Rash caused by lurasidone in old chinese patient with bipolar disorder: case-based review.

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.

Bioanalytical liquid chromatography-tandem mass spectrometry method development and validation for quantification of lurasidone in rat plasma using ion pairing agent.

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.

Exploitation of erythrosine B as a fluorometric marker for lurasidone determination through electrostatic attraction; application to content uniformity test.

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.

Long-term safety and effectiveness of lurasidone in adolescents and young adults with schizophrenia: pooled post hoc analyses of two 12-month extension studies.

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.

Therapeutic monitoring of antipsychotics with a focus on lurasidone and its dosing.

Dose-response relationships are not fully understood for antipsychotics. Especially in the case of multimodal antipsychotics, these relationships cannot be simplified to the level of dopaminergic receptor occupancy alone. In general, for most antipsychotics, there is no linear dose-response relationship. Reasons for this include, among others, pharmacokinetic factors affecting plasma levels. Based on meta-analyses, the doseresponse curve appears to be bell-shaped. However, in the case of some antipsychotics, it appears that even increasing the dose beyond the recommended range could yield further increases in efficacy. It should be stressed that this is an off-label procedure and cannot generally be recommended and there is not enough valid information for general conclusions for these antipsychotics either. Mini-invasive sampling and alternative matrices such as saliva or dry blood spots could open the way to more frequent monitoring of antipsychotics and a better understanding of doseresponse relationships.

Therapeutic monitoring of antipsychotics with a focus on lurasidone and its dosing.

Dose-response relationships are not fully understood for antipsychotics. Especially in the case of multimodal antipsychotics, these relationships cannot be simplified to the level of dopaminergic receptor occupancy alone. In general, for most antipsychotics, there is no linear dose-response relationship. Reasons for this include, among others, pharmacokinetic factors affecting plasma levels. Based on meta-analyses, the doseresponse curve appears to be bell-shaped. However, in the case of some antipsychotics, it appears that even increasing the dose beyond the recommended range could yield further increases in efficacy. It should be stressed that this is an off-label procedure and cannot generally be recommended and there is not enough valid information for general conclusions for these antipsychotics either. Mini-invasive sampling and alternative matrices such as saliva or dry blood spots could open the way to more frequent monitoring of antipsychotics and a better understanding of doseresponse relationships.

Lurasidone and risk of metabolic syndrome: results from short and long-term studies in patients with bipolar depression.

OBJECTIVE: The elevated prevalence of metabolic syndrome (MetS) in patients with depression has been associated with increased mortality. This post hoc analysis assessed the effect of treatment with lurasidone on risk of MetS in patients with bipolar depression. METHODS: Data used in the current analyses consisted of 3 double-blind (DB), placebo-controlled, 6-week studies in adults with bipolar I depression (N = 1192), consisting of 1 monotherapy, and 2 adjunctive trials (lithium or valproate). Also analyzed was a 6-month open-label (OL) extension study (monotherapy, N = 316; adjunctive therapy, N = 497); and a 5-month, OL, stabilization phase followed by randomization to a 28-week DB, placebo-controlled, adjunctive therapy study with lurasidone (N = 490). MetS was defined based on NCEP ATP III criteria (2005 revision). RESULTS: The proportion of patients with new-onset MetS was similar for lurasidone vs placebo in the short-term studies (monotherapy, 13.9% vs 15.3%; adjunctive therapy, 13.6% vs 11.0%); and remained stable during both the 6-month extension phase study (monotherapy, 15.2%; adjunctive therapy, 16.9%), and the 5-month stabilization study (adjunctive therapy, 12.2%). After 28 weeks of DB treatment (following 5-month treatment in the stabilization study), new onset MetS was observed at endpoint (OC) in 26.2% of the lurasidone group, and 30.8% of the placebo group. CONCLUSIONS: This post hoc analysis found that both short and long-term treatment with lurasidone was associated with a relatively low risk for the development of MetS in patients with bipolar I disorder. These findings are consistent with similar analyses in patients with schizophrenia.

NRX-101, a Rapid-Acting Anti-Depressant, Does Not Cause Neurotoxicity Following Ketamine Administration in Preclinical Models.

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.

Therapeutic Potential and Limitation of Serotonin Type 7 Receptor Modulation.

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.

The Novel Atypical Antipsychotic Lurasidone Affects Cytochrome P450 Expression in the Liver and Peripheral Blood Lymphocytes.

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.

Long Acting Ionically Paired Pamoate-based Suspension of Lurasidone: An exploration of Size Effects on in vitro Dissolution and in vivo Pharmacokinetic Behaviors.

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.

Safety and effectiveness of lurasidone in adolescents with schizophrenia: results of a 2-year, open-label extension study.

BACKGROUND: Minimal long-term benefit: Risk data are available regarding antipsychotic treatments for schizophrenia in pediatric populations. This study evaluated the long-term safety, tolerability, and effectiveness of lurasidone in adolescents with schizophrenia. METHODS: Patients aged from 13 to 17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose (20-80 mg/day) lurasidone treatment study. Safety was assessed via spontaneous reporting, rating scales, body weight measurement, metabolic, and prolactin testing. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score. RESULTS: About 271 patients completed 6 weeks of DB treatment and entered the 2-year OL extension study. Altogether, 42.4% discontinued prematurely, 10.7% due to adverse events. During OL treatment, the most common adverse events were headache (24.0%); anxiety (12.9%), schizophrenia, and nausea (12.5%); sedation/somnolence (12.2%); and nasopharyngitis (8.9%). Minimal changes were observed on metabolic parameters and prolactin. Mean change from DB baseline in weight at week 52 and week 104 was +3.3 kg and + 4.9 kg, respectively, compared to an expected weight gain of +3.4 kg and + 5.7 kg, respectively, based on the sex- and age-matched US Center for Disease Control normative data. Continued improvement was observed in PANSS total score, with mean change from OL baseline of -15.6 at week 52 and -18.4 at week 104. CONCLUSION: In adolescents with schizophrenia, long-term lurasidone treatment was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin. Continued improvement in symptoms of schizophrenia was observed over 2 years of lurasidone treatment.

Cost analysis of lurasidone for the treatment of schizophrenia in adolescents and adults within the United Kingdom.

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.

Treatment persistence in patients with schizophrenia treated with lurasidone in Italian clinical practice.

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.

New Atypical Antipsychotics in the Treatment of Schizophrenia and Depression.

Schizophrenia and depression are heterogeneous disorders. The complex pathomechanism of the diseases imply that medication responses vary across patients. Many psychotropic drugs are available but achieving optimal therapeutic effect can be challenging. The evidence correlates well with clinical observations, suggesting that new atypical antipsychotic drugs are effective against negative and cognitive symptoms of schizophrenia, as well as against affective symptoms observed in depression. The purpose of this review presents the background and evidence for the use of the new second/third-generation antipsychotics (aripiprazole, cariprazine, lurasidone, asenapine, brexpiprazole, lumateperone, pimavanserin) in treatment of schizophrenia and depression. We have first provided a brief overview of the major neurobiological underpinnings of schizophrenia and depression. We then shortly discuss efficacy, safety and limitations of ongoing pharmacotherapy used in depression and schizophrenia. Mainly, we have focused this review on the therapeutic potential of new atypical antipsychotic drugs-currently existing-to be effective in psychotic, as well as in affective disorders.

Efficacy and safety of lurasidone in acutely psychotic patients with schizophrenia: A 6-week, randomized, double-blind, placebo-controlled study.

AIM: The aim of this study was to evaluate the efficacy of lurasidone in acute schizophrenia in Japan and other countries. METHODS: Subjects (aged 18-74 years) diagnosed with schizophrenia were randomized to lurasidone 40 mg/day or placebo. The primary efficacy endpoint was change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score at Week 6. Secondary efficacy assessments included the Clinical Global Impression-Severity Scale (CGI-S). Safety endpoints included adverse events, and laboratory and electrocardiogram parameters. RESULTS: A total of 483 subjects were randomized to lurasidone or placebo; 107 subjects were from Japan. Mean changes from baseline at Week 6 endpoint in PANSS total scores were -19.3 in the lurasidone group and -12.7 in the placebo group (treatment difference: P < 0.001, effect size = 0.41). Changes from baseline for Week 6 CGI-S scores were -1.0 for lurasidone and -0.7 for placebo (treatment difference: P < 0.001, effect size = 0.41). All-cause discontinuation during the 6-week, double-blind period was 19.4% for lurasidone and 25.4% for placebo, and discontinuation rates due to adverse event were 5.7% for lurasidone and 6.4% for placebo. The following common treatment-emergent adverse events occurred in more than 2% on lurasidone and at a rate at least twice that of the placebo group: akathisia (4.0%), dizziness (2.8%), somnolence (2.8%), abdominal discomfort (2.0%) and asthenia (2.0%). No significant changes in bodyweight or metabolic parameters were observed. CONCLUSION: Lurasidone 40 mg once daily dosing demonstrated efficacy in a patient population with acute schizophrenia, including subjects from Japan, and was generally safe and well-tolerated.

A missed case of lurasidone induced laryngospasm: A case study and overview of extrapyramidal symptom identification and treatment.

OBJECTIVE: Many patients with bipolar disorder are treated exclusively in primary care settings, and the use of atypical antipsychotics as primary treatment for bipolar depression is increasing. Extrapyramidal symptoms (EPS) are common side effects of antipsychotic medications, and clinicians should actively monitor for these symptoms when prescribing antipsychotic medications. Accurate diagnosis of EPS is especially important as the symptoms can be highly distressing, and in some cases, life threatening. Our aim is to familiarize primary care providers and other clinicians prescribing antipsychotic medications with EPS and to aid in its rapid diagnosis and treatment. METHOD: We describe a case of lurasidone induced dystonia with prominent laryngospasm and oculogyric crisis which was missed for many years in the primary care setting, largely due to misdiagnosis of symptoms as being related to anxiety and panic attacks. RESULTS: In addition to summarizing this illustrative case, we present the most common forms of EPS and summarize the primary therapies for each type of EPS. CONCLUSIONS: With increased management of bipolar disorder in the primary care setting and increased use of atypical antipsychotics as the primary therapy for bipolar disorder, it is essential that all practitioners are prepared to actively monitor for EPS, followed by its rapid diagnosis and treatment.

Effects of Subchronic Administrations of Vortioxetine, Lurasidone, and Escitalopram on Thalamocortical Glutamatergic Transmission Associated with Serotonin 5-HT7 Receptor.

The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R antagonism. A member of a novel class of antidepressants, vortioxetine, which is a serotonin partial agonist reuptake inhibitor (SPARI), also exhibits a higher affinity for serotonin transporter, serotonin receptors type 1A (5-HT1AR) and type 3 (5-HT3R), and 5-HT7R. However, the effects of chronic administration of lurasidone, vortioxetine, and the selective serotonin reuptake inhibitor (SSRI), escitalopram, on 5-HT7R function remained to be clarified. Thus, to explore the mechanisms underlying the clinical effects of vortioxetine, escitalopram, and lurasidone, the present study determined the effects of these agents on thalamocortical glutamatergic transmission, which contributes to emotional/mood perception, using multiprobe microdialysis and 5-HT7R expression using capillary immunoblotting. Acute local administration of a 5-HT7R agonist and antagonist into the mediodorsal thalamic nucleus (MDTN) enhanced and reduced thalamocortical glutamatergic transmission, induced by N-methyl-D-aspartate (NMDA)/glutamate receptor inhibition in the reticular thalamic nucleus (RTN). Acute local administration of a relevant therapeutic concentration of vortioxetine and lurasidone into the MDTN suppressed the thalamocortical glutamatergic transmission via 5-HT7R inhibition, whereas that of escitalopram activated 5-HT7R. Subchronic administration of effective doses of vortioxetine and lurasidone (for 7 days) reduced the thalamocortical glutamatergic transmission, but escitalopram did not affect it, whereas subchronic administration of these three agents attenuated the stimulatory effects of the 5-HT7R agonist on thalamocortical glutamatergic transmission. Subchronic administration of effective doses of vortioxetine, lurasidone, and escitalopram downregulated the 5-HT7R expression of the plasma membrane in the MDTN; the 5-HT7R downregulation induced by vortioxetine and lurasidone was observed at 3 days, but that induced by escitalopram required a longer duration of 7 days. These results indicate that chronic administration of vortioxetine, escitalopram, and lurasidone generate downregulation of 5-HT7R in the thalamus; however, the direct inhibition of 5-HT7R associated with vortioxetine and lurasidone generates more rapid downregulation than the indirect elevation of the extracellular serotonin level via serotonin transporter inhibition by escitalopram.

Stress Modifies the Expression of Glucocorticoid-Responsive Genes by Acting at Epigenetic Levels in the Rat Prefrontal Cortex: Modulatory Activity of Lurasidone.

Epigenetics is one of the mechanisms by which environmental factors can alter brain function and may contribute to central nervous system disorders. Alterations of DNA methylation and miRNA expression can induce long-lasting changes in neurobiological processes. Hence, we investigated the effect of chronic stress, by employing the chronic mild stress (CMS) and the chronic restraint stress protocol, in adult male rats, on the glucocorticoid receptor (GR) function. We focused on DNA methylation specifically in the proximity of the glucocorticoid responsive element (GRE) of the GR responsive genes Gadd45ß, Sgk1, and Gilz and on selected miRNA targeting these genes. Moreover, we assessed the role of the antipsychotic lurasidone in modulating these alterations. Chronic stress downregulated Gadd45ß and Gilz gene expression and lurasidone normalized the Gadd45ß modification. At the epigenetic level, CMS induced hypermethylation of the GRE of Gadd45ß gene, an effect prevented by lurasidone treatment. These stress-induced alterations were still present even after a period of rest from stress, indicating the enduring nature of such changes. However, the contribution of miRNA to the alterations in gene expression was moderate in our experimental conditions. Our results demonstrated that chronic stress mainly affects Gadd45ß expression and methylation, effects that are prolonged over time, suggesting that stress leads to changes in DNA methylation that last also after the cessation of stress procedure, and that lurasidone is a modifier of such mechanisms.

Hospitalization Risk for Adults with Bipolar I Disorder Treated with Oral Atypical Antipsychotics as Adjunctive Therapy with Mood Stabilizers: A Retrospective Analysis of Medicaid Claims Data.

Background: Atypical antipsychotics (AAPs) with mood stabilizers are recommended as a first-line treatment for patients with bipolar disorder. No studies have compared the inpatient health care resource utilization for patients with bipolar disorder treated with lurasidone as adjunctive therapy with mood stabilizers compared with other oral AAPs. Objective: To compare the risk of hospitalization for adult Medicaid beneficiaries with bipolar I disorder when treated with lurasidone compared with other oral AAPs as adjunctive therapy with mood stabilizers. Methods: This retrospective cohort study used the MarketScan Research Databases Multi-State Medicaid Database (IBM, Armonk, NY) claims data to assess patients with bipolar I disorder between January 1, 2014, and June 30, 2019. Adult patients who initiated oral AAP treatment with mood stabilizers (index date) and who were continuously enrolled 12 months before (pre-index) and 24 months after (post-index) the index date were included. Treatment categories assigned by patient-month included lurasidone, aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone with mood stabilizers; no/minimal treatment; AAP monotherapy; and other. Marginal structural models were performed to estimate the all-cause and psychiatric hospitalization rates and hospital length of stay associated with each adjunctive AAP therapy by controlling for both time-invariant and time-varying confounders. Results: Adults with bipolar I disorder (N = 11,426; mean age = 39.4 years; female=73%) treated with an adjunctive oral AAP with mood stabilizers during the index month were categorized into lurasidone (12%), aripiprazole (17%), olanzapine (7%), quetiapine (32%), risperidone (11%), ziprasidone (7%), or other (15%) treatment groups. The adjusted odds of all-cause and psychiatric hospitalization were significantly higher for olanzapine (all causes: adjusted odds ratio [aOR] = 1.59; 95% CI, 1.13-2.25; psychiatric: aOR = 1.61, 95% CI, 1.12-2.32), quetiapine (all-causes: aOR = 1.27, 95% CI, 1.01-1.58; psychiatric: aOR = 1.28, 95% CI, 1.02-1.59), and ziprasidone (all-causes: aOR = 1.68, 95% CI, 1.05-2.66; psychiatric: aOR = 1.55, 95% CI, 1.02-2.35) compared with lurasidone with mood stabilizers. The adjusted odds of all-cause and psychiatric hospitalizations were numerically lower for lurasidone compared with aripiprazole. The all-cause hospital length of stay per 100 patient-months was significantly higher for olanzapine (20.3 days) and quetiapine (16.0 days) compared with lurasidone (12.2 days, both P values < 0.05). Conclusions: In a Medicaid population, adults with bipolar I disorder treated with lurasidone as adjunctive therapy with mood stabilizers had significantly lower all-cause and psychiatric hospitalization rates compared with olanzapine, quetiapine, and ziprasidone. Fewer hospitalizations may reduce the economic burden associated with bipolar disorder. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).