause hyperprolactinemia and metabolic abnormalities. Antipsychotics can induce adaptive changes in the brain that predispose patients to future problems such as tardive dyskinesia and supersensitivity psychosis. When pathophysiology of schizophrenia, and a clear understanding of the pharmacology of existing antipsychotics are included in the evidence-based analysis, use of partial agonists, which are less likely to induce adaptive changes in the brain and less likely to induce metabolic and prolactin side effects, become the preferred agents. [ABSTRACT FROM AUTHOR]

Schizophrenia is a common debilitating disorder characterized by significant impairments in how reality is perceived, combined with behavioural changes. In this review, we describe the lurasidone development programme for adult and paediatric patients. Both the pharmacokinetic and pharmacodynamic characteristics of lurasidone are revisited. In addition, pivotal clinical studies conducted on both adults and children are summarized. Several clinical cases, which demonstrate the role of lurasidone in real-world practice, are also presented. Current clinical guidelines recommend lurasidone as the first-line treatment in the acute and long-term management of schizophrenia in both adult and paediatric populations.

Delusional infestation has been described since 1894. The variety of treatments of delusional infestation has been administered in different atypical antipsychotic agents. Here, we present a case of first treatment with lurasidone on the delusional infestation in a 68-year-old female with vascular dementia, and the literature reviews of the related delusion infestation management.

Abstract Background and rationale Treatment persistence combines clinician and patient judgment of efficacy, tolerability and safety into a comprehensive measure of effectiveness and is defined as the act of continuing a treatment over time. Studies have reported poor treatment persistence to antipsychotic medications in patients with schizophrenia. This study evaluated treatment persistence to lurasidone (LUR) in patients with schizophrenia in a real-world Italian setting. Methods This was a retrospective observational study of patients with schizophrenia who started treatment with LUR ≥ 6 months before inclusion. Following informed consent, data were collected starting from the index date (start of LUR treatment) at all visits occurring as per clinical practice. The primary endpoint was treatment persistence during the first 6 months, defined as the time between index date and all-cause discontinuation. Patients treated with LUR > 180 days were considered persistent. As secondary endpoint, treatment persistence was evaluated for a period of ≥ 18 months. Results Forty-five patients were enrolled and 41 (91.11%) completed the study. Forty-one patients (91.11%) were included in the eligible population as they initiated LUR treatment ≥ 6 months before data collection. Patients were 43.0 ± 15.89 years old and 61% were female. Twenty-two patients (53.66%) started LUR treatment in a hospital setting and 19 (46.34%) in an outpatient setting. Based on Clinical Global Impression—Severity scale (CGI-S) at LUR initiation, 12 patients (29.27%) were severely ill, 17.07% markedly ill, 19.51% moderately ill, 2.44% mildly ill and 4.88% borderline mentally ill. Thirty-two patients (78.05%) were treatment persistent for ≥ 180 days. Among the 19 patients observed for ≥ 18 months, 11 (57.89%) were persistent for ≥ 18 months. Among the 22 study patients observed for

Itaru Miura,1 Kei Watabe,2 Reiko Sakaguchi,3 Keisuke Okamoto,4 Hidenori Maruyama5 1Department of Neuropsychiatry, Fukushima Medical University, Fukushima, Japan; 2Department of Data Science, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 3Department of Clinical Research, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 4Department of Clinical Operation, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 5Medical Affairs, Sumitomo Pharma Co., Ltd, Tokyo, JapanCorrespondence: Itaru Miura, Department of Neuropsychiatry, Fukushima Medical University 1 Hikarigaoka, Fukushima, 960-1295, Japan, Tel +81-24-547-1331, Fax +81-24-548-6735, Email itaru@fmu.ac.jpPurpose: To evaluate the effectiveness and safety of lurasidone 80 mg/day (versus the 40 mg/day dose) during a 12-week, open-label extension study in patients with an acute exacerbation of schizophrenia who had completed a 6-week double-blind study of lurasidone.Patients and Methods: A total of 289 adult patients with schizophrenia completed the double-blind study and enrolled in the 12-week extension study. Lurasidone was flexibly dosed at 40 or 80 mg/day. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) subscale scores, Clinical Global Impression-Severity Scale (CGI-S), and Calgary Depression Scale for Schizophrenia (CDSS), analyzed based on last observation carried forward (LOCF-endpoint). Safety/tolerability assessments included adverse events, body weight, laboratory tests, and discontinuation due to adverse events.Results: Mean endpoint change was greater for lurasidone in modal doses of 80 mg/d (N=136) vs 40 mg/d (N=153) on the PANSS positive subscale (− 3.0 vs − 2.3), PANSS negative subscale (− 1.9 vs − 1.7), PANSS General Psychopathology subscale (− 5.1 vs − 3.8), the CGI-S score (− 0.5 vs − 0.4), and the CDSS score (− 0.7 vs − 0.1). Discontinuation rates due to adverse events on lurasidone modal 80 mg/d vs 40 mg/d were 4.4% vs 7.2%; and the most common adverse events in the modal 80 mg/d group were nasopharyngitis, 7.4% (vs 4.6% on modal 40 mg/d), constipation, 5.9% (vs 2.0%), and headache, 5.9% (vs 2.0%).Conclusion: In patients with acute schizophrenia treated with lurasidone 40 mg/d, increasing the dose to 80 mg/d was well tolerated, and was associated with greater improvement in PANSS subscale scores compared to continued treatment with a dose of 40 mg/d.Keywords: lurasidone, schizophrenia, extension treatment, dose escalation, effectiveness, safety

AIM: We endeavored to evaluate the efficacy of Lurasidone at doses of 40160 mg per day on symptoms of schizophrenia associated with symptoms of depression in real clinical practice in a Russian patient population. METHODS: One hundred sixty eight patients aged 1865 years old, who at the time of the start of the observation were being treated in a hospital or day hospital due to an exacerbation of paranoid schizophrenia accompanied by symptoms of depression, were prescribed lurasidone. Treatment with lurasidone and other concomitant drugs, their prescription, withdrawal, selection, and dose modifications were determined based on the indications for the use of those drugs and the recommended doses in the instructions, clinical need, and patient interests, rather than by the goals of the study. During the observation period, the severity of depressive symptoms according to the Calgary Depression Scale (CDSS) and that of psychotic symptoms according to the Positive and Negative Syndrome Scale (PANSS) were assessed six times (before the start of treatment and then on the 4th, 7th, 14th, 28th, and 42nd days). RESULTS: A statistically significant reduction in the severity of the symptoms was observed with the use of lurasidone in doses ranging from 40 mg to 160 mg per day. The fastest and most significant (p 0.001) reductions in the total PANSS and CDSS scores were observed with lurasidone 120 mg. A somewhat lower efficacy of lurasidone was observed at a dose of 160 mg. The largest reductions in the total PANSS and CDSS scores with lurasidone 120 mg were associated with the highest survival rate and the longest median time from treatment initiation to discontinuation or follow-up. The most commonly reported side effects with lurasidone in this study (nausea, akathisia, tremor and drowsiness) were consistent with the known safety profile of the drug. Adverse events in most cases were assessed as mild, or occasionally moderate. CONCLUSION: A six-week prospective observational study of the real-world clinical effectiveness of lurasidone in doses ranging from 40 mg to 160 mg per day established statistically and clinically significant improvements in both psychotic and depressive symptoms in patients with acute exacerbation of schizophrenia and associated symptoms of depression.

To date, tachycardia and orthostatic hypotension have been reported as one of the negative cardiovascular complications of antipsychotics. The aim of this study was to report a case of sinus bradycardia caused by the addition of lurasidone. The patient, a 46-year-old bipolar disorder female, was admitted to the Affiliated Brain Hospital of Guangzhou Medical University with 28 years of alternating euphoric and dysphoria. On the basis of lithium carbonate 1,200 mg/day and sodium valproate 1,500 mg/day, the patient was given lurasidone 80 mg/day. After 5 days of medication, her heart rate (HR) became 48 beats per minute (beats/min). As a result, lurasidone treatment was held. On 5th day after discontinuing lurasidone, the HR reached 80 beats/min. This case report notifies that although the cardiovascular effects of lurasidone are not significant, it is also important to monitor HR status after the first administration of lurasidone. [ABSTRACT FROM AUTHOR]

Recent research reported that lurasidone degrades in unpreserved ante‐mortem human whole blood inoculated with microorganisms known to dominate postmortem blood specimens. In vitro degradation occurred at a similar rate to risperidone, known to degrade in authentic postmortem specimens until below analytical detection limits. To identify the lurasidone degradation products formed, an Agilent 6520 liquid chromatograph quadrupole‐time‐of‐flight mass spectrometer (LC‐QTOF‐MS) operating in auto‐MS/MS mode was used. Numerous degradation products not previously reported in prior in vitro or in vivo pharmacokinetic studies or forced degradation studies were detected. Accurate mass data, mass fragmentation data, acetylation experiments, and a proposed mechanism of degradation analogous to risperidone supports initial identification of the major degradation product as N‐debenzisothiazole‐lurasidone (calculated m/z [M + H]+ = 360.2646). A standard was unavailable to conclusively confirm this identification. Retrospective data analysis of postmortem cases involving lurasidone identified the presence of the major degradation product in four of six cases where lurasidone was also detected. This finding is significant for toxicology laboratories screening for this drug in postmortem casework. The major postmortem lurasidone degradation product has consequently been added to the LC‐QTOF‐MS drug screen at Forensic Science SA (FSSA) to indicate postmortem lurasidone degradation in authentic postmortem blood specimens and as a marker of lurasidone administration in the event lurasidone is degraded to concentrations below detection limits. [ABSTRACT FROM AUTHOR]

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Lurasidone and quetiapine are effective atypical mood-stabilizing antipsychotics, but lurasidone and quetiapine are listed as lower-risk and high-risk for weight gain/metabolic complications, respectively. The pathophysiology of the discrepancy of metabolic adverse reactions between these antipsychotics remains to be clarified. The GABA isomer, β-aminoisobutyric acid (BAIBA) enantiomer, was recently re-discovered as myokine via an AMP-activated protein kinase activator (AMPK) enhancer and inhibitory gliotransmitter. Notably, activation of AMPK in peripheral organs improves, but in the hypothalamus, it aggravates metabolic disturbances. Therefore, we determined effects of chronic administration of lurasidone and quetiapine on intracellular and extracellular levels of the BAIBA enantiomer. L-BAIBA is a major BAIBA enantiomer in the hypothalamus and astrocytes, whereas L-BAIBA only accounted for about 5% of total plasma BAIBA enantiomers. Chronic lurasidone administration did not affect body weight but decreased the L-BAIBA level in hypothalamus and cultured astrocytes, whereas chronic quetiapine administration increased body weight and the L-BAIBA level in hypothalamus and astrocytes. Contrary, neither lurasidone nor quetiapine affected total plasma levels of the BAIBA enantiomer since D-BAIBA levels were not affected by these antipsychotics. These results suggest that activation of intracellular L-BAIBA signaling is, at least partially, involved in the pathophysiology of metabolic adverse reaction of quetiapine. Furthermore, this study also demonstrated that lurasidone and quetiapine suppressed and enhanced astroglial L-BAIBA release induced by ripple-burst stimulation (which physiologically contributes to cognitive memory integration during sleep), respectively. Therefore, L-BAIBA probably contributes to the pathophysiology of not only metabolic adverse reactions, but also a part of clinical action of lurasidone or quetiapine. [ABSTRACT FROM AUTHOR]

Latuda® is an oral tablet approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia. However, the clinical efficacy of Latuda® is compromised by patient noncompliance due to frequent daily administration, especially for patients experiencing severe schizophrenia, whose medication is often needed for several months to years. Hence, developing a long-acting injectable formulation of lurasidone is urgently needed. Herein, a poorly water-soluble lurasidone pamoate (LP) salt was synthesized via the facile ion pair-based salt formation technology. The solubility of LP was decreased by 233 folds compared with that of lurasidone hydrochloride (LH). Furthermore, suspensions of LH and LP with three different particle sizes, including 400 nm small-sized nanocrystals (SNCs), 4 μm medium-sized microcrystals (MMCs), and 15 μm large-sized microcrystals (LMCs) were prepared and characterized by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The in vitro release results showed that particle sizes had great effects on the sustained release of LH, where large-sized particles exhibited superior sustained release than the smaller ones. Besides, LP suspensions exhibited better sustained release than LH suspensions at the same size scale. Moreover, the pharmacokinetics showed that LP LMCs produced an extended in vivo intramuscularly injectable profile for up to 45 days, which was 10 days longer than that of the LH LMCs. Our findings demonstrated that particle size had appreciable impacts on drug sustained release and provided valuable knowledge for the rational design of optimized micronized suspensions for long-acting injectables. [ABSTRACT FROM AUTHOR]

Introduction: Kato et al. reported results of a 6‐week, double‐blind, randomized, placebo‐controlled trial of lurasidone in adults with bipolar depression (BDep). Aim: We performed a post hoc analysis using data from the lurasidone trial to predict later responses from early improvements. Methods: An early improvement was defined as a ≥20% reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) total score at Week 2; response was defined as a ≥50% reduction in MADRS total score at Week 6; symptomatic remission were defined as a score of ≤8 on MADRS total score at Week 6. Results: Both sensitivity and negative predictive value (NPV) were higher for the remission outcome than for the response outcome. The interpretation of sensitivity and NPV in the lurasidone group when remission is an outcome is as follows. It means (1) that, from all remitters at Week 6, 80.6% was identified as such at Week 2 on the basis of their early improvement and (2) that a patient showing non‐improvement at 2 weeks had 93.5% probability of being a non‐remitters at Week 6. However, the values of specificity for both response and remission in the lurasidone group were not high. Conclusion: Patients who did not show an early response at Week 2 cannot be predicted with a high probability to also show poor improvement at Week 6. In fact, some patients who did not show early response at 2 weeks might have marked improvement at 6 weeks. [ABSTRACT FROM AUTHOR]

Somnolence is a common adverse effect of antipsychotic drugs used to treat psychotic disorders. It causes problems in many areas of life, such as gainful employment, driving, childcare, and social interactions. Somnolence is a major problem for a relatively new antipsychotic drug, lurasidone, whose dose-effect relationship remains unclear. Based on data from a bioequivalence study of two 40 mg lurasidone hydrochloride tablets, we designed two case-control studies to explore the correlation between somnolence and exposure to lurasidone and determine the factors associated with lurasidone-induced somnolence. In the first case-control study, lurasidone was administered to healthy volunteers; 30 experienced somnolence (as pre-defined) but 29 did not. Moreover, plasma concentration at 1 h was significantly associated with somnolence (OR = 1.124; p = 0.001). In the second case-control study, 48 volunteers administered lurasidone were classified into somnolence and no-somnolence groups based on different time-related criteria. We observed a positive association between plasma concentration at 0.75 h and somnolence (OR = 1.024; p = 0.002). Receiver operating characteristic analysis revealed that a plasma lurasidone concentration >21.65 ng/mL 1 h after administration strongly predicted somnolence. Our findings in healthy volunteers need to be further validated in patients in clinical settings to determine the optimal dose and duration of lurasidone administration.

Background: Schizophrenia is a severe mental disorder characterized by positive, negative, affective, and cognitive symptoms. Affective symptoms in patients with schizophrenia have traditionally been overlooked or even neglected because they are not considered as fundamental as positive and negative symptoms in the choice of medication. Methods: This paper aims to systematically evaluate the efficacy and safety of lurasidone in the treatment of depressive symptoms of schizophrenia. Results: Lurasidone appears to be particularly effective on the depressive symptomatology of schizophrenia while also alleviating the positive and negative symptoms associated with the illness. Conclusions: The efficacy of lurasidone in treating patients with first-episode psychosis who present with predominant depressive symptoms suggests that this medication may be a valuable treatment option not only for established cases of schizophrenia but also for individuals in the early stages of the illness. The good tolerability of lurasidone is an important factor that may positively influence treatment decisions.

Abstract Background Schizophrenia is a serious mental health condition characterised by distortions in thought processes, perception, mood, sense of self, and behaviour. Lurasidone, a second-generation atypical antipsychotic, represents an additional treatment option alongside existing antipsychotics for adolescents and adults with schizophrenia. An economic model was developed to evaluate the incremental costs of lurasidone as a first-line treatment option compared to existing antipsychotics. Methods A Markov model was developed to estimate the cost impact of lurasidone as a first-line treatment option for both adolescents and adults. The sequence-based model incorporated the following health states: stable (no relapse or discontinuation), discontinuation (due to adverse events or other reasons), and relapse. Data used to determine the movement of patients between health states were obtained from network meta-analyses (NMAs). The time horizon ranged from three to five years (depending on the patient population) and a six-weekly cycle length was used. Unit costs and resource use were reflective of the UK NHS and Personal Social Services and consisted of the following categories: outpatient, adverse events, primary and residential care. Extensive deterministic sensitivity analysis was undertaken to assess the level of uncertainty associated with the base case results. Results Lurasidone is demonstrated to be cost-saving as a first-line treatment within the adolescent and adult populations when compared to second-line and third-line respectively. Lurasidone is more expensive in terms of treatment costs, resource use (in the stable health state) and the treatment of adverse events. However, these costs are outweighed by the savings associated with the relapse health state. Lurasidone remains cost-saving when inputs are varied in sensitivity analysis and scenario analysis. Conclusions Lurasidone is a cost-saving first-line treatment for schizophrenia for both adolescents and adults.

Although a number of mood-stabilising atypical antipsychotics and antidepressants modulate serotonin type 7 receptor (5-HT7), the detailed contributions of 5-HT7 function to clinical efficacy and pathophysiology have not been fully understood. The mood-stabilising antipsychotic agent, lurasidone, and the serotonin partial agonist reuptake inhibitor, vortioxetine, exhibit higher binding affinity to 5-HT7 than other conventional antipsychotics and antidepressants. To date, the initially expected rapid onset of antidepressant effects—in comparison with conventional antidepressants or mood-stabilising antipsychotics—due to 5-HT7 inhibition has not been observed with lurasidone and vortioxetine; however, several clinical studies suggest that 5-HT7 inhibition likely contributes to quality of life of patients with schizophrenia and mood disorders via the improvement of cognition. Furthermore, recent preclinical studies reported that 5-HT7 inhibition might mitigate antipsychotic-induced weight gain and metabolic complication by blocking other monoamine receptors. Further preclinical studies for the development of 5-HT7 modulation against neurodevelopmental disorders and neurodegenerative diseases have been ongoing. To date, various findings from various preclinical studies indicate the possibility that 5-HT7 modifications can provide two independent strategies. The first is that 5-HT7 inhibition ameliorates the dysfunction of inter-neuronal transmission in mature networks. The other is that activation of 5-HT7 can improve transmission dysfunction due to microstructure abnormality in the neurotransmission network—which could be unaffected by conventional therapeutic agents—via modulating intracellular signalling during the neurodevelopmental stage or via loss of neural networks with aging. This review attempts to describe the current and novel clinical applications of 5-HT7 modulation based on preclinical findings. [ABSTRACT FROM AUTHOR]

The biopharmaceutical classification system groups low-solubility drugs into two groups: II and IV, with high and low permeability, respectively. Most of the new drugs developed for common pathologies present solubility issues. This is the case of lurasidone hydrochloride—a drug used for the treatment of schizophrenia and bipolar depression. Likewise, the stability problems of some drugs limit the possibility of preparing them in liquid pharmaceutical forms where hydrolysis and oxidation reactions can be favored. Lurasidone hydrochloride presents the isoindole-1,3-dione ring, which is highly susceptible to alkaline hydrolysis, and the benzisothiazole ring, which is susceptible to a lesser extent to oxidation. Herein, we propose to study the increase in the solubility and stability of lurasidone hydrochloride by the formation of higher-order inclusion complexes with hydroxypropyl-β-cyclodextrin. Several stoichiometric relationships were studied at between 0.5 and 3 hydroxypropyl-β-cyclodextrin molecules per drug molecule. The obtained products were characterized, and their solubility and stability were assessed. According to the obtained results, the formation of inclusion complexes dramatically increased the solubility of the drug, and this increased with the increase in the inclusion ratio. This was associated with the loss of crystalline state of the drug, which was in an amorphous state according to infrared spectroscopy, calorimetry, and X-ray analysis. This was also correlated with the stabilization of lurasidone by the cyclodextrin inhibiting its recrystallization. Phase solubility,1H-NMR, and docking computational characterization suggested that the main stoichiometric ratio was 1:1; however, we cannot rule out a 1:2 ratio, where a second cyclodextrin molecule could bind through the isoindole-1,3-dione ring, improving its stability as well. Finally, we can conclude that the formation of higher-order inclusion complexes of lurasidone with hydroxypropyl-β-cyclodextrin is a successful strategy to increase the solubility and stability of the drug. [ABSTRACT FROM AUTHOR]

Rationale : While meta-analyses of clinical trials found that lurasidone and partial dopamine agonists (brexpiprazole and aripiprazole) were the antipsychotics less likely to cause QTc prolongation, and sertindole, amisulpride, and ziprasidone were the most frequently associated with this adverse drug reaction; no real-world studies have investigated this risk between the different antipsychotics. Objectives and methods: Using data recorded from 1967 to 2019 in VigiBase®, the World Health Organization's Global Individual Case Safety Reports database, we performed disproportionality analysis to investigate the risk of reporting QT prolongation between 20 antipsychotics. Results: Sertindole had the highest risk of reporting QT prolongation, followed by ziprasidone and amisulpride. Lurasidone was associated with the lowest risk. First-generation antipsychotics were associated with a greater QT prolongation reporting risk (ROR, 1.21; 95%CI, 1.10–1.33) than second-generation antipsychotics. A positive correlation was found between the risk of reporting QT prolongation and affinity for hERG channel (R2 = 0.14, slope = Pearson coefficient = 0.41, p value = 0.1945). Conclusions: This large study in a real-world setting suggests that sertindole and ziprasidone were the antipsychotics drugs associated with the highest risk of QT prolongation reporting. Our results suggest that lurasidone is less associated with QT interval prolongation reports. Our study also suggests that antipsychotics with the higher hERG affinity are more associated with to QT prolongations reports. [ABSTRACT FROM AUTHOR]

Background and rationale: Treatment persistence combines clinician and patient judgment of efficacy, tolerability and safety into a comprehensive measure of effectiveness and is defined as the act of continuing a treatment over time. Studies have reported poor treatment persistence to antipsychotic medications in patients with schizophrenia. This study evaluated treatment persistence to lurasidone (LUR) in patients with schizophrenia in a real-world Italian setting. Methods: This was a retrospective observational study of patients with schizophrenia who started treatment with LUR ≥ 6 months before inclusion. Following informed consent, data were collected starting from the index date (start of LUR treatment) at all visits occurring as per clinical practice. The primary endpoint was treatment persistence during the first 6 months, defined as the time between index date and all-cause discontinuation. Patients treated with LUR > 180 days were considered persistent. As secondary endpoint, treatment persistence was evaluated for a period of ≥ 18 months. Results: Forty-five patients were enrolled and 41 (91.11%) completed the study. Forty-one patients (91.11%) were included in the eligible population as they initiated LUR treatment ≥ 6 months before data collection. Patients were 43.0 ± 15.89 years old and 61% were female. Twenty-two patients (53.66%) started LUR treatment in a hospital setting and 19 (46.34%) in an outpatient setting. Based on Clinical Global Impression—Severity scale (CGI-S) at LUR initiation, 12 patients (29.27%) were severely ill, 17.07% markedly ill, 19.51% moderately ill, 2.44% mildly ill and 4.88% borderline mentally ill. Thirty-two patients (78.05%) were treatment persistent for ≥ 180 days. Among the 19 patients observed for ≥ 18 months, 11 (57.89%) were persistent for ≥ 18 months. Among the 22 study patients observed for < 18 months, 12 (54.54%) were persistent. An improvement in schizophrenia severity according to CGI-S was observed at inclusion (following LUR therapy) compared to the index date. Six patients (14.63%) experienced at least one adverse drug reaction: akathisia (7.32%), extrapyramidal disorder (4.88%), hyperprolactinemia (2.44%), restlessness (2.44%), and galactorrhea (2.44%). None were serious. Conclusions: Persistence to LUR in patients with schizophrenia was relatively high: 78% and 58% of patients were still on LUR after 6 and 18 months of treatment, respectively. This may reflect LUR's relatively favorable balance between efficacy and tolerability, as well as favorable patient satisfaction and acceptance. [ABSTRACT FROM AUTHOR]

Formulation-induced microbiota changes were linked with pro-inflammatory response. [Display omitted] • Amorphous solid dispersion and lipid nanoemulsion improve lurasidone bioavailability. • Lipid nanoemulsion triggered reductions in gut microbiota diversity and abundance. • The PVP-based amorphous solid dispersion was 'gut neutral'. Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable ∼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a 'gut neutral' effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota – an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition. [ABSTRACT FROM AUTHOR]