Second-generation Antipsychotic Drugs Research Articles

Incidence of hypercholesterolaemia and hyperglycaemia in schizophrenic patients: Atypical antipsychotic medication and clinical variables

Background: Atypical or second-generation antipsychotic drugs commonly used in the management of schizophrenia include risperidone. Risperidone is linked to the incidence of metabolic syndrome-related adverse effects. Objective: This study aims to investigate the correlation between the administration of risperidone therapy and the incidence of metabolic syndrome in outpatients diagnosed with schizophrenia. This inquiry involves an examination of relevant laboratory parameters, specifically cholesterol, blood glucose, and haemoglobin A1c (HbA1C) levels, alongside an evaluation of pertinent clinical variables that may exert an influence. Methods: This study adopted a cross-sectional approach to receiving risperidone therapy for a minimum of three months at Grhasia Mental Hospital in Yogyakarta, Indonesia. Sampling was executed using an accidental sampling technique, targeting patients who met the predefined inclusion criteria. Results: The study enrolled a total of 97 participants, comprising 58 males and 39 females. Subsequent statistical analyses failed to demonstrate any statistically significant associations between hyperglycemia and various factors, including the risperidone regimen (p = 0.574), risperidone dosage (p = 0.619), and the duration of risperidone therapy (p = 1.000). Conclusion: Risperidone has a long-term risk of causing hyperglycemia in people with schizophrenia; consequently, blood glucose and HbA1C levels must be monitored on a regular basis.

Depicted simulation model for removal of second-generation antipsychotic drugs adsorbed on Zn-MOF: adsorption locator assessment.

Electronic durable behavior on the material surface was accompanied by a class of antipsychotic drugs (APD) to describe the surface modification in the designed adsorption model. Hierarchically Zn-MOF system was utilized for estimating its capacity for drug molecule removal. Geometrically optimized strategy on the studied systems was performed using DFT/GGA/PBE. FMOs analysis was depicted based on the same level of calculations, and molecular electrostatic potential surface (MEP) was generated for unadsorbed and adsorbed systems to illustrate the variation in the surface-active sites. By interpreting the electronic density of states (DOS), the atomic orbital can be identified as a major or minor electronic distribution by PDOS graph. Adsorption locating behavior was considered to detect the significant surface interaction mode between APD and Zn-MOF surface based on lower adsorption energy. The stability of the adsorbed model was best described through dynamic simulation analysis with time through elevated temperatures. The non-covalent interactions were described using RDG/NCI analysis to show the major favorable surface interaction predicting the highly stable adsorption system. The most accurate geometrical computations were performed using the materials studio software followed by surface cleavage and vacuum slab generation. The first principle of DFT was used to apply CASTEP module with GGA/PBE method for band structure and DOS calculations. Three systems of antipsychotic drugs were computationally studied using CASTEP simulation package and adsorbed on an optimized Zn-MOF surface. Adsorption locator module predicted the preferred adsorption mechanistic models, in which the first model was arranged to be more stable, to confirm the occurrence of some interactions in the adsorption mechanism.

THE FIRST GENERATION AND SECOND-GENERATION ANTIPSYCHOTIC DRUGS AND THEIR PHARMACOLOGY IN TREATMENT OF SCHIZOPHRENIA

Schizophrenia is a complex and severe psychiatric disorder that affects millions of people worldwide. Antipsychotic drugs have been widely used for the treatment of schizophrenia for over 60 years. The first-generation antipsychotic drugs (FGAs) were introduced in the 1950s and revolutionized the treatment of schizophrenia. However, their use is associated with a number of adverse effects, including Extrapyramidal Symptoms (EPS) and Tardive Dyskinesia (TD). Second-generation antipsychotic drugs (SGAs), also known as atypical antipsychotics, were developed in the 1990s and have become the preferred treatment for schizophrenia due to their lower incidence of EPS and TD. They also have a broader range of therapeutic effects, such as improving negative symptoms and cognitive impairment associated with schizophrenia. This review article summarizes the pharmacology of both FGAs and SGAs, including their mechanism of action, pharmacokinetics, and adverse effects. The efficacy and safety of these drugs in the treatment of schizophrenia are also discussed. In addition, this review examines the controversy surrounding the use of SGAs and their potential metabolic side effects, such as weight gain, hyperlipidemia, and diabetes. Despite the availability of SGAs, FGAs still have a role in the treatment of schizophrenia, particularly for patients who are unresponsive to SGAs or experience intolerable side effects. Furthermore, research continues to identify new pharmacological targets and treatment strategies for schizophrenia. Understanding the pharmacology and clinical use of antipsychotic drugs is essential for optimizing the treatment of schizophrenia and improving patient outcomes.

Addendum: Drugs for depression.

In our article on Drugs for Depression, we should have included tardive dyskinesia (TD) in our list of adverse effects of second-generation antipsychotic (SGA) drugs. TD, which is more commonly associated with first-generation antipsychotics, can also occur in patients taking an SGA, especially with prolonged use. A meta-analysis found that the annualized incidence of TD was 2.6% in SGA users (M Carbon et al. World Psychiatry 2018; 17:330). Older adults are at increased risk.

D-Optimal Mixture Design Enabled Development of Lyophilized Nanoemulsifying Drug Delivery System of Paliperidone

Background: Schizophrenia is a chronic disease with acute psychotic symptoms, which is having frequent recurrence. Paliperidone palmitate (PP) is a second-generation antipsy-chotic drug to treat schizophrenia. Aims: The aim of the study was to prepare lyophilized nanoemulsifying drug delivery system (NEDDS) of paliperidone (PD). Objective: The primary objective of the current research work was to develop a lyophilized nanoemulsifying drug delivery system (NEDDS) of paliperidone (PD) to improve its oral bioa-vailability and stability. Methods: Optimization using D-Optimal Mixture Design DMD) was conducted, and optimized NEDDS was further lyophilized to improve stability. The lyophilized optimized NEDDS was fur-ther evaluated for biopharmaceutical evaluation. Result: A saturation solubility study revealed Peceol, Tween 80, and Plurol Olique CC497 as suitable candidates for oil, surfactant, and co-surfactant, respectively. Optimized NEDDS of PD showed mean globule size (MGS) of 185 nm, PDI of 0.27 and cumulative % drug release within 15 min Q15 of 86.6%. Lyophilized optimized NEDDS was found to have no significant change in quality attributes within the stability study period. A pharmacokinetic study revealed more than two-fold increases in bioavailability for lyophilized optimized NEDDS. Conclusion: Hence, lyophilized NEDDS of PD can be used as an effective approach for the im-provement of oral bioavailability and stability.

Quetiapine-Related Deaths: In Search of a Surrogate Endpoint.

Quetiapine is a second-generation antipsychotic drug available for two and half decades. Due to increased misuse, prescription outside the approved indications, and availability on the black market, it is being encountered in medicolegal autopsies more frequently. For instance, it has been linked to increased mortality rates, most likely due to its adverse effects on the cardiovascular system. Its pharmacokinetic features and significant postmortem redistribution challenge traditional sampling in forensic toxicology. Therefore, a systematic literature review was performed, inclusive of PubMed, the Web of Science-core collection, and the Scopus databases; articles were screened for the terms "quetiapine", "death", and "autopsy" to reevaluate each matrix used as a surrogate endpoint in the forensic toxicology of quetiapine-related deaths. Ultimately, this review considers the results of five studies that were well presented (more than two matrices, data available for all analyses, for instance). The highest quetiapine concentrations were usually measured in the liver tissue. As interpreted by their authors, the results of the considered studies showed a strong correlation between some matrices, but, unfortunately, the studies presented models with poor goodness of fit. The distribution of quetiapine in distinct body compartments/tissues showed no statistically significant relationship with the length of the postmortem interval. Furthermore, this study did not confirm the anecdotal correlation of peripheral blood concentrations with skeletal muscle concentrations. Otherwise, there was no consistency regarding selecting an endpoint for analysis.

In brief: Three new injectable antipsychotic drugs.

Three extended-release injectable formulations of second-generation antipsychotic drugs — two of risperidone (Rykindo, Uzedy) and one of aripiprazole (Abilify Asimtufii) — have been approved by the FDA for treatment of schizophrenia in adults.

Lurasidone blocks the voltage-gated potassium channels of coronary arterial smooth muscle cells

Lurasidone is a second-generation antipsychotic drug used to treat schizophrenia, mania, and bipolar disorder. The drug is an antagonist of the 5-HT2A and D2 receptors. No effect of lurasidone on the voltage-gated K+ (Kv) channels has yet been identified. Here, we show that lurasidone inhibits the vascular Kv channels of rabbit coronary arterial smooth muscle cells in a dose-dependent manner with an IC50 of 1.88 ± 0.21 μM and a Hill coefficient of 0.98 ± 0.09. Although lurasidone (3 μM) did not affect the activation kinetics, the drug negatively shifted the inactivation curve, suggesting that the drug interacted with the voltage sensors of Kv channels. Application of 1 or 2 Hz train steps in the presence of lurasidone significantly increased Kv current inhibition. The recovery time after channel inactivation increased in the presence of lurasidone. These results suggest that the inhibitory action of lurasidone is use (state)-dependent. Pretreatment with a Kv 1.5 subtype inhibitor effectively reduced the inhibitory effect of lurasidone. However, the inhibitory effect on Kv channels did not markedly change after pretreatment with a Kv 2.1 or a Kv7 subtype inhibitor. In summary, lurasidone inhibits vascular Kv channels (primarily the Kv1.5 subtype) in a concentration- and use (state)-dependent manner by shifting the steady-state inactivation curve.

Insights into the Mechanism of Action of Antipsychotic Drugs Derived from Animal Models: Standard of Care versus Novel Targets.

Therapeutic intervention for schizophrenia relies on blockade of dopamine D2 receptors in the associative striatum; however, there is little evidence for baseline overdrive of the dopamine system. Instead, the dopamine system is in a hyper-responsive state due to excessive drive by the hippocampus. This causes more dopamine neurons to be in a spontaneously active, hyper-responsive state. Antipsychotic drugs alleviate this by causing depolarization block, or excessive depolarization-induced dopamine neuron inactivation. Indeed, both first- and second-generation antipsychotic drugs cause depolarization block in the ventral tegmentum to relieve positive symptoms, whereas first-generation drugs also cause depolarization in the nigrostriatal dopamine system to lead to extrapyramidal side effects. However, by blocking dopamine receptors, these drugs are activating multiple synapses downstream from the proposed site of pathology: the loss of inhibitory influence over the hippocampus. An overactive hippocampus not only drives the dopamine-dependent positive symptoms, but via its projections to the amygdala and the neocortex can also drive negative and cognitive symptoms, respectively. On this basis, a novel class of drugs that can reverse schizophrenia at the site of pathology, i.e., the hippocampal overdrive, could be effective in alleviating all three classes of symptoms of schizophrenia while also being better tolerated.

Brexpiprazole (Rexulti) for agitation in Alzheimer's dementia.

The FDA has approved the oral second-generation antipsychotic drug brexpiprazole (Rexulti – Otsuka/Lundbeck) for once-daily treatment of agitation associated with dementia due to Alzheimer's disease (AD).

Thermodynamic analysis and molecular dynamic simulation of solid–liquid equilibrium behavior of antipsychotic drug aripiprazole (Form III) in three binary solvent mixtures

Aripiprazole (APZ), an effective second-generation antipsychotic drug indicated for the treatment of schizophrenia, was chosen to investigate its solubility in three binary solvent mixtures at the temperature range of 278.15–318.15 K. Due to clinical usage Form III is metastable, and the solubility was studied via the synthetic method. It was found that in the butanone + acetone and butanone + ethyl acetate mixed solvent systems, the solubility values of APZ Form III increased with the increase of the proportion of butanone solvent, and the maximum mole fraction solubility at each selected temperature point ranges from 0.001924 to 0.009015. However, in the mixed solvent system of butanone and n-propanol, the solubility of APZ Form III reaches its maximum when the molar fraction of butanone is 0.6 with the maximum mole fraction solubility at each selected temperature point ranging from 0.003126 to 0.012721. The modified Apelblat model, λh model, Van’t Hoff model, and NRTL model were used to correlate the experimental solubility data of APZ Form III, and the results showed that these models are suitable. In addition, according to the result of mixing thermodynamic functions, the negative values of ΔmixG and ΔmixH in all binary solvent mixtures are negative, indicating that the dissolution process of APZ Form III in the binary solvent mixtures is spontaneous and entropy-driven. Furthermore, the molecular dynamic simulations were used to illustrate and understand the dissolution behavior of APZ Form III in selected solvents from a molecular perspective.

Quetiapine Albumin Nanoparticles as an Efficacious Platform for Brain Deposition and Potentially Improved Antipsychotic Activity.

Quetiapine (QP) is a second-generation short-acting antipsychotic drug extensively metabolized in the liver, producing pharmacologically inactive metabolites and leading to diminished bioavailability. Therefore, this study aimed to develop an intravenous QP albumin nanoparticles (NPs) system for improving QP antipsychotic activity and brain targeting. QP-loaded albumin NPs were prepared by the desolvation method. The fabricated NPs were characterized in terms of particle size, zeta potential, entrapment efficiency (EE%), and in vitro drug release. In vivo pharmacokinetics and biodistribution in rats were studied. In addition, the antipsychotic activity of the optimized platform was also investigated. Human serum albumin (HSA) concentration, pH, and stirring time were modulated to optimize QP albumin NPs with a particle size of 103.54 ± 2.36 nm and a QP EE% of 96.32 ± 3.98%. In addition, the intravenous administration of QP albumin NPs facilitated QP brain targeting with a 4.9-fold increase in targeting efficiency compared to the oral QP solution. The QP albumin NPs improved the QP antipsychotic activity, indicated by suppressing rats' hypermobility and reducing the QP's extrapyramidal side effects. The obtained results proposed that intravenous QP- NPs could improve QP brain targeting and its antipsychotic efficiency.

Investigating the symptomatic and morphological changes in the brain based on pre and post-treatment: A critical review from clinical to neuroimaging studies on schizophrenia.

Pharmacological treatment for schizophrenia has been a long-standing concern. As a severe neuropsychological illness, schizophrenia is always a challenging disorder to unravel its pathophysiology. Since it exhibits both positive and negative symptoms, such as hallucination and delusion, as well as social isolation and cognitive impairment, following the symptomatic changes is a crucial task for clinicians. Although various pharmacological treatments are available in the form of antipsychotics, however, their actual consequences need to be examined with the observable changes in symptoms as well as the unobservable changes in brain functioning. This study is a first of its kind to critically investigate both clinical and neuroimaging studies to find out the changes being observed in schizophrenia patients after clinical intervention with various antipsychotics. We observed several symptomatic changes being reported in clinical studies incorporating clinical trials of various first-generation and second-generation antipsychotic drugs. Alongside, we encapsulated several neuroimaging studies showing functional and structural changes in the brain of schizophrenia patients triggered by a variety of drugs. The basal ganglia, frontal lobe, temporal lobe, cuneus, and middle occipital gyrus are some of the notable brain regions that were observed to show subtle functional and structural changes. This critical review paper may pave the way for future research into the study of the pathological and morphological changes in the brains of schizophrenia patients as they progress through the course of medicinal therapy.

Cariprazine (Vraylar) for adjunctive treatment of depression.

The FDA has approved the second-generation antipsychotic drug cariprazine (Vraylar — Abbvie) for adjunctive treatment of major depressive disorder (MDD) in adults. Cariprazine was previously approved for treatment of schizophrenia and bipolar depression, and for acute treatment of manic or mixed episodes associated with bipolar I disorder.

Antipsychotic drugs and risk of acute pancreatitis: A nationwide case-control study.

Use of antipsychotic drugs, especially second-generation agents, has been suggested to cause acute pancreatitis in multiple case reports; however, such an association has not been corroborated by larger studies. This study examined the association of antipsychotic drugs with risk of acute pancreatitis. Nationwide case-control study, based on data from several Swedish registers and including all 52,006 cases of acute pancreatitis diagnosed in Sweden between 2006 and 2019 (with up to 10 controls per case; n = 518,081). Conditional logistic regression models were used to calculate odds ratios (ORs) in current and past users of first-generation and second-generation antipsychotic drugs (dispensed prescription <91 and ≥91 days of the index date, respectively) compared with never users of such drugs. In the crude model, first-generation and second-generation antipsychotic drugs were associated with increased risk of acute pancreatitis, with slightly higher ORs for past use (1.58 [95% confidence interval 1.48-1.69] and 1.39 [1.29-1.49], respectively) than for current use (1.34 [1.21-1.48] and 1.24 [1.15-1.34], respectively). The ORs were largely attenuated in the multivariable model-which included, among others, alcohol abuse and the Charlson comorbidity index-up to the point where only a statistically significant association remained for past use of first-generation agents (OR 1.18 [1.10-1.26]). There was no clear association between use of antipsychotic drugs and risk of acute pancreatitis in this very large case-control study, indicating that previous case report data are most likely explained by confounding.

Cardiac adverse events associated with quetiapine: Disproportionality analysis of FDA adverse event reporting system.

Quetiapine, an atypical second-generation antipsychotic drug, is approved for treatment of schizophrenia, bipolar disorder, and depression. Due to the limitations of clinical trials, the association between quetiapine and rare cardiac adverse events (AEs) is still unclear. This study is to evaluate quetiapine-associated cardiac AEs through data mining of FDA Adverse Event Reporting System (FAERS). Reporting odds ratio (ROR) was used to quantify the signals of quetiapine-related cardiac AEs from the first quarter (Q1) of 2018-2022 Q1. Serious and nonserious cases were compared, and signals were prioritized using a rating scale. A total of 1004 cases of quetiapine-associated cardiac AEs were identified, with 31 signals being detected, among which 13 AEs were identified as new and unexpected signals. Besides, nine and 22 cardiac AEs were identified as moderate and weak clinical priority. The median TTO for moderate and weak clinical priority signals were 0 and 4 days, respectively. All of the cardiac AEs had early failure type characteristics, suggesting that most of the patients developed cardiac AEs in a few days after quetiapine treatment, and that the risk of cardiac AEs occurrence would be gradually decreased over time. Our study provided valuable evidence for health-care professionals to mitigate the risk of quetiapine-associated cardiac AEs based on an extensive analysis of a real-world, large-sample FAERS database, and prioritize cardiac AE signals.

The use of first and second-generation antipsychotic drugs and the potential to develop gestational diabetes mellitus among perinatal patients with psychosis.

There is limited knowledge about the effects of antipsychotic exposure on the development of gestational diabetes mellitus (GDM) in women with mental illness. Studies have demonstrated an association between antipsychotic medications and metabolic problems such as weight gain and diabetes mellitus in non-pregnant patients with psychiatric disorders. GDM increases the risk of adverse maternal outcomes, including pregnancy-induced hypertension, antepartum and postpartum haemorrhage, and caesarean delivery. The National Register of Antipsychotic Medication in Pregnancy (NRAMP) is a prospective Australian cohort study that observed women who took antipsychotics during pregnancy. Data from 205 women were extracted for the final analysis and included women who took first or second-generation antipsychotics (FGA,SGA) during the first trimester of pregnancy (at minimum) and had a diagnosis of a psychotic disorder (n = 180). The comparison (non-exposed) group (n = 25) were women with psychosis who chose not to take any antipsychotic during the first trimester (at minimum). The comparison groups were not matched, although groups were homogenous in terms of sex, age range, diagnosis and perinatal status. The results of logistic regression analysis revealed that women who were exposed to FGAs, SGAs were seven and five times, respectively, more likely to develop GDM compared to non-exposed groups. When adjusted for confounding variables such as BMI and family history of diabetes, the potential of developing GDM decreased for women taking SGAs. In conclusion, the risk of developing GDM is lower in women taking SGAs compared with women taking FDAs. In addition, family history of diabetes and BMI adds to the risk.

Sex differences in antipsychotic efficacy and side effects in psychosis

AbstractThere are a lot of studies investigating gender differences in the side effects of first and second-generation antipsychotic drugs. Even though some side effects are seen at higher rates in women, it is not determined yet the influence of gender on the efficacy and side effects of antipsychotic agents is still not well clear. In this review, we give a brief overview of antipsychotic side effects leading probably to distinguished clinical outcomes in both sexes.Disclosure of InterestNone Declared

Efficacy of clozapine compared with other second-generation antipsychotic drugs in patients with treatment-resistant schizophrenia: protocol for a systematic review and individual patient data meta-analysis of randomised controlled trials

IntroductionGuidelines recommend clozapine for treatment-resistant schizophrenia. However, meta-analysis of aggregate data (AD) did not demonstrate higher efficacy of clozapine compared with other second-generation antipsychotics but found substantial heterogeneity between trials...

Factors Influencing Blood Prolactin Levels in Patients with Schizophrenia under Risperidone Treatment

Abstract Objectives: Risperidone, a dopamine and serotonin antagonist or a second-generation (atypical) antipsychotic drug, is commonly prescribed for various psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders. While effective, risperidone often leads to hyperprolactinemia, impacting about 40%–80% of patients. In this study, we intended to examine the prevalence of hyperprolactinemia in Taiwanese patients with schizophrenia who received risperidone medication and to analyze potential links between prolactin blood levels and clinical variables. Methods: Patients with schizophrenia receiving risperidone monotherapy were included in this cross-sectional study. Blood levels of prolactin and metabolic parameters were measured. Results: A total of 176 participants diagnosed with schizophrenia, including 87 women and 89 men, were enrolled in our study. The prevalence of hyperprolactinemia and metabolic syndrome was 75.6% and 31.8%, respectively. Patients with hyperprolactinemia showed significantly higher insulin blood levels (p &lt; 0.05) and significantly higher homeostasis model assessment for insulin resistance (HOMA-IR) indexes (p &lt; 0.05) than those without hyperprolactinemia. The results of multivariate linear regression analysis showed that female sex (p = 0.001), HOMA-IR index (p &lt; 0.01), and risperidone daily dosage (p &lt; 0.05) were significantly associated with prolactin blood level. Conclusion: This study adds to the existing knowledge concerning risperidone-induced hyperprolactinemia in Taiwanese patients with schizophrenia. Hyperprolactinemia and metabolic syndrome are prevalent in patients with schizophrenia treated with risperidone. Clinicians are advised to be aware of these problems and monitor them regularly with their patients who receive treatment with risperidone.