Efficacy In Schizophrenia Research Articles

Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment.

Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.

A new sensitive fluorescence probe based on the molecular recognition for the detection of antipsychotics in human urine

Risperidone, olanzapine and aripiprazole have good efficacy in schizophrenia. Monitoring the concentration of antipsychotics in patients is helpful to provide a precise medication administration. Although many detection techniques based on large instruments have been developed, they are expensive and cumbersome, which are not conducive to clinical promotion. In this paper, rose bengal (RB) was firstly used as a low-cost fluorescent probe for the detection of antipsychotic drugs. Under the condition of pH 3.9, there is a strong negative electrostatic potential region in RB, which attracts positively charged antipsychotic drugs. This property allows the halogen atoms and oxygen atoms of RB to act as hydrogen bond donors to molecularly bond with the H atoms of the antipsychotic drugs, forming a non-luminous complex. The fluorescence intensity showed a linear quench relationship with the increasing concentration of risperidone, olanzapine and aripiprazole with low detection limits of 103, 82.0 and 81.0 μg L−1, respectively. This fluorescent method has good selectivity and can be successfully utilized in detecting antipsychotic medications in human urine and pharmaceutical tablets.

Muscarinic drug shows efficacy in schizophrenia but much is left to be discovered

Muscarinic drug shows efficacy in schizophrenia but much is left to be discovered

The association between inflammation and kynurenine pathway metabolites in electroconvulsive therapy for schizophrenia: Implications for clinical efficacy

The kynurenine pathway (KP) of tryptophan has been implicated in the pathogenesis of schizophrenia and its interaction with the immune system has been suggested to play a role. In this study, 28 schizophrenia patients and 25 healthy controls were recruited and divided into different inflammatory subgroups using a two-step recursive clustering analysis. Cytokine gene expression and plasma KP metabolites were measured before, during and after treatment. Our findings indicated that schizophrenia patients had lower levels of Tryptophan (TRP), N-formylkynurenine (NFK), xanthinic acid (XA), quinolinic acid (QA), kynurenic acid (KYNA), KYNA/KYN and QA/KYNA, but higher levels of IL-18 mRNA, KYN/TRP compared to healthy controls (all p < 0.05). After electroconvulsive therapy (ECT), patients with low inflammation achieved better clinical improvement (PANSS scores) compared to those with high inflammation (F = 5.672, P = 0.025), especially in negative symptoms (F = 6.382, P = 0.018, η2 = 0.197). While IL-18 mRNA (F = 32.910, P < 0.0001) was significantly decreased following ECT, the KYN/TRP (F = 3.455, p = 0.047) and KYNA/TRP (F = 4.264, P = 0.026) only significantly decreased in patients with low inflammation. Correlation analyses revealed that baseline IL-18 gene expression significantly correlated with pre- (r = 0.537, p = 0.008) and post-KYNA/TRP (r = 0.443, p = 0.034), post-KYN/TRP (r = 0.510, p = 0.013), and post-negative symptoms (r = 0.525, p = 0.010). Moreover, baseline TRP (r = -0.438, p = 0.037) and XA (r = -0.516, p = 0.012) were negatively correlated with baseline PANSS, while post-KYN (r = -0.475, p = 0.022), 2-AA (r = -0.447, p = 0.032) and KYN/TRP (r = -0.566, p = 0.005) were negatively correlated with Montreal Cognitive Assessment (MoCA) following ECT. Overall, these findings suggested that the association between inflammation and kynurenine pathway plays an essential role in mechanism of ECT for schizophrenia and that the regulation of ECT on KP is influenced by inflammatory characteristics, which may relate to clinical efficacy in schizophrenia.

A Potential Immune-Related miRNAs Regulatory Network and Corresponding Diagnostic Efficacy in Schizophrenia.

Immune-related pathways actively participate in the progression of schizophrenia (SCZ), however, roles of immune-related miRNAs in SCZ are still unclear. A microarray expression study was conducted to explored roles of immune-related genes in SCZ. Functional enrichment analysis by using "clusterProfiler" was used to identify molecular alterations of SCZ. Protein-protein interaction (PPI) network was constructed and helped core molecular factors identification. Based on The Cancer Genome Atlas (TCGA) database, clinical significances of hub immune-related genes in cancers were also been explored. Then, correlation analyses were used to determine immune-related miRNAs. We further validated that hsa-miR-1299 could be an effective diagnostic biomarker for SCZ via analyzing multi-cohorts' data and quantitative real-time PCR (qRT-PCR). A total of 455 mRNAs and 70 miRNAs that were differentially expressed between SCZ and control samples. Functional enrichment analysis based on differentially expressed genes (DEGs) hinted that immune-related pathways were significantly correlated with SCZ. Furthermore, a total of 35 immune-related genes that involved in disease onset and showed significant co-expressed relationships. Hub immune-related gene CCL4 and CCL22 are valuable in tumor diagnosis and survival prediction. Furthermore, we also identified 22 immune-related miRNAs that play important roles in this disease. An immune-related miRNAs-mRNAs regulatory network was constructed to provide miRNAs regulatory roles in SCZ. Core miRNAs expression status of hsa-miR-1299 were also validated in another cohort, which suggested its diagnostic performance for SCZ. Our study reports the downregulation of some miRNAs in the process of SCZ are important. Shared genomics characteristics between SCZ and cancers also provide novel insights for cancers. A significant alteration of hsa-miR-1299 expression is effective as biomarker for the diagnosis of SCZ, suggesting that this miRNA could be a specific biomarker.

Review of the TAAR1 Agonist Ulotaront: Part I—From Discovery to Clinic

AbstractIntroductionTrace amine-associated receptors (TAARs) are a family of G-protein-coupled receptors (GPCRs) first identified in 2001. TAAR1 has emerged as a promising therapeutic target due to its ability to modulate monoaminergic and glutamatergic neurotransmission. Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity that has received FDA Breakthrough Therapy Designation for the treatment of schizophrenia. Here we provide a brief review of the discovery of ulotaront and preclinical research suggesting efficacy in schizophrenia, leading to the first clinical trial of ulotaront resulting in FDA Breakthrough Therapy Designation.MethodsUlotaront was discovered through a target-agnostic approach optimized to identify drug candidates that demonstrate an antipsychotic-like profile in vivo but lack D2 and 5-HT2A receptor antagonism. Ulotaront was further characterized by in vitro pharmacology, electrophysiology, behavioral, and imaging studies.ResultsUlotaront demonstrated an antipsychotic-like profile in a high-throughput, phenotypic behavior screening platform, as well as efficacy in preclinical models of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition of acoustic startle, and subchronic PCP-induced deficits in social interaction. Although not fully elucidated, ulotaront’s mechanism of action appears to be mediated by agonism at trace amine-associated 1 (TAAR1) and 5-HT1A receptors. This was further corroborated with whole cell patch clamp recordings, demonstrating inhibition of dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) neuronal firing via 5-HT1A and TAAR1 receptors. Furthermore, ulotaront attenuated the ketamine-induced increase in striatal dopamine synthesis capacity, suggesting that it may modulate presynaptic dopamine dysfunction which is hypothesized to contribute to the pathophysiology of schizophrenia.ConclusionsPreclinical studies have identified ulotaront as a TAAR1 agonist with antipsychotic-like activity. Ulotaront’s unique receptor profile led to its designation as a member of the new “-taront” class of TAAR1 agonists, distinct in pharmacology from the D2/5-HT2A class of antipsychotics. A companion poster will summarize the efficacy and safety of ulotaront based on initial clinical trials in schizophrenia.FundingSunovion Pharmaceuticals, Inc., and Otsuka Pharmaceutical Development &amp; Commercialization, Inc.

Cognitive Behavioral Therapy Efficacy in Schizophrenia: A Literature Review

Schizophrenia is part of psychosis disorders and happens in one percent of the population. Schizophrenia can cause distress and functional impairment. Cognitive Behavioral Therapy (CBT), a form of psychological treatment in which there is an effort to change a patients mindset, is one of many choices for non-pharmacologic therapy in schizophrenia. This article aims to explain CBTs efficacy in schizophrenia. We concluded that CBT is an effective therapy for Schizophrenia because CBT can assist patients in gaining more understanding and reduce the intensity of any remaining positive symptoms. Therefore, CBT must be effectively used throughout psychiatric clinics and community-based mental health systems.

Partial Agonists and Dual Disorders: Focus on Dual Schizophrenia.

Dual disorder is a term applied to patients with an addictive disorder and other mental disorder. Epidemiological studies have established that dual disorders are an expectation rather than an exception. They are difficult to diagnose and treat and constitute a huge burden for both patients and their relatives and society. Current treatments are a combination of those needed to treat the addictive disorder with those focused on the co-occurring psychiatric disorder. Focusing specifically on schizophrenia, growing scientific evidence supports the existence of a shared vulnerability for substance use in these patients and those at risk. Various antipsychotics have been found to be useful in the treatment of psychotic symptoms and disorders; however, few effective treatments have been identified until now for substance use disorders in patients with dual schizophrenia. Partial agonism stands as a new pharmacological option available in recent years. Molecules with this kind of action may act as functional agonists or as antagonists, depending on the surrounding levels of the neurotransmitter. Studies have found their efficacy in schizophrenia, addiction, anxiety and depression. Certain partial agonist antipsychotics seem to have a role in the treatment of dual schizophrenia. That could be the case with cariprazine. Because of its higher affinity for dopaminergic D3 receptors compared to D2, a potential to prevent relapse to addiction, added to its antipsychotic efficacy, has been suggested. Here we briefly review current advances and future directions and introduce some personal insights into the role of partial agonists in co-occurring schizophrenia and substance use.

Association Between the COMT Val158Met Polymorphism and Antipsychotic Efficacy in Schizophrenia: An Updated Meta-Analysis.

Background Catechol-O-methyltransferase (COMT) contributes to the control of synaptic dopamine (DA) transmission by catalyzing DA degradation in the presynaptic space. The COMT Val158Met polymorphism (rs4680) substantially alters enzymatic activity and consequently synaptic DA concentration in the prefrontal cortex and hippocampus. The COMT genotype could, therefore, exert a major influence on antipsychotic treatment response as many of these agents also target dopaminergic transmission.Objective The present meta-analysis aimed to test a putative relationship between the COMT Val158Met polymorphism and antipsychotic response across different populations and antipsychotic types.Methods Searches of PubMed, Web of Science, EMBASE, OVID, Google Scholar, and Baidu Scholar databases yielded 30 peer-reviewed studies published before January 2020 with a pooled total of 6291 participants. The Lipták-Stouffer Z score method for meta-analysis was applied to combine data. The Z score was also calculated separately for Caucasian and Asian subgroups.Results Pooled results indicated a highly significant association between COMT Val158Met and antipsychotic response (Z = 6.709, P = 9.8 × 10-12). Further, this relationship remained significant in subgroup analyses of Caucasian patients (Z = 3.180, P = 7.4 × 10-4) and Asian patients (Z = 4.487, P = 3.6 × 10-6).Conclusion Pooled evidence supports the hypothesis that the COMT Val158Met polymorphism influences the antipsychotic response in Caucasian and Asian schizophrenia patient populations. Prediction of antipsychotic response by patient genotyping may warrant closer consideration in randomized clinical trials of efficacy.

Clozapine induces metformin-resistant prediabetes/diabetes that is associated with poor clinical efficacy in patients with early treatment-resistant schizophrenia

BackgroundTwo distinct subtypes of treatment-resistant schizophrenia (TRS) have been recently reported, including early-treatment resistance (E-TR) and late-treatment resistance (L-TR). This study was to assess clozapine-induced metformin-resistant prediabetes/diabetes and its correlation with clinical efficacy in schizophrenia E-TR subtype. MethodsThis prospective cohort study enrolled 230 patients with schizophrenia E-TR subtype and they were treated with adequate doses of clozapine for 16 weeks, during which patients with prediabetes/diabetes were assigned to receive add-on metformin. The main outcomes and measures included incidence of clozapine-induced prediabetes/diabetes and metformin-resistant prediabetes/diabetes, and the efficacy of clozapine as assessed by the Positive and Negative Syndrome Scale (PANSS) score. ResultsClozapine-induced prediabetes/diabetes occurred in 76.52% of patients (170 prediabetes and 6 diabetes), of which the blood sugar of 43 (24.43%) patients was controlled with metformin. Despite add-on metformin, 47.06% (74/170) of prediabetes patients progressed to diabetes. In total, the incidence of clozapine-induced metformin-resistant prediabetes/diabetes was 75.57% (133/176). On completion of 16-week clozapine treatment, 16.52% (38/230) patients showed clinical improvement with PANSS scores of ≥50% declining. Furthermore, clozapine-induced prediabetes/diabetes was significantly correlated with the poor clinical efficacy of clozapine for schizophrenia E-TR subtype. ConclusionsThe incidence of clozapine-induced metformin-resistant prediabetes/diabetes was considerably high in the schizophrenia E-TR subtype. Clozapine-induced metformin-resistant prediabetes/diabetes represents an independent risk factor that adversely affects the clinical efficacy of clozapine for the schizophrenia E-TR subtype. This study provided new evidence for re-evaluating the use of clozapine for TRS, especially E-TR subtype, and the use of metformin for the glycemic control of clozapine-induced prediabetes/diabetes.

Plasma Levels of Long-Acting Injectable Antipsychotics in Outpatient Care: A Retrospective Analysis.

PurposeAntipsychotic efficacy in schizophrenia depends on its availability in the body. Although therapeutic outcomes remain still far from satisfactory, therapeutic drug monitoring is not a common part of clinical practice during treatment with long-acting injectable antipsychotics (LAI AP). The real effectiveness of LAI AP is thus uncertain.Patients and MethodsWe made a retrospective evaluation of plasma levels of LAI AP. Collection of blood samples was performed just before the drug application and one week later. Forty patients with a stabilized clinical condition and steady-state plasma levels were included.ResultsIn the observed cohort of patients, flupentixol decanoate (n = 23) was the most often used drug, followed by fluphenazine decanoate (n = 7), haloperidol decanoate (n = 5), paliperidone palmitate (n = 3), and risperidone microspheres (n = 2). Just 5 of 40 patients were treated with a monotherapy. In the period before the application, 60% of the patients did not reach the therapeutic reference range (TRR) and 20% of the patients had an undetectable plasma level. At the time of collection of the second blood samples performed after 7 days, 24% of the patients were under the TRR.ConclusionWe have found a surprisingly high incidence of plasma levels under the TRR in patients treated with LAI AP. Notwithstanding individual variability in pharmacokinetics, it seems that LAI AP may be underdosed in usual clinical practice.

Clozapine Induces Metformin-Resistant Prediabetes/Diabetes that Is Associated with Poor Clinical Efficacy in Patients with Early Treatment-Resistant Schizophrenia

Background: Two distinct subtypes of treatment-resistant schizophrenia (TRS) have been recently reported, including early-treatment resistance (E-TR) as the dominant subtype and late-treatment resistance (L-TR). However, the response rate to clozapine, incidence of clozapine-induced prediabetes/diabetes, and effects of metformin at preventing clozapine-induced prediabetes/diabetes in patients with schizophrenia E-TR subtype need investigating. To assess clozapine-induced metformin-resistant prediabetes/diabetes and its correlation with clinical efficacy in schizophrenia E-TR subtype. Methods: This prospective cohort study enrolled 230 patients with schizophrenia E-TR subtype from Tianjin Kangtai Hospital between January 2015 and December 2020.The patients were treated with adequate doses of clozapine for 16 weeks, during which patients with prediabetes/diabetes were assigned to receive add-on metformin. Incidence of clozapine-induced prediabetes/diabetes and metformin-resistant prediabetes/diabetes and the efficacy of clozapine as assessed by the Positive and Negative Syndrome Scale (PANSS) score. Findings: Clozapine-induced prediabetes/diabetes occurred in 176 patients (170 prediabetes and 6 diabetes), with 76.52% incidence. The blood sugar of 43 (24.43%) patients was controlled with metformin. Despite add-on metformin, 47.06% (74/170) of patients with clozapine-induced prediabetes progressed to diabetes. In total, the incidence of clozapine-induced metformin-resistant prediabetes/diabetes was 75.57% (133/176). On completion of 16-week clozapine treatment, 16.52% (38/230) patients showed clinical improvement with PANSS scores of ≥50% declining. Furthermore, clozapine-induced prediabetes/diabetes was significantly correlated with the poor clinical efficacy of clozapine for schizophrenia E-TR subtype. In comparison with patients that did not have clozapine-induced prediabetes/diabetes, clinical efficacy was significantly lower in patients with clozapine-induced prediabetes/diabetes. Of note, the lowest clinical efficacy detected in patients with clozapine-induced diabetes [odds ratio (OR) of 0.18; 95% confidence interval (CI), 0.07–0.44]. Interpretation: The incidence of clozapine-induced metformin-resistant prediabetes/diabetes was considerably high in the schizophrenia E-TR subtype. Clozapine-induced metformin-resistant prediabetes/diabetes represents an independent risk factor that adversely affects the clinical efficacy of clozapine for the schizophrenia E-TR subtype. This study provided new evidence for re-evaluating the use of clozapine for TRS, especially E-TR subtype, and the use of metformin for the glycemic control of clozapine-induced prediabetes/diabetes. Funding: This study was supported by the National Natural Science Foundation of China (81871052 and 81571319). Declaration of Interests: All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and there is no conflict of interest to disclose. Ethics Approval Statement: The study protocol was reviewed and approved by the Ethic Committee of Tianjin Kangtai Hospital (Tianjin, China).

A Potential Autophagy-Related Competing Endogenous RNA Network and Corresponding Diagnostic Efficacy in Schizophrenia.

Competing endogenous RNA (ceRNA) and autophagy were related to neurological diseases. But the relationship among ceRNA, autophagy and Schizophrenia (SZ) was not clear. In this study, we obtained gene expression profile of SZ patients (GSE38484, GSE54578, and GSE16930) from Gene Expression Omnibus (GEO) database. Then we screened the autophagy-related differentially expressed lncRNA, miRNA, and mRNA (DElncRNA, DEmiRNA, and DEmRNA) combined with Gene database from The National Center for Biotechnology Information (NCBI). In addition, we performed enrichment analysis. The result showed that biological processes (BPs) mainly were associated with cellular responses to oxygen concentration. The enriched pathways mainly included ErbB, AMPK, mTOR signaling pathway and cell cycle. Furthermore, we constructed autophagy-related ceRNA network based on the TargetScan database. Moreover, we explored the diagnostic efficiency of lncRNA, miRNA and mRNA in ceRNA, through gene set variation analysis (GSVA). The result showed that the diagnostic efficiency was robust, especially miRNA (AUC = 0.884). The miRNA included hsa-miR-423-5p, hsa-miR-4532, hsa-miR-593-3p, hsa-miR-618, hsa-miR-4723-3p, hsa-miR-4640-3p, hsa-miR-296-5p, and hsa-miR-3943. The result of this study may be helpful for deepening the pathophysiology of SZ. In addition, our finding may provide a guideline for the clinical diagnosis of SZ.

Cariprazine modulates sleep architecture in rats.

Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist compound recently introduced to treat schizophrenia and bipolar disorder. Although cariprazine is clinically classified as a low-somnolence drug, to date no detailed polysomnographic study is available on its effect on sleep. This study examined the acute systemic effects of cariprazine on the rat sleep architecture and electroencephalography spectral power. Sprague Dawley rats were recorded during their normal sleep period for four hours, and their sleep stages were classified. Cariprazine (0.3 mg/kg i.p.) reduced the time spent in rapid eye movement (REM) sleep and increased REM latency. This dose of cariprazine decreased the gamma (40-80 Hz) band frequency oscillations and increased the theta (4-9 Hz) and alpha (9-15 Hz) frequencies during the wake periods but not during slow-wave sleep. The 0.03 mg/kg dose of cariprazine only increased the alpha power during the wake periods, while the 0.003 mg/kg dose was without any effect. Taken together, the present results suggest that the REM-suppressing effect of cariprazine may be related to its effectiveness in improving depressive symptoms, as various drugs with similar REM-reducing properties effectively treat the depressive state, whereas the gamma power-reducing effect of cariprazine may be indicative of its efficacy in schizophrenia or mania, as similar effects have been observed with other D2 and 5-HT2 receptor antagonist drugs. These data contribute to our understanding of the complex mechanism of action that may stand behind the clinical efficacy of cariprazine.

The Gut Microbiome and Schizophrenia: The Current State of the Field and Clinical Applications.

Schizophrenia is a debilitating psychiatric disorder, leading to both physical and social morbidity. Despite its importance, the etiology of schizophrenia remains poorly understood. Furthermore, its mainstream treatments fail to address all aspects of the disorder and are associated with significant side-effects. Recently, there has been growing interest in the relationship between the gut microbiome and mental health, including in schizophrenia. In this article, we review the existing evidence implicating dysbiosis in schizophrenia and discuss how the presumed dysbiosis could fit within known hypotheses of its pathogenesis, focusing on inflammation, tryptophan metabolites, and BDNF levels. We also evaluate the clinical potential of manipulating the gut microbiome with probiotics and prebiotics as adjunctive treatments in schizophrenia, based on existing clinical and pre-clinical studies. Overall, the current data showing microbiome alterations in schizophrenia are highly discrepant and insufficient to conclude whether microbiome changes are associated with increased risk of the disorder, or are simply the result of external factors or treatment. Despite some encouraging results of pro/prebiotic supplementation, there is also inconclusive evidence for their efficacy in schizophrenia. Thus, further research and more clinical trials are needed to test the validity of manipulating the gut microbiome to improve the treatment of this disorder.

Discovery of aryl-piperidine derivatives as potential antipsychotic agents using molecular hybridization strategy

Schizophrenia is a chronic, disabling mental disorder that affects about one percent of world’s population. Drugs acting on multiple targets have been demonstrated to provide superior efficacy in schizophrenia than agents acting on single target. In this study, based on FW01, a selective potent 5-HT1A receptor agonist discovered via dynamic pharmacophore-based virtual screening, molecular hybridization strategy was employed to optimize its in vitro activity over D2 and 5-HT2A receptors. The optimized compound 9f was found to show dual potent D2 and 5-HT2A receptors antagonistic activity. In addition, compound 9f showed good in vivo metabolic stability with t1/2 of 2 h in ICR mice and good capability to penetrate the blood-brain barrier with Kp value of 4.03. These results demonstrated that the dual D2 and 5-HT1A receptor antagonist 9f could serve as a promising lead compound to discover potent antipsychotic agents.

Evaluation of Family Psychoeducation Efficacy in Schizophrenia: A Way to Do it More Simply for Routinely Monitoring

Background: Despite many control trials and meta-analyses proving the positive effect and the economic interest of family psychoeducation in schizophrenia, this practice remains marginal. There may be several reasons behind the clinicians' lack of motivation to implement such programs. Simple and common evaluation tools to compare program efficacy, improve the programs' content, and guaranty the fidelity of the delivery over time by routinely monitoring the efficacy level would be a way (among many) to stimulate clinical interest in psychoeducation. Two common self-administered questionnaires used in combination, the Center for Epidemiologic Studies Depression (CESd) to assess caregivers' depressive symptoms and 20-item Life Skill Profile (LSP-20) to assess patient functioning, would be good candidates for that. Methods: Family caregivers (n = 78) of seven consecutive groups participating in a program named Profamille filled in these questionnaires before and at the end of the program and 1 year later. More than the half of the caregivers have an initial depressive score indicating a higher risk of cardiovascular mortality/morbidity. Results: Both CESd and LSP20 significantly changed 1 year later. The size effect for CESd was 1.4 and for LSP20 was 0.6. These changes were linked to a statistically significant reduction in the number of hospitalized days for the patients (by a factor 3) and a number of days lost at work for the caregivers (by a factor 4). Conclusions: These two questionnaires are therefore useful to compare different programs, obtain preliminary evidence from exploratory trials, like for the Profamille V3 program, and help ensure the fidelity of program delivery.

A randomized, placebo-controlled, phase 1 study to evaluate the effects of TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects

RationalePhosphodiesterase 10A inhibitor TAK-063 has shown effects that suggest efficacy in schizophrenia treatment.ObjectiveThis randomized, double-blind, placebo-controlled, incomplete-crossover study investigated effects of single oral administration of TAK-063 on ketamine-induced changes in blood oxygen level-dependent (BOLD) signal in healthy males.MethodsHealthy men aged 18 to 45 years with normal magnetic resonance imaging (MRI) scans and electroencephalogram measurements at screening were eligible. Each subject was randomized to one of nine treatment schedules: all subjects received placebo and two of three doses of TAK-063 followed by ketamine. The primary endpoint was ketamine-induced brain activity in select regions of the brain during resting state. Secondary endpoints included pharmacokinetic parameters of TAK-063, proportion of subjects with treatment-emergent adverse events (AEs), and percentage of subjects meeting criteria for abnormal safety laboratory tests and vital sign measurements.ResultsThe study comprised 27 subjects. Prior to ketamine infusion, TAK-063 exerted region-specific effects on resting state functional MRI (fMRI) BOLD signal. After ketamine administration, TAK-063 reduced the Cohen’s effect size for resting-state fMRI BOLD signal in key brain regions examined, and exerted similar effects on BOLD signal during the working memory task across all doses. TAK-063 was safe and well tolerated.ConclusionsOur results are consistent with non-clinical studies of ketamine and TAK-063 and clinical studies of ketamine and risperidone. It is unknown whether these data are predictive of potential antipsychotic efficacy, and further analyses are required.

Discovery and Development of Non-Dopaminergic Agents for the Treatment of Schizophrenia: Overview of the Preclinical and Early Clinical Studies.

Schizophrenia is a chronic psychiatric disorder that affects about 1 in 100 people around the world and results in persistent emotional and cognitive impairments. Untreated schizophrenia leads to deterioration in quality of life and premature death. Although the clinical efficacy of dopamine D2 receptor antagonists against positive symptoms of schizophrenia supports the dopamine hypothesis of the disease, the resistance of negative and cognitive symptoms to these drugs implicates other systems in its pathophysiology. Many studies suggest that abnormalities in glutamate homeostasis may contribute to all three groups of schizophrenia symptoms. Scientific considerations also include disorders of gamma-aminobutyric acid-ergic and serotonergic neurotransmissions as well as the role of the immune system. The purpose of this review is to update the most recent reports on the discovery and development of non-dopaminergic agents that may reduce positive, negative, and cognitive symptoms of schizophrenia, and may be alternative to currently used antipsychotics. This review collects the chemical structures of representative compounds targeting metabotropic glutamate receptor, gamma-aminobutyric acid type A receptor, alpha 7 nicotinic acetylcholine receptor, glycine transporter type 1 and glycogen synthase kinase 3 as well as results of in vitro and in vivo studies indicating their efficacy in schizophrenia. Results of clinical trials assessing the safety and efficacy of the tested compounds have also been presented. Finally, attention has been paid to multifunctional ligands with serotonin receptor affinity or phosphodiesterase inhibitory activity as novel strategies in the search for dedicated medicines for patients with schizophrenia.

The Role of Dopamine D3 Receptor Partial Agonism in Cariprazine-Induced Neurotransmitter Efflux in Rat Hippocampus and Nucleus Accumbens

Cariprazine is an approved antipsychotic and antidepressant which is a dopamine (DA) D3-preferring D3/D2 receptor partial agonist, serotonin (5-HT) 5-HT1A receptor partial agonist, and 5-HT2B and 5-HT2A receptor antagonist, a profile unique for atypical antipsychotic drugs. The purpose of this study was to clarify the effects of cariprazine and selective D3 receptor ligands on neurotransmitter efflux in the rat nucleus accumbens (NAC) and ventral hippocampus (HIP), brain regions important for reality testing, rewarded behavior, and cognition. In vivo microdialysis was performed in awake, freely moving rats after administration of cariprazine; (+)-PD-128907 [(4aR,10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], a D3 receptor-preferring agonist; and SB-277011A [trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide hydrochloride], a selective D3 receptor antagonist, alone or combined, and extracellular levels of multiple neurotransmitters and metabolites were measured in the NAC and HIP by ultraperformance liquid chromatography with tandem mass spectrometry. Cariprazine increased DA, norepinephrine (NE), and 5-HT efflux in both regions, whereas it increased glycine (Gly) and glutamate efflux only in the NAC and efflux of DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) only in the HIP. Similarly, SB-277011A increased DA, NE, DOPAC, and HVA, but not 5-HT, efflux in the NAC and HIP, and acetylcholine efflux in the HIP. Most of these effects of cariprazine and SB-277011A were fully or partially attenuated by the D3 receptor agonist (+)-PD-128907, suggesting these effects of cariprazine are related to its D3 receptor partial agonism, and that this mechanism, leading to diminished stimulation of D3 receptors, may contribute to its efficacy in both schizophrenia and bipolar disorder. The possible role of Gly in the action of cariprazine is discussed. SIGNIFICANCE STATEMENT: The novel atypical antipsychotic drug cariprazine increased nucleus accumbens and hippocampal neurotransmitter efflux, similar to the actions of the D3 receptor antagonist SB-277011A [trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide hydrochloride]. The D3 receptor-preferring agonist (+)-PD-128907 [(4aR, 10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], diminished the effects of both compounds on neurotransmitter efflux in both regions. These results suggested D3 receptor partial agonist activity of cariprazine, producing functional antagonism, may contribute to its efficacy in schizophrenia and bipolar disorder.