lurasidone-hydrochloride and Cognition-Disorders

Cognition deficit is one of the most common symptoms of schizophrenia, including abstract thinking and memory, and attention deficits. Previous studies have suggested that the improvement of cognition is very important for the recovery of disease and social function for the patients. Recent studies indicated that two new atypical antipsychotics, blonanserin and lurasidone, are expected to improve the cognitive impairment in patients with schizophrenia. This review introduces pathogenesis of cognitive impairment in schizophrenia, mechanisms of blonanserin and lurasidone in the improvement of cognitive impairment and progress in their clinical application for schizophrenia. We hope that this review could guide clinical use of antipsychotics and provide new directions for future studies.. 认知功能障碍是精神分裂症常见症状之一，主要表现为抽象思维、记忆、注意等方面的障碍。认知功能的改善对患者疾病康复、社会功能恢复具有至关重要的意义。近来研究表明新型非典型抗精神病药物布南色林和鲁拉西酮具有独特的受体作用机制，有望使患者认知功能障碍得到更好的改善。笔者从精神分裂症患者认知功能障碍的病因机制入手，综述布南色林和鲁拉西酮改善精神分裂症患者认知功能的作用机制；介绍两种药物的临床应用进展，以便更好地指导临床用药，为进一步研究提供新方向。.

Topics: Antipsychotic Agents; Cognition Disorders; Humans; Lurasidone Hydrochloride; Piperazines; Piperidines; Schizophrenia; Schizophrenic Psychology

Lurasidone is a benzisothiazol derivative, approved by the US Food and Drug Administration for the acute treatment of adults with schizophrenia. Lurasidone's binding affinities are highest for the 5-HT(2A), 5-HT(7), and D(2) receptors; with lower and similar binding affinities for the norepinephrine α(2C) and 5-HT(2C) receptor subtypes. It has demonstrated efficacy in fixed-dose studies across a variable dose range (i.e., 40 - 160 mg), with a recommended starting dose of 40 mg and a maximum recommended dose of 80 mg. Lurasidone's preclinical profile is predictive not only of efficacy against psychotic and negative symptoms but also of affective symptomatology and cognitive deficits. Controlled trials are currently underway to evaluate lurasidone's efficacy in bipolar depression as well as its procognitive effects in individuals with schizophrenia. Lurasidone is administered once a day with ≥ 350 calories of food, regardless of fat content. Lurasidone is not known to adversely affect body composition, anthropometrics, metabolic and/or electrocardiographic parameters. Although prolactin elevation might be observed, prolactin-related adverse events are rarely reported.. This paper presents the pharmacodynamics and pharmacokinetics of lurasidone, and discusses its efficacy, safety and tolerability data.. Lurasidone's simplicity of use and favorable metabolic profile are distinct advantages relative to several other agents (e.g., olanzapine). Outcomes in cognitive data analyses are awaited to determine if there is a key differentiator between lurasidone and other atypical agents with respect to efficacy. Moreover, lurasidone's efficacy in bipolar depression is awaited to determine whether this agent can be considered as a treatment alternative for depressive symptoms in adults with bipolar disorder.

Topics: Bipolar Disorder; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cognition Disorders; Double-Blind Method; Humans; Isoindoles; Lurasidone Hydrochloride; Randomized Controlled Trials as Topic; Schizophrenia; Thiazoles

We previously reported that treatment with 160mg/d of lurasidone improved cognitive performance in a manner superior to placebo, quetiapine XR 600mg/d, and lurasidone 80mg/d, based on a 6-week randomized trial of patients with an acute exacerbation of schizophrenia. The objective of this post-hoc analysis was to explore the cognitive and functional performance of patients whose final doses of lurasidone were 40/80mg/d, 120mg/d, and 160mg/d compared to quetiapine XR 200-800mg/d (QXR) during a 6-month, double-blind continuation study that followed a short-term trial. Subjects who received final doses of lurasidone 120mg/d (n=77) and 160mg/d (n=49) showed significantly greater improvement in overall cognitive performance compared to QXR (n=85) at week 32 (month 6 of the extension study), while those on last doses of 40/80mg/d (n=25) showed a trend towards significance at week 32. Mean changes in neurocognitive composite z-score from pre-treatment baseline were significant for the 3 lurasidone final dose groups at both weeks 19 and 32, with composite change scores of z=1.53, z=1.43, and z=1.34 for the lurasidone 40/80mg/d, 120mg/d, and 160mg/d, respectively, at week 32. In contrast, the composite change score was not statistically significant in the overall quetiapine group (z=0.46), with none of the individual quetiapine doses showing any significant improvement. Functional capacity scores improved in all treatment groups. Our findings indicate improved cognitive performance in patients treated with each of the flexible doses of lurasidone 40-160mg/d, compared to quetiapine XR 200-800mg/d. All doses of lurasidone were superior to all doses of quetiapine for cognitive performance.

Topics: Antipsychotic Agents; Cognition; Cognition Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Least-Squares Analysis; Lurasidone Hydrochloride; Neuropsychological Tests; Psychiatric Status Rating Scales; Quetiapine Fumarate; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome

The aim of this analysis was to compare the effects of 2 atypical antipsychotic agents, lurasidone (80 mg/d or 160 mg/d) and quetiapine XR (600 mg/d), on daytime alertness, and to evaluate the effects of daytime sleepiness on treatment outcomes in patients with an acute exacerbation of schizophrenia.. Patients who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) criteria for schizophrenia were randomized to 6 weeks of double-blind treatment with fixed doses of lurasidone 80 mg/d (n = 125), lurasidone 160 mg/d (n = 121), quetiapine XR 600 mg/d (n = 119), or placebo (n = 121), all dosed once daily in the evening, with food. Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS).. Daytime sleepiness improved in the lurasidone and placebo-treated groups but worsened in the quetiapine XR treatment group when compared to placebo (p = 0.001) and to either dose of lurasidone (both p < 0.01). Sedation associated with quetiapine XR treatment mediated an improvement in agitation [assessed by the Positive and Negative Syndrome Scale-Excitement (PANSS-EC) subscale] and a worsening in functional capacity [assessed by the University of California-San Diego (UCSD) Performance-Based Skills Assessment-Brief Version (UPSA-B) total score]; these mediating relationships were not observed for the lurasidone or placebo treatment groups.. In this 6-week double-blind study, treatment with lurasidone 80 mg or 160 mg, administered once daily in the evening, was associated with a reduction in daytime sleepiness similar in magnitude to placebo, while quetiapine XR 600 mg/d was associated with a significant increase in daytime sleepiness, compared to both lurasidone dose groups and placebo. Daytime sleepiness was associated with improvement in agitation and worsening in functional capacity for quetiapine XR, but not lurasidone or placebo-treated patients.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Cognition Disorders; Dibenzothiazepines; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Isoindoles; Lurasidone Hydrochloride; Male; Middle Aged; Psychiatric Status Rating Scales; Quetiapine Fumarate; Schizophrenia; Thiazoles; Treatment Outcome; Young Adult

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project produced a battery of tests, the MATRICS Consensus Cognitive Battery (MCCB), designed to assess cognitive treatment effects in clinical trials of patients with schizophrenia. In validation studies, the MCCB demonstrated excellent reliability, minimal practice effects and significant correlations with measures of functional capacity. This study addresses whether the MCCB demonstrates these favorable characteristics when administered in the context of the type of large multi-site industry trial for which it was designed.. In a clinical trial comparing risperidone and lurasidone, 323 clinically-stable outpatients with schizophrenia at 29 sites were assessed with MCCB at screening and a median of 15days later at baseline. A measure of functional capacity, the UCSD Performance-based Skills Assessment-Brief (UPSA-B) was administered at baseline.. All 323 (100%) patients had sufficient data for computing a composite score according to the MCCB criteria. The test-retest reliability of the MCCB composite score was excellent (ICC=0.88). The severity of cognitive impairment was T=24.7 (SD=12.1) at screening and T=26.7 (SD=12.4) at baseline. The MCCB composite score demonstrated a large correlation with the UPSA-B composite score (r=.60, df=304, p<.001). The practice effect on the composite score was small (z=0.18).. In the context of a 29-site antipsychotic trial in stable outpatients with schizophrenia, the MCCB is sensitive to cognitive deficits in all domains, demonstrates excellent test-retest reliability and small practice effects, and is strongly correlated with a leading measure of functional capacity.

Topics: Adult; Antipsychotic Agents; Cognition Disorders; Female; Humans; Isoindoles; Lurasidone Hydrochloride; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Psychometrics; Reproducibility of Results; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles

Improving cognitive functioning in people with schizophrenia is a major treatment goal. In addition, interview-based measures have been developed to supplement performance-based assessments. However, few data are available regarding whether interview-based measures are sensitive to treatment-related changes.. Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomized to 21 days of double-blind treatment with lurasidone 120 mg once daily (N=150) or ziprasidone 80 mg BID (N=151). A similar proportion of patients completed the study on lurasidone (67.5%) and ziprasidone (69.3%). Study participants were assessed with the majority of the tests from the MATRICS Consensus Cognitive Battery (MCCB) and an interview-based assessment of cognitive functioning, the Schizophrenia Cognition Rating Scale (SCoRS). SCoRS ratings were based on the interviewer's best judgment, after interviews with the patient and a caregiver when available. The study was conducted from April 2006 to January 2007.. There were no between-group treatment differences in performance on the MCCB or the SCoRS ratings. Lurasidone patients demonstrated significant within group-improvement from baseline on the MCCB composite score (p=0.026) and on the SCoRS (p<0.001), but ziprasidone patients did not improve on either the MCCB composite (p=0.254) or the SCoRS (p=0.185). At endpoint there was a statistical trend (p=0.058) for lurasidone to demonstrate greater improvement from baseline in SCoRS ratings. Improvements in interview-based aspects of cognition were not related to MCCB test changes, and had minimal correlations with changes in symptoms.. These data suggest that interview-based cognitive measures such as the SCoRS may be sensitive to changes after 3weeks of treatment in patients with schizophrenia. Lurasidone is being assessed further in ongoing clinical trials with additional outcome measures.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Cognition Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Interview, Psychological; Isoindoles; Lurasidone Hydrochloride; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Thiazoles; Young Adult

Many acute treatments transiently reverse the deficit in novel object recognition (NOR) produced by subchronic treatment with the N-methyl-d-aspartate receptor non-competitive antagonist, phencyclidine (PCP), in rodents. Treatments which restore NOR for prolonged periods after subchronic PCP treatment may have greater relevance for treating the cognitive impairment in schizophrenia than those which restore NOR transiently. We examined the ability of post-PCP subchronic lurasidone, an atypical APD with potent serotonin (5-HT)1A partial agonism and subchronic tandospirone, a selective 5-HT1A partial agonist, to enable prolonged reversal of the subchronic PCP-induced NOR deficit. Rats treated with subchronic PCP (2mg/kg, twice daily for 7 days) or vehicle, followed by a 7day washout period were subsequently administered lurasidone or tandospirone twice daily for 7 days (day 15-21), and tested for NOR weekly for up to two additional weeks. Subchronic lurasidone (1, but not 0.1mg/kg) or tandospirone (5, but not 0.6mg/kg) significantly reversed the PCP-induced NOR deficit at 24h and 7days after the last injection, respectively. The effect of lurasidone persisted for one more week (day 36, 14 days after the last lurasidone dose), while tandospirone-treated rats were able to perform NOR at 7, but not 14, days after the last tandospirone dose. Co-administration of WAY100635 (0.6mg/kg), a 5-HT1A antagonist, with lurasidone, blocked the ability of lurasidone to restore NOR, suggesting that 5-HT1A receptor stimulation is necessary for lurasidone to reverse the effects of PCP. The role of dopamine, GABA and the MAPK/ERK signalling pathway in the persistent, but not indefinite, restoration of NOR is discussed.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Isoindoles; Lurasidone Hydrochloride; Phencyclidine; Piperazines; Psychotropic Drugs; Pyridines; Pyrimidines; Random Allocation; Rats, Long-Evans; Receptor, Serotonin, 5-HT1A; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Schizophrenic Psychology; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Time

Enhancement of cholinergic function via nicotinic acetylcholine (ACh) receptor (nAChR) agonism is a potential approach for the treatment of cognitive impairment associated with schizophrenia (CIAS). Some atypical antipsychotic drugs (AAPDs) enhance ACh release in rodent brain, indirectly stimulating these receptors. Here, we elucidate which nAChR subtypes mediate novel object recognition (NOR) in normal rats and contribute to the ability of the AAPD, lurasidone, to improve the NOR deficit in sub-chronic (sc) phencyclidine (PCP)-treated rats, a model for CIAS.. The ability of lurasidone and nAChR ligands to reverse the scPCP-induced deficit in NOR was assessed in female, Long-Evans rats.. The broad acting nAChR antagonist, mecamylamine (MEC), induced a NOR deficit in normal rats. The NOR deficit secondary to scPCP was reversed by either selective α4β2* nAChR agonism (A-85380) or α7 nAChRs agonism (PNU-282987); these effects were blocked by DHβE and MLA, selective antagonists of α4β2* and α7 nAChR, respectively. The ability of lurasidone to reverse the scPCP-induced NOR deficit was blocked by MEC, but not MLA or DHβE. However, sub-effective doses (SED) of either A-85380 or PNU-282987 potentiated the ability of SED lurasidone to reverse the scPCP-induced NOR deficit.. These results identify both α4β2* and α7 nAChRs as candidates for enhancing the ability of lurasidone and other AAPDs, which increase the release of ACh, to improve CIAS.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Azetidines; Benzamides; Bridged Bicyclo Compounds; Cognition Disorders; Disease Models, Animal; Female; Lurasidone Hydrochloride; Mecamylamine; Nicotinic Agonists; Nicotinic Antagonists; Nootropic Agents; Phencyclidine; Random Allocation; Rats, Long-Evans; Receptors, Nicotinic

N-Methyl-D-aspartate (NMDA) receptor (NMDAR) hypofunction has been postulated to contribute to the cognitive deficit of schizophrenia. In this study, we examined the effect of lurasidone (Latuda; Dainippon Sumitomo Pharma Co. Ltd., Tokyo, Japan), a newly approved atypical antipsychotic drug (APD), on NMDAR synaptic function in rat frontal cortical pyramidal neurons. In vivo administration of lurasidone produced a significant and selective enhancement of NMDAR-mediated synaptic responses and surface expression of NR2A and NR2B subunits. Lurasidone has high affinity for serotonin 5-HT(1A), 5-HT(2A), and 5-HT(7) receptors and dopamine D(2) receptors. In vivo administration of the 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2 -(2-(4-methyl-1-piperidinyl)ethyl)pyrrolidine (SB-269970) mimicked the enhancing effect of lurasidone on NMDAR responses, whereas the D(2) receptor antagonist haloperidol failed to do so. Previous studies have found that short-term administration of lurasidone reverses the cognitive impairment induced by subchronic administration of phencyclidine (PCP), an NMDAR noncompetitive antagonist. In this study, we found that lurasidone, as well as the prototypical atypical APD clozapine, restored NMDAR-mediated synaptic responses to normal levels in the PCP model of schizophrenia. These results suggest that NMDAR is the potential key molecular target of lurasidone, possibility via antagonizing 5-HT(7) receptors, which is consistent with evidence that 5-HT(7) receptor antagonism contributes to cognitive enhancement by atypical APDs in patients with schizophrenia.

Topics: Animals; Antipsychotic Agents; Clozapine; Cognition Disorders; Disease Models, Animal; Isoindoles; Lurasidone Hydrochloride; Rats; Receptor, Serotonin, 5-HT2A; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Synaptic Transmission; Thiazoles

Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT)(2A)/dopamine D(2) antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT(1A) partial agonist properties, tandospirone, a selective 5-HT(1A) partial agonist, haloperidol, a D(2) antagonist, and pimavanserin, a 5-HT(2A) inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1 mg/kg), tandospirone (5 mg/kg), pimavanserin (3 mg/kg), or haloperidol (1 mg/kg) b.i.d. 30 min before PCP (2 mg/kg, b.i.d.) for 7 days (day1-7), followed by a 7-day washout (day 8-14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT(1A) antagonists, further evidence for the importance of 5-HT(1A) receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Female; Haloperidol; Isoindoles; Lurasidone Hydrochloride; Phencyclidine; Piperazines; Piperidines; Pyridines; Pyrimidines; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Agonists; Thiazoles; Urea