Pharmacotherapy Of Schizophrenia Research Articles

Current advances in pharmacotherapy for schizophrenia

Background: Schizophrenia is a complex psychiatric disorder characterized by hallucinations, delusions, and cognitive deficits, often leading to functional decline. Pharmacotherapy has long played a central role in schizophrenia management with our evolving understanding shaping the treatment.Current Concepts: Antipsychotic agents are the mainstay of the pharmacological treatment of schizophrenia. Although second-generation antipsychotics (atypical) reduce extrapyramidal side effects, they give rise to metabolic concerns. Personalized treatment, guided by the response and side effects of the patient, determines suitable medications and dosages. Long-acting injectable antipsychotics have enhanced medication adherence, and the consideration of clozapine is warranted for treatment-resistant cases. In addition, potential combination therapies with other psychotropic medications could be explored to address specific symptoms or comorbidities.Discussion and Conclusion: Antipsychotics are pivotal in acute intervention and schizophrenia treatment maintenance. Individualized plans, accounting for drug response, side effects, and adherence, are essential when selecting specific antipsychotic agents. Long-acting injectables and clozapine with combination therapies for treatment resistance offer effective and tolerable management. Ongoing studies and novel antipsychotic development hold promise for improving schizophrenia treatment and patient life quality.

The kynurenine pathway in treatment-resistant schizophrenia at the crossroads between pathophysiology and pharmacotherapy

Two cardinal elements in the complex and multifaceted pathophysiology of schizophrenia (SCZ) are neuroinflammation and dysregulation of glutamatergic neurotransmission, with the latter being especially involved in treatment-resistant schizophrenia (TRS). Interestingly, the Kynurenine (KYN) pathway (KP) is at the crossroad between them, constituting a potential causal link and a therapeutic target. Although there is preclinical and clinical evidence indicating a dysregulation of KP associated with the clinical phenotype of SCZ, clinical studies investigating the possible relationship between changes in biomarkers of the KP and response to pharmacotherapy are still limited. Therefore, we have studied possible differences in the circulating levels of biomarkers of the metabolism of tryptophan along the KP in 43 responders to first-line treatments (FLR) and 32 TRS patients treated with clozapine, and their possible associations with psychopathology in the two subgroups. Plasma levels of KYN were significantly higher in TRS patients than in FLR patients, indicating a greater activation of KP. Furthermore, the levels of quinolinic (NMDA receptor agonist) and kynurenic acid (NMDA negative allosteric modulator) showed a negative and a positive correlation with several dimensions and the overall symptomatology in the whole sample and in FLR, but not in TRS, suggesting a putative modulating effect of clozapine elicited through the NMDA receptors. Despite the cross-sectional design of the study that prevents us from demonstrating causation, these findings show a significant relationship among circulating KP biomarkers, psychopathology, and response to pharmacotherapy in SCZ. Therefore, plasma KP biomarkers should be further investigated for developing personalized medicine approaches in SCZ.

S-MARSA: A novel assay for quantifying biomarkers in Parkinson’s disease and schizophrenia pharmacotherapy monitoring

S-MARSA: A novel assay for quantifying biomarkers in Parkinson’s disease and schizophrenia pharmacotherapy monitoring

THE EFFECT OF HYDROXYZINE ON AKATHISIA AND OTHER NEUROLOGICAL SIDE EFFECTS OF ANTIPSYCHOTICS IN THE TREATMENT OF PARANOID SCHIZOPHRENIA

Side effects of antipsychotic drugs are the most urgent problem in the pharmacotherapy of schizophrenia. Medications used to correct side effects of various pharmacological groups, including correctors of cholinolytics, tranquilizers-benzodiazepines, have severe side effects, which justifies the search for no less effective and at the same time safer alternatives. The aim of the study was to evaluate the corrective effect of Hydroxyzine on akathisia and other neurological disorders that develop as side effects of antipsychotic therapy. Materials and methods. The study analyzed the severity of side effects in 43 patients suffering from paranoid schizophrenia receiving monotherapy with antipsychotics, before their administration, on the 7th and 21st day after the start of taking Hydroxyzine. The severity of side effects was assessed by the ESRS scales and the scale of evaluating drug-induced akathisia. Results. A significant corrective effect of Hydroxyzine on akathisia and other neurological side effects of antipsychotics was shown on the 7th day of Hydroxyzine therapy, the severity of Parkinsonism, dyskinesia, akathisia and tremor significantly decreased. Patients noted an improvement in general well-being, a decrease in the level of anxiety associated with the disease, staying in a psychiatric hospital, side effects of psychopharmacotherapy. Hydroxyzine significantly reduced the severity of akathisia, assessed both objectively and subjectively by patients. There was a decrease in the need of patients to move, to change the position of the body, improved sleep, reduced emotional stress. In general, Hydroxyzine had a positive effect in the form of a decrease in pathological motor activity and a decrease in the severity of emotional manifestations associated with the side effect of antipsychotics, which persisted on the 21st day of Hydroxyzine therapy in the absence of clinically significant undesirable side effects. Conclusions. The results of the study show the effectiveness of Hydroxyzine for correcting neurological side effects of antipsychotics along with good tolerability and substantiate the possibility of expanding its use in the complex therapy of paranoid schizophrenia.

Inhibitors of Endocannabinoids' Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice.

Treating schizophrenia with the available pharmacotherapy is difficult. One possible strategy is focused on the modulation of the function of the endocannabinoid system (ECS). The ECS is comprised of cannabinoid (CB) receptors, endocannabinoids and enzymes responsible for the metabolism of endocannabinoids (fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL)). Here, the aim of the experiments was to evaluate the impact of inhibitors of endocannabinoids' enzymatic degradation in the brain: KML-29 (MAGL inhibitor), JZL-195 (MAGL/FAAH inhibitor) and PF-3845 (FAAH inhibitor), on the memory disturbances typical for schizophrenia in an acute N-methyl-D-aspartate (NMDA) receptor hypofunction animal model of schizophrenia (i.e., injection of MK-801, an NMDA receptor antagonist). The memory-like responses were assessed in the passive avoidance (PA) test. A single administration of KML-29 or PF-3845 had a positive effect on the memory processes, but an acute administration of JZL-195 impaired cognition in mice in the PA test. Additionally, the combined administration of a PA-ineffective dose of KML-29 (5 mg/kg) or PF-3845 (3 mg/kg) attenuated the MK-801-induced cognitive impairment (0.6 mg/kg). Our results suggest that the indirect regulation of endocannabinoids' concentration in the brain through the use of selected inhibitors may positively affect memory disorders, and thus increase the effectiveness of modern pharmacotherapy of schizophrenia.

Dopaminergic and glutamatergic models of psychosis show differential sensitivity to aripiprazole and a novel experimental compound modulating D2/5-HT receptor activity

Dopamine type 2 receptors (D2Rs) constitute the main molecular target in the pharmacotherapy of schizophrenia. However, the second and third generation of antipsychotics comprises multi-target ligands, also binding serotonin type 3 receptors (5-HT3Rs) and other receptor classes as well. Here, we examined two experimental compounds (marked compound K1697 and K1700) from the group of 1,4-di-substituted aromatic piperazines, previously described in the study of Juza et al., 2021, and compared them with the chosen reference antipsychotic, aripiprazole. Their efficacy against schizophrenia-like behavior was tested in two different models of psychosis in the rat, induced by acute administration of either amphetamine (1.5 mg/kg) or dizocilpine (0.1 mg/kg), reflecting the dopaminergic and glutamatergic hypotheses of schizophrenia. The two models exhibited broadly similar behavioral manifestations: hyperlocomotion, disrupted social behavior and impaired prepulse inhibition of the startle response. However, they differed in their treatment responses as hyperlocomotion and prepulse inhibition deficit in the dizocilpine model were resistant to antipsychotic treatment, unlike the amphetamine model. One of the experimental compounds, K1700, ameliorated all the observed schizophrenia-like behaviors in the amphetamine model with an efficacy comparable to or greater than aripiprazole. Whereas social impairments caused by dizocilpine were strongly suppressed by aripiprazole, K1700 was less efficient. Taken together, K1700 showed antipsychotic properties comparable to those of aripiprazole, although the efficacy of the two drugs differed in specific domains of behavior and was also model-dependent. Our present results highlight the differences in these two schizophrenia models and their responsiveness to pharmacotherapy, and confirm compound K1700 as a promising drug candidate.

Prediction of Schizophrenia Risk and the Identification of a Potential Preventative Pharmacotherapy for Schizophrenia in the Context of the 22q11.2 Deletion Syndrome

Prediction of Schizophrenia Risk and the Identification of a Potential Preventative Pharmacotherapy for Schizophrenia in the Context of the 22q11.2 Deletion Syndrome

Brexpiprazole augmentation in a clozapine-resistant young schizophrenic patient: a successful case report.

IntroductionAlthough clozapine is considered the most effective drug for Treatment Resistant Schizophrenia (TRS), only 40% of patients treated will meet clinical response. Literature reviews and meta-analytic data offer no definite conclusions about the most effective clozapine augmentation strategies. Nevertheless, it has been suggested that the lack of evidence should not discourage clinicians from trying out new strategies in individual patients. Brexpiprazole is a novel 5-HT and DA modulator antipsychotic that exhibits partial agonism to D2/D3 and 5HT1A receptors, antagonism to 5HT2A and α-1B/2C receptors and represents a promising new drug in the pharmacotherapy of schizophrenia for both acute and maintenance treatment. In current literature there is no evidence of experiences in brexpiprazole augmentation for clozapine resistant patients.ObjectivesThis case report describes a successful clinical experience of brexpiprazole augmentation in a complicated case of clozapine resistant paranoid schizophrenia with consistent negative symptoms, the clinical evolution and metabolic improvement consequent to this therapy combination.MethodsIn a 27 male TRS patient, sequentially treated with adequate doses of risperidone, cariprazine, aripiprazole and olanzapine monotherapy, prescribed for adequate time, clozapine treatment was started, with a gradual titration from 25 to 300 mg/day, without significant clinical response on both positive and negative symptoms. Successively was introduced fluoxetine, from 10 to 30 mg/day, with no relevant clinical improvement. After 2 months of pharmacological stabilization with clozapine and fluoxetine described dosages, brexpiprazole was introduced starting from 1 mg/day and rapidly increasing till 4 mg/day.ResultsAfter 6 weeks of treatment, PANSS positive and negative subscales showed a significant decrease, respectively from 28 to 17 and from 42 to 20, while general psychopathology subscale decreased from 66 to 34. Negative sub-items with major improvement were those regarding blunted affect, emotional withdrawal, poor rapport, and passive/apathetic social withdrawal. Brexpiprazole augmentation also allowed to slowly decrease (in 6 months) clozapine dose till actual 150 mg/day, with a significant improvement in general tolerability and a slow decline in metabolic parameters (BMI from 36.5 to 30.3; fasting glucose from 112 to 92 mg/dL; total cholesterol from 248 to 182 mg/dL; total triglycerides from 392 to 198 mg/dL).ConclusionsIn this case report brexpiprazole augmentation in a clozapine resistant young schizophrenic patient was an effective strategy with significant symptoms improvement, in particular in PANSS general psychopathology and PANSS negative subscales. The consequent clozapine dose reduction contribute to the slow decrease in metabolic parameters considered.Disclosure of InterestNone Declared

Epigenetic Targets in Schizophrenia Development and Therapy.

Schizophrenia is regarded as a neurodevelopmental disorder with its course progressing throughout life. However, the aetiology and development of schizophrenia are still under investigation. Several data suggest that the dysfunction of epigenetic mechanisms is known to be involved in the pathomechanism of this mental disorder. The present article revised the epigenetic background of schizophrenia based on the data available in online databases (PubMed, Scopus). This paper focused on the role of epigenetic regulation, such as DNA methylation, histone modifications, and interference of non-coding RNAs, in schizophrenia development. The article also reviewed the available data related to epigenetic regulation that may modify the severity of the disease as a possible target for schizophrenia pharmacotherapy. Moreover, the effects of antipsychotics on epigenetic malfunction in schizophrenia are discussed based on preclinical and clinical results. The obtainable data suggest alterations of epigenetic regulation in schizophrenia. Moreover, they also showed the important role of epigenetic modifications in antipsychotic action. There is a need for more data to establish the role of epigenetic mechanisms in schizophrenia therapy. It would be of special interest to find and develop new targets for schizophrenia therapy because patients with schizophrenia could show little or no response to current pharmacotherapy and have treatment-resistant schizophrenia.

Usefulness of Low-Dose Olanzapine for Initial and Maintenance Treatments of Very-Late-Onset Schizophrenia-Like Psychosis: A Case Report

In pharmacotherapy for schizophrenia, it is recommended that antipsychotic medications should not be discontinued, and their dosage should not be reduced during the stabilization and maintenance phases. Nevertheless, these drugs also have side effects that can increase extrapyramidal symptoms and mortality in the elderly population. It is yet to be determined whether antipsychotics should be reduced or discontinued in patients with very-late-onset schizophrenia-like psychosis (VLOSLP) during the stabilization and maintenance stages. Therefore, we describe the case of an elderly woman for whom low-dose olanzapine was useful throughout the initial, stabilization, and maintenance phases of VLOSLP. The patient was a 70-year-old woman who had experienced persistent hallucinations and delusions for 3 years. Two years after her diagnosis, except for relapse due to self-discontinuation, she remained in remission of her psychotic symptoms by continuing olanzapine treatment (2.5 mg/day). The standard effective dose of olanzapine was 10 mg/day, and she was able to respond to therapy with a low dose of olanzapine in the initial and subsequent phases of stabilization and maintenance. It is suggested that the discontinuation of antipsychotics should be avoided to avoid recurrence, even if the dose is lower than the standard amount during the stabilization and maintenance phases. Additionally, if the patient progresses to dementia, the treatment approach may vary, and it is imperative to monitor cognitive decline and self-discontinuation of oral medications during the follow-up of VLOSLP.

Development of sensitive magnetic nanoparticle assisted rapid sandwich assay(s-MARSA) to monitor Parkinson's disease and Schizophrenia pharmacotherapy

Parkinson's disease and Schizophrenia fall under low dopamine neurodegenerative and high dopamine psychiatric disorders respectively. Pharmacological interventions to correct mid-brain dopamine concentrations sometimes overshoots the physiological dopamine levels leading to psychosis in Parkinson's disease patients and, extra-pyramidal symptoms in schizophrenia patients. Currently no validated method is available to monitor side effects in such patients, Apolipoprotein E is one of the CSF biomarkers identified in the recent past that shows an inverse relation to mid-brain dopamine concentration. In this study, we have developed s-MARSA for the detection of Apolipoprotein E from ultra-small volume (2 μL) of CSF. s-MARSA exhibits a broad detection range (5 fg mL−1 to 4 μg mL−1) with a better detection limit and could be performed within an hour utilizing only a small volume of CSF sample. The values measured by s-MARSA strongly correlates with the values measured by ELISA. Our method has advantages over ELISA in having a lower detection limit, a broader linear detection range, shorter analysis time, and requiring a low volume of CSF samples. The developed s-MARSA method holds promise for the detection of Apolipoprotein E with clinical utility for monitoring pharmacotherapy of Parkinson's and Schizophrenia patients.

Association of the Level of Serum Prolactin with Polymorphic Variants of the GRIN2A, GPM3, and GPM7 Genes in Patients with Schizophrenia Taking Conventional and Atypical Antipsychotics

The dopamine, serotonin and glutamate systems are jointly involved in the pathogenesis and pharmacotherapy of schizophrenia. We formulated a hypothesis that polymorphic variants of the GRIN2A, GRM3, and GRM7 genes may be associated with the development of hyperprolactinemia in patients with schizophrenia taking conventional and atypical antipsychotics as basic treatment. 432 Caucasian patients diagnosed with schizophrenia were examined. DNA was isolated from peripheral blood leukocytes using the standard phenol-chloroform method. For pilot genotyping, 12 SNPs in the GRIN2A gene, 4 SNPs in the GRM3 gene, and 6 SNPs in the GRM7 gene were selected. Allelic variants of the studied polymorphisms were determined by real-time PCR. The level of prolactin was determined by enzyme immunoassay. Among persons taking conventional antipsychotics, there were statistically significant differences in the distribution of genotype and allele frequencies in groups of patients with normal and elevated prolactin levels for the GRIN2A rs9989388 and GRIN2A rs7192557 polymorphic variants, as well as differences in serum prolactin levels depending on the genotype of the GRM7 rs3749380 polymorphic variant. Among persons taking atypical antipsychotics, statistically significant differences were found in the frequencies of genotypes and alleles of the GRM3 rs6465084 polymorphic variant. An association of polymorphic variants of the GRIN2A, GRM3, and GRM7 genes with the development of hyperprolactinemia in patients with schizophrenia taking conventional and atypical antipsychotics has been established for the first time. The identified associations of polymorphic variants of the GRIN2A, GRM3 and GRM7 genes with the development of hyperprolactinemia in patients with schizophrenia taking conventional and atypical antipsychotics have been established for the first time. These associations not only confirm the close connection of the dopaminergic, serotonergic, and glutamatergic systems in the development of schizophrenia, but also demonstrate the potential of taking into account the genetic component during therapy.

The characteristics of discharge prescriptions including pro re nata psychotropic medications for patients with schizophrenia and major depressive disorder from the survey of the “Effectiveness of guidelines for dissemination and education in psychiatric treatment (EGUIDE)” project

BackgroundSeveral guidelines recommend monotherapy in pharmacotherapy for schizophrenia and major depressive disorder. The content of regular prescriptions has been reported in several studies, but not enough research has been conducted on the content of pharmacotherapy, including pro re nata (PRN) medications. The purpose of this study was to evaluate the content of pharmacotherapy, including PRN medications, and to clarify the relationship with regular prescriptions.MethodsWe used data from the “Effectiveness of Guidelines for Dissemination And Education in psychiatric treatment” (EGUIDE) project to investigate the presence or absence of PRN psychotropic medications at discharge for each drug category. We compared the PRN psychotropic prescription ratio at discharge by diagnosis for each drug category. The antipsychotic monotherapy ratio and no prescription ratio of other psychotropics for schizophrenia at discharge and the antidepressant monotherapy ratio and no prescription ratio of other psychotropics for major depressive disorder at discharge were calculated for each regular prescription, including PRN psychotropic medications, as quality indicators (QIs). Spearman's rank correlation test was performed for QI values of regular prescriptions and the QI ratio between regular prescriptions and prescriptions including PRN medications for each diagnosis.ResultsThe PRN psychotropic prescription ratio at discharge was 28.7% for schizophrenia and 30.4% for major depressive disorder, with no significant differences by diagnosis. The prescription ratios of PRN antipsychotic medications and PRN antiparkinsonian medications were significantly higher for schizophrenia. The prescription ratios of PRN anxiolytic and hypnotic and PRN antidepressant medications were significantly higher for patients with major depressive disorder. For both schizophrenia and major depressive disorder, the QI was lower for discharge prescriptions, including PRN medications, than for regular prescriptions. QI values for regular prescriptions and the QI ratio were positively correlated.ConclusionsConsidering PRN psychotropic medications, the monotherapy ratio and no prescription ratio of other psychotropics at discharge decreased in pharmacotherapy for schizophrenia and major depressive disorder. A higher ratio of monotherapy and no prescription of other psychotropics on regular prescriptions may result in less concomitant use of PRN psychotropic medications. Further studies are needed to optimize PRN psychotropic prescriptions.

Efficacy and Safety of Second-generation Antipsychotics in Schizophrenia Pharmacotherapy: A Comparative Narrative Review

Antipsychotic medications are essential in schizophrenia pharmacotherapy, with notable differences in efficacy and safety. This review aims to discuss and compare the differences in efficacy and safety among various second-generation antipsychotic drugs (SGAs). A narrative review was conducted involving the English-based published literature in three scientific databases between 2000 and January 2021: Google Scholar, Scopus, and PubMed. Clozapine is widely considered an effective therapy option in cases of resistance. Maintenance of schizophrenia treatment with paliperidone palmitate was effective and resulted in a longer duration between relapses. The risk of weight gain and diabetes mellitus was increased significantly with clozapine and olanzapine. Risperidone caused neuroleptic malignant syndrome (NMS) and significantly elevated prolactin levels. The extent of safety concerns reported varied by study design. While there were minor differences in the dose-dependent role of SGAs in acute episode treatment, there were significant differences in the type and intensity of side effects, and hence adherence determinants.

Development of individual fitness score for conformity of prescriptions to the "Guidelines For Pharmacological Therapy of Schizophrenia".

The Guidelines for the Pharmacotherapy of Schizophrenia were established to improve the quality of medical care, and the EGUIDE project was conducted to train clinicians on guideline usage. A quality indicator (QI) was established to measure the prevalence of the guidelines, and a survey was conducted, which revealed a gap between the guidelines and actual clinical practice (evidence-practice-gap). The purpose of this study was to develop an individual fitness score (IFS) formula that expresses the degree to which prescribers adhere to the Guidelines for Pharmacological Therapy of Schizophrenia in a simple manner, and to determine the validity of this formula from a survey of the prescriptions of the EGUIDE project participants'. To establish appropriate scores, members discussed the proposed formula and then voted on them. The IFS formula developed was set up so that antipsychotic monotherapy would be given 100 points, with points deducted if concomitant or adjunctive antipsychotic medications were used, and a minimum score of 0. To validate this formula, prescriptions of hospitalized schizophrenic patients at admission and at discharge were scored and compared. IFS points vary and ranged from 0 to100. The average pre-admission score for all subjects was 45.6, and the average score at discharge was 54, those were significantly higher during discharge. We developed an IFS formula, a tool to easily visualize the degree to which current prescriptions conform to the guidelines for the pharmacological treatment of schizophrenia.

Influence of NOS1AP Risk Variants on the Corrected QT (QTc) Interval in the Pharmacotherapy of Schizophrenia.

The variants of the gene for nitric oxide synthase 1 adaptor protein (NOS1AP) are associated with schizophrenia and cardiovascular deficits involving corrected QT (QTc) interval prolongation. Here, we investigated a possible pharmacogenetic effect of antipsychotic treatment on QTc length in interaction with two NOS1AP variants (rs12143842 and rs10494366) whose minor alleles are associated with increased QTc interval length. We conducted a retrospective analysis of electrocardiographic (ECG) and genotype data of 239 patients diagnosed with schizophrenia. We converted antipsychotics dosage to chlorpromazine equivalents and defined daily doses. We analysed the effects of the minor (i. e. rs12143842-CT/TT and rs10494366-GT/GG) and major (i. e. rs12143842-CC and rs10494366-TT) allele genotypes to QTc interval for female and male participants separately. As expected, rs12143842 and rs10494366 exhibit strong linkage disequilibrium. Both polymorphisms had no direct effect on antipsychotic use or QTc interval. However, there was a continuous increase in QTc interval with increasing antipsychotic dosage in males. For both variants, positive correlation of QTc length with antipsychotic dosage was found in homozygous male carriers of the major alleles (i. e. rs12143842-CC and rs10494366-TT), but not in minor allele carriers. There was no significant interaction between antipsychotic dosage and QTc interval for either genotype in female patients. In this study, a significant interaction was found between both NOS1AP variants, rs12143842 and rs10494366, and antipsychotic treatment on the QTc interval in a sex-dependent manner. Our findings might be relevant for adequate antipsychotic treatment in rs12143842 and rs10494366 major allele carriers.

Multitarget Derivatives of D2AAK1 as Potential Antipsychotics: The Effect of Substitution in the Indole Moiety.

Schizophrenia is a complex disease which is best treated with multitarget drugs, such as atypical antipsychotics. Previously, using structure-based virtual screening, we found a virtual hit, D2AAK1, with nanomolar affinity for dopamine and serotonin receptors important in schizophrenia pharmacotherapy. As a part of an optimization campaign of D2AAK1, we obtained 17 derivatives that also display a multitarget profile. Selected compounds were tested against off-targets in schizophrenia, i. e., histamine H1 receptor and muscarinic M1 receptor, and these did not display considerable affinity for these receptors. The two most promising compounds were subjected to behavioral studies. These compounds decreased amphetamine-induced hyperactivity in mice which indicates their antipsychotic potential. The compounds did not interfere with the memory consolidation in mice, as determined in the passive avoidance test. The favorable pharmacological profile of these compounds was rationalized using molecular modeling.

P607. Effect of Antipsychotics in the Angiotensin Converting Enzyme-1 (ACE) Activity in First-Episode Psychosis Patients and Animal Models for Schizophrenia

Angiotensin-I converting enzyme (ACE) is a key component of renin-angiotensin system (RAS), and its association with cognitive impairments in brain disorders has been recently recognized. Higher ACE activity in plasma of chronic patients with schizophrenia (SCZ) compared with healthy controls (HCs) paired by sex and age, and the relevance of ACE activity in SCZ was suggested by us. We now propose a translational analysis to understand how SCZ pharmacotherapy with antipsychotics can affect the ACE activity in clinical samples and animal model for SCZ studies.

Identification of Inhibitors of Phosphate-activated Glutaminase for the Pharmacotherapy of Schizophrenia

In the brain, phosphate-activated glutaminase catalyzes the recycling of glutamine back to glutamate for excitatory neurotransmission. In mice, genetic knockdown of phosphate-activated glutaminase has been shown to confer resilience to schizophrenia-like symptoms, suggesting that inhibition of glutaminase may have therapeutic potential for the pharmacotherapy of schizophrenia. As there are no known neuroactive inhibitors of glutaminase, i.e. inhibitors that get into the brain, high-throughput screening of a library of 58,000 neuroative compounds was conducted using a fluorescence-based assay; this screen identified 320 potential glutaminase inhibitors. A secondary screen was carried out to access specificity; this yielded 10 hits. Using a kinetic analysis, two leads with low micromolar activity were found.

Therapeutic drug monitoring of aripiprazole as part of the individualization of the pharmacotherapy of schizophrenia

To personalize pharmacotherapy with aripiprazole in patients with schizophrenia via therapeutic drug monitoring (TDM). TDM of aripiprazole (ARI) and its active metabolite dehydroaripiprazole (DHA) was performed for patients diagnosed with schizophrenia (ICD-10 F20.00; F20.01; F20.02). Thirty-six parameters were assessed. To carry out TDM, the method of high-performance liquid chromatography with mass spectrometry was chosen employing a validated method. TLM was performed in a group of young patients: 26.5±10.1 years old, average weight 77.2±16.2 kg, average PANSS score 81.4±21.4, UKU score 14.5±3.9. An average ARI concentration was 18.4±7.9 mg, serum ARI concentration 417.9±362.4 ng/ml, serum DHA concentration 117.5±116.1 ng/ml and the total concentration 535.4±478.5 ng/ml. Equations of correlation dependences of concentration on dose are obtained for ARI and DHA. The results show the significant metabolism of ARI. A combined determination of the main substance and its active metabolite DHA in the patient's blood serum is advisable for correct assessment of the TLM result in patients with mental diseases.