Risk Of Extrapyramidal Side Effects Research Articles

Evaluation of antipsychotic side effects on schizophrenia patients at Dr Radjiman Wediodiningrat Hospital, Indonesia

Background: Schizophrenia is the most common mental illness with a poor prognosis. Antipsychotics are the major treatment for Schizophrenia. Objective: This study examines schizophrenia patients' side effects and antipsychotic medication. Method: A retrospective study with cross-sectional observational analysis was conducted in June 2023, with only the data from schizophrenia patients in Dr. Radjiman Wediodiningrat Hospital, Indonesia. Data were collected from the prescription records of schizophrenia inpatients from January to June 2023. The Chi-square test was used to analyse and measure the relationship between the incidence of adverse events with antipsychotics in schizophrenia patients. Result: Schizophrenia inpatients were majority male (74.7%) and the age 18-35 years was 41%. This study showed that the pattern of prescription of antipsychotics is atypical monotherapy (37.6%) and combinations (24.9%) were the most antipsychotics prescribed. Most of the schizophrenia outpatients have extrapyramidal syndrome side effects (31.9%), such as rigidity (12.2%), tremor (3.5%), dystonia (6.6%), and other side effects (11.8%). Conclusion: This study highlighted that atypical antipsychotics were the most common choice for treatment in the inpatient setting. Atypical have a lower risk of extrapyramidal side effects than typical. The negative effects of atypical antipsychotics, including metabolic syndrome, have not been identified. Thus, more research is required.

Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis.

Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D2 receptor (D2R) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The D2R occupancy curves showed that the risk increased substantially when D2R occupancy exceeded 75-85%, except for D2R partial agonists that had smaller ORs albeit high D2R occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current D2R therapeutic window for EPS.

Extrapyramidal side effects in first-episode schizophrenia treated with flupenthixol decanoate.

BackgroundConcern for the development of extrapyramidal side effects (EPSEs) represents a barrier to the routine use of long-acting injectable (LAI) antipsychotic medication in patients with first-episode schizophrenia (FES). Flupenthixol decanoate is a first-generation antipsychotic, which is readily available in the public healthcare system in South Africa.AimThe aim of this study was to describe the nature, occurrence and severity of EPSEs and their impact on patients with FES over 12 months of treatment with flupenthixol decanoate (fluanxol depot).SettingThe study was based in Cape Town, South Africa, and patients with FES were recruited from inpatient services at Stikland and Tygerberg Hospitals and surrounding psychiatric clinics. This was a sub-study of a larger study, which examined several outcomes in patients with FES treated with the lowest effective dose of flupenthixol decanoate.MethodsThe Extrapyramidal Symptom Rating Scale (ESRS) was used to assess both subjective experience and objective measures of EPSEs in a cohort of patients with FES (N = 130). The relationship between demographic and clinical risk factors for individual subsets of EPSEs was also determined.ResultsIn the context of an overall good 12-month tolerability, EPSEs peaked at month 3. Patients with akathisia were more likely to have greater symptoms of depression, and Parkinsonism was predicted by higher Positive and Negative Syndrome Scale scores (independent of medication dosage). Black and white patients showed higher total ESRS and higher subjective ESRS scores, compared with patients of mixed ancestry, and white patients scored higher on Parkinsonism ratings.ConclusionFlupenthixol decanoate is well tolerated in patients with FES. Certain clinical features of schizophrenia may be related to EPSEs. Ethnicity is a socio-cultural construct, and hence the differential risk of EPSEs should be interpreted according to ethnicity. Variations in the environment, diet, substance use and genetics may all affect the pharmacokinetics and pharmacodynamics of psychotropic drugs and warrant further investigation.

The interaction of folate cycle enzyme genes and the risk of extrapyramidal side effects of antipsychotics

Personalized medicine means the selection of therapy for patients, taking into account the assessment of genetic risk factors for side effects. A number of studies show that folate metabolism disorders, including single nucleotide polymorphisms (SNPs) in the genes of folate-metabolizing enzymes, are more frequently detected in schizophrenic patients than in the general population. The role of SNPs of the key folate cycle enzymes in developing the extrapyramidal side effects of antipsychotics has not yet been studied, although there is evidence of their association with other movement disorders.Objective: to analyze the association between the carriage of SNP alleles of MTHFR 677C>T, MTR 2756A>G, and MTRR 66A>G and the severity of extrapyramidal side effects of antipsychotics in patients with schizophrenia.Patients and methods. The investigation included 61 patients with schizophrenia (according to the criteria for ICD-10 Code F20). All the patients took antipsychotics for at least 7 hospital days were examined using real-time polymerase chain reaction (PCR) with allele-specific primers, followed by detection for the carriage of SNP alleles of MTHFR 677C>T, MTR 2756A>G, and MTRR 66A>G. The standardized Simpson–Angus scale (SAS) was used to evaluate the severity of extrapyramidal symptoms; the PCR test results were unknown during their examination.Results and discussion. In the patients carrying a low-functional 677 T allele in the gene of the key folate cycle enzyme MTHFR, the severity of extrapyramidal side effects of antipsychotics was statistically significantly higher than in the carriers of the wild-type genotype: 13.27±5.10 versus 9.84±6.03 SAS scores, respectively (t=-2.40; p=0.020). In addition, the carriage of the wild allele A of SNP in the MTRR 66A>G gene (F=3.83; p=0.0283; pcorr.=0.043) is associated with the severity of extrapyramidal symptoms. There was a direct moderate correlation of the number of risk alleles at two loci with the total SAS score (r=0.51; p=0.00017).Conclusion. The polymorphic allele of MTHFR 677T and the wild allele of MTRR 66A can be regarded as risk alleles for the development of extrapyramidal side effects of antipsychotics.

Akathisia and Newer Second-Generation Antipsychotic Drugs: A Review of Current Evidence.

Akathisia continues to present a significant challenge in clinical practice. As a class, so-called atypical, or second-generation, antipsychotics (SGAs) are the mainstay of treatment for schizophrenia and are commonly used to treat mood disorders. These medications have traditionally been distinguished from first-generation antipsychotics by their lowered risk of extrapyramidal side effects (EPS) such as dystonia, dyskinesia, akathisia, and pseudoparkinsonism. However, the occurrence of EPS, particularly akathisia, has been demonstrated to some degree in all commercially available SGAs. This review examines the incidence of akathisia in nine newer SGAs in patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD). We performed a search of PubMed, ClinicalTrials.gov, Cochrane Central Register, and Google Scholar, as well as manufacturer websites and product labeling for published and unpublished clinical trials, meta-analyses, and systematic reviews. Studies evaluating adult patients with schizophrenia, bipolar disorder, or MDD were eligible for inclusion. Data on treatment-emergent akathisia rates were gathered from each study, and potential dose-response relationships were explored. A total of 177 studies were included in this review, comprising 58,069 patients across 414 treatment arms. Compared with placebo with a composite 3.7% incidence of akathisia, individual SGAs produced akathisia at total composite rates ranging from 2.9-13.0% across the included studies. High doses of an SGA were generally associated with an increased risk of akathisia. Clinicians should consider the risk of akathisia when choosing a treatment option and monitor for akathisia in patients beginning therapy with an SGA or following a dose increase of the SGA.

Development and implementation of clozapine protocol in patients with schizophrenia in Greece

Clozapine is an atypical antipsychotic used for the treatment of resistant schizophrenia, exhibiting significant advantages over other antipsychotic agents. Clozapine efficacy is well established in people diagnosed with schizophrenia via reducing both positive and negative symptoms. Also, is associated with a low risk of extrapyramidal side effects compared to other antipsychotics. Despite the above, clozapine is an unpopular therapeutic option for patients not previously responded to other antipsychotics, because of adverse side effects, such as hyper-salivation and weight gain or critical side effects, i.e., risk for developing neutropenia and agranulocytosis and the need for a systematic and vigilant patients' monitoring, causing discomfort to them and increased expenses to the healthcare system. The aim of the present article is to describe (a) the development of a "clozapine treatment monitoring protocol", and (b) the monitoring process applied at the Department of Psychiatry of Aghioi Anargyroi Cancer Hospital in patients under clozapine treatment. For the protocol development a systematic review of the existing literature was conducted. An advanced search in Medline, CINAHL, Scopus and Google Scholar was conducted, as well as at the National Organization of Greece for Medicines database, with the following key- words: "clozapine", "clozapine protocol", "clozapine monitoring", "clozapine guidelines". Based on this procedure, the Victorian Consensus View protocol applied in Australia was evaluated as the most appropriate since it encompasses: (a) monitoring of multiple systems based on a holistic healthcare approach towards patients, and (b) Intense cardiovascular functioning monitoring, highly relevant to the Greek population due to increased incidence of myocarditis. Overall, the necessary interventions prior and after clozapine treatment initiation are, monitoring of heamatological and cardiovascular function and related side effects, metabolic monitoring and related side effects, monitoring of metabolic adverse effects, gastrointestinal and neurological adverse effects, hepatic function monitoring and related side effects. Clozapine treatment monitoring protocol applied at special settings, e.g., Clozapine Clinics, is highly beneficial, since the risk of neutropenia, agronulocytosis is minimized, while suicidal behavior and substance use are reduced along with risky health behaviors, i.e., nicotine use and sedentary lifestyle. The current protocol may be applied by mental healthcare professionals aiming to empower individuals with schizophrenia through promoting their independency and quality of life.

Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor.

Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R, whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and revealed that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimization of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.

CYP2D6 genetic polymorphism and genetic ancestry on extrapyramidal side-effects of long-term treatment with classical antipsychotics in cuban patients with schizophrenia

Background: Different factors alter a patient’s susceptibility to adverse neuroleptic reactions. The CYP2D6 gene codes for a human cytochrome P450 2D6 enzyme, which is responsible for the metabolism of many psychiatric drugs. Ethnicity may also influence the susceptibility to adverse effects of long-term treatment with classical Antipsychotics (AP) because allele frequencies differ in correspondence with interethnic differences. Objective: To evaluate whether the CYP2D6 allelic variants/predicted metabolic capacity status and the genetic ancestry are associated with classical antipsychotic-induced extrapyramidal side-effects (EPS) in Cuban patients with schizophrenia. Methods and findings: A cross-sectional study was carried out. 209 patients were included: 61 of them with EPS at present and 148 patients without EPS. DNA samples were genotyped to estimate of admixture proportions and CYP2D6 genotype. Homozygous patients with non-functional alleles have a higher risk of developing EPS (RR=3.418). These patients have a higher proportion of European genes (0.82). Conclusion: The Poor Metabolizer (PM) genotype may be a predisposing factor for EPS. The study did not find evidence that ethnic differences played a large part in the risk of EPS.

Factors associated with long length of stay in an inpatient psychiatric unit in Lilongwe, Malawi.

Studies of factors affecting length of stay during psychiatric hospitalization in sub-Saharan Africa are sparse. A better understanding of such factors may lead to interventions resulting in quicker patient stabilization and discharge, freeing up needed psychiatric beds and reducing health care system expenditures. Therefore, we sought to identify factors associated with long length of stay in Malawi. We reviewed the charts of 417 patients hospitalized at Kamuzu Central Hospital's Bwaila Psychiatric Unit in Lilongwe, Malawi from January 1 to December 31, 2011. Multivariate logistic regression analysis was employed to test for associations between patient factors and long length of stay (defined as more than 28 days). Mean length of stay was 22.08 ± 27.70 days (range 0-243). 21.82% (91/417) of patients stayed longer than 28 days. Long length of stay was associated with living outside of Lilongwe district [aOR: 3.65 (1.66-8.01), p = 0.001] and treatment for antipsychotic extrapyramidal side effects (EPS) during hospitalization [aOR: 3.45 (1.32-9.03), p = 0.012]. Patients who had more interactions with medical providers for this episode of illness prior to presentation at the unit were less likely to have a long length of stay [aOR: 0.35 (0.16-0.76), p = 0.008]. Our findings demonstrate areas of possible intervention to reduce length of stay, including securing means for patient transport home, rapid identification and treatment of EPS, and reducing the risk of EPS by decreased use of high potency first-generation antipsychotics.

Meta regression: Relationship between antipsychotic receptor binding profiles and side-effects

Our objective was to examine the association between antipsychotic receptor binding profiles and the magnitude of common side-effects. We used regression analysis to examine the association between the receptor binding affinities of antipsychotic agents (log Ki) and degree of specific antipsychotic side-effects. Data on magnitude of weight gain, prolactin increase and QTc prolongation (in Standardized Mean Difference) and risk of sedation and extrapyramidal symptoms (in Odds Ratio) between individual antipsychotic medications as compared to placebo was based on a recent network meta-analysis examining the treatment of schizophrenia. Receptor affinities (in log Ki) were examined for the D2, 5-HT1A, 5-HT2A, 5-HT2C, H1, alpha1, alpha2, M1, M3 and M4 receptors. Medications were weighted in the analysis using the generic inverse variance method utilizing variance estimates from the previous meta-analysis.Magnitude of weight gain was significantly associated with the affinity of antipsychotic medications to M1, M3, 5-HT2C and H1 receptors. Risk of sedation was significantly associated with the affinity to the M1 and M4 receptors. Magnitude of hyperprolactinemia was significantly associated with the affinity to M1 and M4 receptors. Risk of extrapyramidal side effects was associated with the affinity to 5-HT2C and M1 receptors. QT prolongation was not significantly associated with antipsychotic receptor affinities. Our meta-analysis demonstrated that increased affinity of antipsychotics for certain receptors are significantly associated with higher risk of sedation, hyperprolactinemia, extrapyramidal side effects and weight gain.

A Population Approach to Guide Amisulpride Dose Adjustments in Older Patients With Alzheimer's Disease.

We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [¹⁸F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS. Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P < .01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and < 30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged > 75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged > 85 years of low body weight. These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged > 75 years, the maximally tolerated dose.

Risperidone (depot) for schizophrenia.

This is a copy of an article published in the Cochrane Database of Systematic Reviews © 2016 Cochrane Collaboration Publications. © The Author(s). http://www.cochranelibrary.com/

Risk of extrapyramidal side effects comparing continuous vs. bolus intravenous metoclopramide administration: a systematic review and meta‐analysis of randomised controlled trials

To provide evidence about whether intravenous metoclopramide continuous infusion is associated with fewer extrapyramidal side effects than bolus infusion. Many studies have described the effects produced by the administration of metoclopramide, as a continuous intravenous infusion or intravenous bolus directly, but there is a lack of consensus about the best administration of this drug to minimise extrapyramidal side effects. A meta-analysis was conducted. The search data base was conducted in: Cochrane Library, PubMed, Web of Knowledge and Scopus, to collect randomised controlled trials examining the association between extrapyramidal side effects and intravenous metoclopramide continuous or bolus infusion. Meta-analyses were conducted for the eligible randomised controlled trials by Comprehensive Meta-Analysis. Risk difference and 95% CIs were calculated with the Cochran's Q-statistic, and heterogeneity was assessed with the I(2) test. Eleven randomised controlled trials were included. Meta-analysis showed that continuous intravenous infusion of metoclopramide produced less extrapyramidal side effects (8%; 95% CI, 5-11%; p < 0·001; I(2) = 65%). These improvements were particularly strong in studies scored ≥3 in the Jadad scale (12%; 95% CI, 3-24%; I(2) = 0%), in emergency patients (12%; 95% CI, 2-25%; I(2) = 0%), in patients who used concomitant drugs (9%; 95% CI, 5-12%; I(2) = 80%) and when observation (8%; 95% CI, 5-14%; I(2) = 69%) or analogue scale (7%; 95% CI, 1-13%; I(2) = 64%) were used to quantify the number of extrapyramidal reactions in patients. Compared with bolus administration, continuous intravenous infusion of metoclopramide reduces the appearance of extrapyramidal side effects. Continuous infusion is an effective intervention to reduce in patients discomfort caused by the extrapyramidal side effects of metoclopramide. Clinicians also reduce the time spent on alleviating these unwanted effects.

Late-onset neutropenia due to clozapine.

Sir, Clozapine is an antipsychotic drug effective against treatment-resistant schizophrenia. Compared with the classic neuroleptic drugs, clozapine carries a lower risk of extrapyramidal side effects.[1] Despite these advantages, clozapine-induced neutropenia and agranulocytosis can occur with a cumulative incidence of 2.7% and 0.73%, respectively.[2] Although the risk of blood dyscrasias is the highest during the first 6–18 weeks;[3] hence, this side effect can occur even after ≥5 years of treatment with clozapine.[4] Here, we report the case of a 46-year-old woman who developed neutropenia due to clozapine after 8 years of treatment. A 46-year-old woman with a history of schizophrenia since 2004 was treated with therapeutic doses of risperidone for the first 6 months after diagnosis. Because of the lack of improvement in her clinical status, risperidone was replaced by clozapine at an initial dose of 25 mg/day in December 2004; this dose was slowly titrated up to 300 mg/day. Because of her alterations in electroencephalography patterns, valproate 500 mg/day was added in May 2005. Sertraline 100 mg/day was initiated in September 2007 to treat depressive symptoms, and was discontinued in June 2008 because of the clinical improvement. Between 2004 and 2011, the results of hematological monthly monitoring were normal. Although the white blood cell (WBC) count was 6500/mm3 with an absolute neutrophil count (ANC) of 5100/mm3 in December 2011, it declined to 4100/mm3 and 3800/mm3, respectively, over 2 months (ANC was 3170/mm3 and 2660/mm3, respectively). In March 2012, her WBC count had dropped to 2100/mm3 with an ANC of 1280/mm3; however, there were no signs of infection. Laboratory tests and hematological consultations ruled out infectious diseases that could cause neutropenia. The results of her physical examination were unremarkable. After the diagnosis of neutropenia was made, all medications were discontinued, and blood counts were measured weekly. The WBC count reached the normal limit (WBC: 6300/mm3) within 3 weeks after the discontinuation of her medications. Since then, the patient's mental status has been stable with pharmacotherapy, including sertindole 16 mg/day and amisulpride 800 mg/day. Her clinical status remains good, without any recurrence of adverse hematological events. Neutropenia, in this case, could have been due to either clozapine or valproate or a combination of both. A case report described a patient who developed late-onset neutropenia because of sodium valproate; however, the drop in WBC counts emerged after dose escalation in this case.[5] To the best of our knowledge, delayed-onset neutropenia due to a stable dose of valproate has not yet been reported, although it has been observed in the association with a stable dose of clozapine, even after several years.[4] We cannot be certain drugs that caused by the side effect, because of both the drugs were discontinued at the same time, we believe that the neutropenia was most likely to be caused by clozapine. Our case report underscores the importance of regular blood monitoring in patients treated with clozapine. Clinicians should also be aware of other psychotropic medications that can impose the risk of blood dyscrasias. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Mechanism of Action of Antipsychotic Medications

Article AbstractA variety of antipsychotic medications exist for treating patients with schizophrenia. Knowledge of pharmacokinetics (the body's effect on the drug) and pharmacodynamics (the drug's effect on the body) can help clinicians select antipsychotics and make timely dose adjustments to improve patient outcomes. Currently, the only known effective mechanism to reduce positive psychotic symptoms is dopamine D2 blockade. However, several relevant dopamine pathways exist, and increasingly sophisticated insight into the role of subsections of the striatum has helped link dopamine D2 blockade in specific pathways to the beneficial and adverse effects of antipsychotics, including extrapyramidal side effects (EPS) and secondary negative or cognitive effects. Antipsychotics with low D2 affinity (partial D2 agonism) that modulate dopamine transmission via blockade of histamine or cholinergic receptors or that bind more tightly to serotonin 5-HT2A receptors than D2 receptors generally have less risk for EPS. However, some of the mechanisms that balance dopamine tone can be associated with sedation, central and peripheral anticholinergic effects, weight gain and metabolic abnormalities. Thus, treatment selection needs to be individualized based on the pharmacokinetic and pharmacodynamic profiles of available antipsychotics as well as their effects in a given patient with past treatment response patterns, comorbidities, and preferences. Importantly, new medications with either additional or exclusive nondopaminergic pharmacologic mechanisms need to be developed that can address not only positive symptoms of schizophrenia but also negative and cognitive symptoms, which do not appear to be primarily related to dopamine dysfunction.See the entire activity.

Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator.

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT1A) and D2/3 receptors, combined with potent antagonist effects on 5-HT2A, α1B-, and α2C-adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED50 = 6.0 mg/kg), apomorphine- or d-amphetamine-induced hyperactivity (ED50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED50 = 2.9) in rats at clinically relevant D2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED50 = 20) well above clinically relevant D2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D2 occupancies. In the NOR test, the 5-HT1A agonist buspirone and the 5-HT2A antagonist M100907 [(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)piperidin-4-yl]methanol] partially but significantly reversed PCP-induced impairment. Furthermore, the effect of brexpiprazole was reversed by cotreatment with the 5-HT1A antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate). The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. The effects of brexpiprazole in the cognitive tests are superior to those of aripiprazole. We propose that the pharmacologic profile of brexpiprazole be based on its balanced effects on 5-HT1A, D2, and 5-HT2A receptors, with possible modulating activity through additional monoamine receptors.

Dopamine D2 receptor occupancy as a predictor of catalepsy in rats: a pharmacokinetic-pharmacodynamic modeling approach.

Dopamine D2 receptor occupancy (D2RO) is the major determinant of efficacy and safety in schizophrenia drug therapy. Excessive D2RO (>80%) is known to cause catalepsy (CAT) in rats and extrapyramidal side effects (EPS) in human. The objective of this study was to use pharmacokinetic and pharmacodynamic modeling tools to relate CAT with D2RO in rats and to compare that with the relationship between D2RO and EPS in humans. Severity of CAT was assessed in rats at hourly intervals over a period of 8h after antipsychotic drug treatment. An indirect response model with and without Markov elements was used to explain the relationship of D2RO and CAT. Both models explained the CAT data well for olanzapine, paliperidone and risperidone. However, only the model with the Markov elements predicted the CAT severity well for clozapine and haloperidol. The relationship between CAT scores in rat and EPS scores in humans was implemented in a quantitative manner. Risk of EPS not exceeding 10% over placebo correlates with less than 86% D2RO and less than 30% probability of CAT events in rats. A quantitative relationship between rat CAT and human EPS was elucidated and may be used in drug discovery to predict the risk of EPS in humans from D2RO and CAT scores measured in rats.

Investigation of Cigarette Smoking among Male Schizophrenia Patients

Male schizophrenia patients are known to have a heavier smoking pattern compared with the general population. However, the mechanism for this association is not known, though hypothesis that smoking could alleviate symptomatology of schizophrenia and reduce side effects of antipsychotics has been suggested. The aims of this study were to validate the heavier smoking pattern among male schizophrenia patients and to investigate the possible mechanisms for the association. To enhance the reliability of the study, we recruited two large independent samples with 604 and 535 male Chinese schizophrenia patients, and compared their smoking pattern with that of 535 healthy male controls recruited from general population. Validated multiple indicators and multiple causes structure equation model and regression models were used to investigate the association of smoking with factors of schizophrenia symptomatology and with the usage of antipsychotics and their extra-pyramidal side effects (EPS). Schizophrenia patients had significantly heavier smoking pattern compared with healthy controls in our sample (42.4% vs. 16.8%, p<0.001 for current smoking prevalence; 23.5% vs. 43.3%, p<0.001 for smoking cessation rate; 24.5% vs. 3.0%, p<0.001 for heavy smoker proportion). Their smoking status was also found to be consistently and significantly associated with reduced negative factor scores for schizophrenia symptomatology (β = −0.123, p = 0.051 for sample-A; β = −0.103, p = 0.035 for sample-B; β = −0.082, p = 0.017 for the combined sample). However, no significant association was found between smoking and antipsychotics usage or risk of EPS. These results support that smoking is associated with improved negative symptoms, which could account for the heavier smoking pattern among schizophrenia patients.

Dopamine D2 Receptor Occupancy and Cognition in Schizophrenia: Analysis of the CATIE Data

Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions. D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%. These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.

Striatal and extrastriatal dopamine D2 receptor occupancy by the partial agonist antipsychotic drug aripiprazole in the human brain: a positron emission tomography study with [11C]raclopride and [11C]FLB457

Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D₂ receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D₂ receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D₂ receptors have reported inconsistent results regarding regional differences of dopamine D₂ receptor occupancy by aripiprazole. To test the hypothesis of preferential binding to extrastriatal dopamine D₂ receptors by aripiprazole, we investigated its regional dopamine D₂ receptor occupancies in healthy young subjects. Using PET and two radioligands with different affinities for dopamine D₂ receptors, [¹¹C]raclopride and [¹¹C]FLB457, striatal and extrastriatal dopamine D₂ receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects. Our data showed that dopamine D₂ receptor occupancies in the striatum measured with [¹¹C]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [¹¹C]FLB457 ranging from 46.6% to 58.4%. In the present study, preferential extrastriatal dopamine D₂ receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D₂ receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole.