Exploring Aripiprazole Analogs as Antipsychotic Agents: Scaffold Morphing Approach, ADMET Profile Predictions, and Molecular Docking Studies

Cancer is the second leading cause of death worldwide. Uncontrolled proliferation of cells is a hallmark of cancer development and progression. Ki-67 (a marker of proliferation Kiel-67) and Proliferating Cell Nuclear Antigen (PCNA) are two major proliferations, diagnostic and prognostic biomarkers as these are over expressed in cancerous cells. Pharmacological inhibition of Ki-67 and PCNA could effectively inhibit the growth of cancer cells. Objective: To identify Sesquiterpene Lactones (SLs) as potential inhibitors of Ki-67 and PCNA to reduce cancer burden. Methods: The inhibitory potential of SLs, namely sulfocostunolide A, sulfocostunolide B, ilicol, eucalyptone, and ascleposide E, were investigated using Molecular Docking (MD) analysis. MD analysis and visualization of ligand-protein complexes were performed using softwares such as MGL tools, BIOVIA Discovery Studio visualizer and LigPlot plus. Additionally, drug likeness and pharmacokinetic properties of SLs were assessed via pkCSM and ADMET analysis. Results: Results showed that eucalyptone with binding energy of -8.1 kcal/mol with Ki-67 while sulfocostunolide B with -6.4 kcal/mol binding energy with PCNA are the most potent proliferative inhibitors of Ki-67 and PCNA. ADMET properties, MD studies and toxicity prediction shows that current investigated ligands bind effectively with Ki-67 and PCNA without showing any toxicity. Conclusions: Current study concludes that eucalyptone with Ki-67 and sulfocostunolide B with PCNA made stable complexes and can be considered as novel inhibitors. In addition to that, these suggested ligands have also shown effective drug likeness and ADMET profile. Further, in-vitro and in-vivo studies are required to validate these findings.

Resistance to folate antagonists is caused by mutations in the dihydrofolate reductase (DHFR) genes. These mutations affect the amino acids at positions 51, 59, 108 and 164 of DHFR, which appear to play a major role in malaria treatment failure. Therefore, the design of new drugs able to overcome the problem of antifolate drug resistance should receive urgent attention. In this study, a three-dimensional quantitative structure-activity relationship (3 D-QSAR) and molecular docking studies have been performed on antimalarial quinazoline derivatives. The CoMFA (Q2 = 0.63, R2 = 0.83 and = 0.70) and the CoMSIA (Q2 = 0.584, R2 = 0.816, and = 0.73) models show a good prediction of antimalarial activity. The reliability and robustness of the proposed models have been tested using several validation methods, which showed that the steric, electrostatic, hydrophobic and H-bond acceptor fields of the CoMSIA model play a key role in the prediction of antimalarial activity. Molecular docking studies reveal important interactions between two isomeric compounds (meta and para) and the DHFR receptor in its wild and mutant forms. The obtained outcomes of molecular docking studies have been validated using a new method based on visual inspection. The DFT study of the two isomeric compounds confirms clearly the trends of 3 D-QSAR and molecular docking for the design of new compounds. Moreover, the consistency between theoretical, 3 D-QSAR and molecular docking analysis provides guidance for the design of new drug candidates, which have been tested using ADMET properties and drug likeness analysis. Communicated by Ramaswamy H. Sarma

Prostate cancer (PCa) is the second most common malignancy amongst men worldwide. Under PCa maintenance therapy drugs acting as antagonists/partial agonists of hormone receptors against the prostate tissue are used in clinical practices. Prominent drugs being Cyproterone acetate, Flutamide, Bicalutamide, they not only cause acute and long-term toxicity, but also develops drug resistance among patients. Our focus has been on phytochemicals which do not exhibit any cytotoxicity and have significant androgen receptor (AR) inhibition activity. As Protein- Ligand interactions play a key role in structure based drug design, so by using molecular docking, we screened 803 phytochemicals and investigated their binding affinity against AR. The three dimensional (3D) structure of AR was retrieved from Protein Data Bank, and docked with 3D Pubchem structures of 803 phytochemicals using Argus Lab. Molecular docking and drug likeness studies were made using ADMET properties while Lipinski’s rule of five was performed for the phytochemicals to evaluate their anti-prostate cancer activity. The results showed that Isobavachin exhibited best binding affinity of −13.73 kcal/mol with AR followed by Glabranin, Anthocyanin and Eriosemation. Our studies therefore reveal that these four phytochemicals could be promising candidates for further evaluation for PCa prevention or management.

Cancer is a major health problem throughout the world. Androgens like testosterone and dihydrotestosterone are essential for the growth and development of the prostate gland. Androgenic receptors are overexpressed, which promotes the progression of prostate cancer (PC) therefore, androgenic receptors are a key target in the therapy of PC. A non-steroidal antiandrogen drug called enzalutamide (ENZ) is used to treat PC; however, it also causes toxicities such as cardiovascular toxicity, acute myocarditis, hypertension, and seizures. The study's goal is to use a bioisosteric approach to replace the aryl group in the ENZ molecule in order to generate a less toxic analogues with improve pharmacokinetic properties and reduce toxicity. The physicochemical, medicinal, pharmacokinetic, and toxicological characteristics of the designed analogues were calculated using ADMETlab 2.0. Drug likeness (DL) and drug score (DS) of analogues were calculated using OSIRIS property explorer (PEO). The docking analysis of designed ENZ analogues was carried out with the help of AutoDock Vina (ADV). Designed analogues met the requirements for acceptability and followed the Lipinski rule of five. The ADMET profile of designed analogues was found to be optimal to good. However, no hydrogen bond was found in docking interactions between ligands and protein. Based on their QED score, ADMET properties, toxicity score, DL, DS and docking interactions, ligands E6 and E20 may be used for further screening as androgen receptor (AR) antagonists in management of PC.

Two-dimensional Quantitative Structure Activity Relationship (QSAR) study was performed on a series of 3-(aryl)-5-aryl amino-1,2,4-Oxadiazoles in order to establish the quantitative relationship between physicochemical properties and antiproliferative activity using Molecular Design Suite (VLifeMDS). The data set for this investigation consisted of 20 chemicals, which were divided into training and test set using the sphere exclusion (SE) algorithm and manual selection techniques. The QSAR models were constructed using the PLSR approach and the stepwise (SW) forward-backward variable selection method. Statistically significant QSAR models were generated. Most significant model generated (Model-1), explains 88% (r2 = 0.8229) of the overall variance in the training set as well as it has internal (q2) and external (pred_r2) predicative ability of 62% (q2 = 0.6202) and 76% (pred_r2 = 0.7566), respectively. The QSAR model (Model-1) indicates descriptors SKMostHydrophilic, T_C_N_7 and AveragePotential contributing 40%, 32% and 28 %, respectively to biological activity. Pharmacokinetic and Toxicity [Absorption, distribution, metabolism, excretion and toxicity (ADMET)] properties, drug likeness (DL) and drug score (DS) were also computed. All the compounds show good NR-AR score > 0.7, indicating that they interact with androgen receptor and may be effective in AR-dependent prostate cancer and other androgen related diseases. DL and DS score of most active compound 2t was found 0.23 and 0.51, respectively. Furthermore, DL score of Compounds 2g, 2m, 2k and 2s has been found 2.6, 1.28, 0.88 and 0.77, respectively and are relatively safe as far as toxicity is concerned. Lipinski rule of five for all compounds met under acceptance criteria which suggest compounds may be having good bioavailability as well as drug-like properties.

Pharmacoepidemiology studies use and effects of drugs in large numbers of people. It thus allows the investigation and quantification of rare beneficial or adverse events of drugs used by the general population under “real-world” conditions. Pharmacoepidemiologic research strongly depends on and has been facilitated by the development of large scale health care databases. Among these the U.K. Clinical Practice Research Datalink (CPRD) stands as one of the largest and best validated medical records databases worldwide. CPRD was initiated more than 25 years ago and contains records on diagnoses, drug prescriptions, demographics, lifestyle variables and medical procedures performed from over 12 million patients contributing 64 million person-years of prospectively recorded primary healthcare data. CPRD data was employed in all studies carried out in this thesis. The goal was set to identify and analyze risk factors of new-onset seizures in patients with neuropsychiatric disorders. While it has long been suspected that patients suffering from neuropsychiatric disorders exhibit an increased risk of new-onset seizures no significant real-world evidence exists on risk factors causing these seizures. We first investigated risk factors of new-onset seizures in adult patients with depression. Our results suggest that patients suffering from depression were at an increased risk of seizures if they abused drugs, suffered from alcoholism, had a history of cerebrovascular disease or recent brain injury, comorbid dementia, or comorbid psychiatric disorders. Additionally we found current users of cephalosporins or antiarrhythmics to be at an increased risk of seizures compared with non-users of these drug classes. In a follow-up study we assessed the association between antidepressant drug use and new-onset seizures in adult patients with depression. Our data suggest that the absolute risk of seizures in this population was rare, irrespective of whether patients used antidepressants or not. Additionally we found that the use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) was associated with a twofold increased risk of seizures compared to non-use. However, tricyclic antidepressants (TCAs) at low doses, as prescribed in this primary care setting, were not associated with seizures. Among users of SSRIs and SNRIs, treatment initiation was associated with a higher risk of seizures compared to longer-term treatment. Finally, we could demonstrate that higher doses of antidepressants prescribed showed a clear tendency to be associated with an increased risk of seizures than lower doses, although small sample sizes limited conclusiveness. In the final study of this thesis, the potential association between antipsychotic drug use and new-onset seizures among patients with different underlying neuropsychiatric disorders was investigated. The results obtained in this study demonstrate that the association between antipsychotic drug use and seizures is strongly modified by the underlying neuropsychiatric indication. Our data shows that patients with dementia exhibited a significantly higher risk of seizures than patients with affective disorders, irrespective of the use of antipsychotics. Additionally, in patients with affective disorders, current use of medium to high potency first-generation antipsychotics (haloperidol, prochlorperazine, or trifluoperazine) was associated with a more than twofold increased risk of seizures compared to non-use of antipsychotics. Lastly, in all of these patients, use of all other antipsychotics was not associated with new-onset seizures. In patients with dementia, current use of the second-generation antipsychotics amisulpride, aripiprazole, risperidone, or sulpiride, was not associated with seizures, while current use of all other antipsychotics was associated with an increased risk of seizures. We found that the inability to adjust for confounding by disease severity, the unproven validity of the diagnoses of affective disorders and seizures, and the limited sample sizes in sub-analyses posed a certain limit to our studies. Nevertheless, all studies carried out in this thesis provide new insight into the poorly understood relationship between neuropsychiatric disorders and new-onset seizures. Formally quantifying the occurrence of seizures and assessing risk factors for seizures among this restricted study population was only feasible through access to the large existing data set comprising detailed patient information available from the CPRD.

One of the foremost contributors to mortality worldwide is cancer. Chemotherapy remains the principal strategy for cancer treatment. A significant factor leading to the failure of cancer chemotherapy is the phenomenon of multidrug resistance (MDR) in cancer cells. The primary instigator of MDR is the over expression of P-glycoprotein (P-gp), a protein that imparts resistance and facilitates the ATP-dependent efflux of various anticancer agents. Numerous efforts have been made to inhibit P-gp function with the aim of restoring the effectiveness of chemotherapy due to its broad specificity. The main objective has been to create compounds that either serve as direct P-gp inhibitors or interact with cancer therapies to modulate transport. Despite substantial in vitro achievements, there are currently no approved drugs available that can effectively "block" P-gp mediated resistance. Cabozantinib (CBZ), a multi-kinase inhibitor, is utilized in the treatment of various carcinomas. CBZ has been shown to inhibit P-gp efflux activity, thereby reversing P-gp mediated MDR. Consequently, P-gp has emerged as a critical target for research in anti-cancer therapies. The purpose of this study was to computationally identify new andsafer analogues of CBZ using bioisosteric approach, focusing on improved pharmacokinetic properties andreduced toxicity. The physicochemical, medicinal, and ADMET profiles of generated analogues were computed using the ADMETLab 3.0 server. We also predicted the drug likeness (DL) and drug score (DS) of analogues. The molecular docking studies of screened analogues against the protein (PDB ID: 3G5U) were conducted using AutoDock Vina flowing by BIOVIA Discovery Studio for visualizing interactions.Molecular dynamics (MD) simulation of docked ligands was done using Schrödinger suite. The docking scores for the ligands CBZ01, CBZ06, CBZ11, CBZ13, CBZ25, CBZ34, and CBZ38 ranged from -8.0 to -6.4 kcal/mol against the protein (PDB ID: 3G5U). A molecular dynamics (MD) simulation of CBZ01, CBZ13, and CBZ38 was conducted using the Schrödinger suite, revealing that these complexesmaintained stability throughout the 100 ns simulation. An integrated computational approach combining bioisosteric approach, molecular docking, drug likeness calculations, and MD simulations highlights the promise of ligands CBZ01 and CBZ13 as candidates for the development of potential anticancer agents for the treatment of various cancers.

Background: Although a significant amount of literature regarding use of aripiprazole (APZ) in autistic spectrum disorders (ASDs) has benne published, APZ is not approved for use in autism or ASDs in countries other than the United States. Even in the United States, approved use of APZ is limited to the patients with autism in children and adolescents. This review and case reports focus on the available evidence and clinical experience regarding the use of APZ in patients with ASDs including adults Methods: A literature review was conducted, using the PubMed search term ‘aripiprazole’and(‘autistic spectrum disorder’, ‘pervasive developmental disorders’ or ‘Asperger’s disorder’). Results: In previous reports, APZ can target symptoms such as anxiety, depression, aggression, and irritability. Compared with other antipsychotics, APZ also causes fewer adverse events that can lead to drug discontinuation. The case reports supported the literature review: APZ has moderate sedative, antidepressant, and antianxiety effects, when used to treat ASDs. None of the patients experienced adverse reactions (e.g., extrapyramidal symptoms,weight gain, and sedation). Conclusion: APZ reduces aggression in ASDs and improves qualitative deficits in interpersonal interactions and motivation. APZ also causes fewer adverse events. APZ may be associated with favorable treatment compliance,and may improve treatment of ASDs.

Inflammation is a natural process; however, chronic inflammation may result in numerous health issues. Etoricoxib (ETX), a selective cyclooxygenase-2 (COX-2) inhibitor, serves as an anti-inflammatory agent for various types of arthritis. However, prolonged use of ETX is associated with several adverse effects, including cardiovascular toxicity. The current research aims to design an analogue of ETX having superior pharmacokinetic properties and safer toxicological profiles employing the bioisosteric approach. The bioisosteres of various groups in ETX were produced utilizing the MolOpt online tool, resulting in the generation of novel ETX analogues. The pharmacokinetics (ADME) and toxicological profiles of the generated analogues were calculated by ADMETLab 3.0 server. The druglikeness (DL) and drugscore (DS) were calculated using OSIRIS property explorer (PEO). The molecular docking analysis of the ETX analogues against the target protein (PDB ID: 5KIR) was carried out using AutoDock Vina, and their results were visualized by Discovery Studio 2021. Molecular Dynamics (MD) simulation of the top three complexes was conducted using the Schrödinger suite. Binding free energy for the A098-5KIR, A188-5KIR, and D121- 5KIR complexes was conducted using MM-GBSA/PBSA method. A total of 1200 ETX bioisosteres were produced; among them, 51 were screened on the basis of ADMET profile, DL, and DS scores and selected for the docking study. A docking study revealed that 12 analogues show good interactions and docking scores. Furthermore, the molecular dynamics simulation of ligands A098, A188, and D121 demonstrated stability throughout the 100 ns simulation period. The findings of the ADMET study, DL, DS, docking study, MD simulation, and binding free energy calculation indicate that the analogues A098, A188, and D121, which are bioisosteres of ETX, may serve as potential anti-inflammatory agents for inflammation-related disorders.

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are potent insulin sensitizers in treating type 2 diabetes. Despite being very effective in the fight against diabetes-mediated complications, PPARγ agonists are accompanied by severe side effects leading to complicated health problems, making the discovery of novel safe ligands highly pertinent. A significant intense research effort is in progress to explore the PPARγ activating potential of a wide range of natural compounds. Lemon (Citrus limon) contains various bioactive flavonoids, and eriocitrin is the major flavonoid. It possesses substantial antioxidant and anticancer, lipid-lowering activities and prevents obesity-associated metabolic diseases. Eriocitrin is metabolized to eriodictyol in the intestine, and the absorbed eriodictyol undergoes conversion to numerous metabolites in vivo. It is unclear if eriocitrin or its metabolites are responsible for their beneficial effects. We have used molecular docking, ADMET properties, drug-likeness score and molecular dynamics simulation study to find if eriocitrin and its metabolites are potent binders for PPARγ. Docking studies revealed that eriocitrin binds to PPARγ with the highest binding energy, but ADMET properties and in vivo studies show that the bioavailability of eriocitrin is very poor. Molecular dynamics studies were carried out to validate the docking results, and multiple parameters like RMSD, RMSF, Radius of gyration, SASA, hydrogen bond analysis, interaction energy, principal component analysis, Gibbs free energy and MM-PBSA were calculated. Based on our studies, eriodictyol, eriodictyol 7-O-glucuronide, eriodictyol 3′-O-glucuronide, homoeriodictyol and homoeriodictyol 7-O-glucuronide which are metabolites of eriocitrin appear to be potent partial agonists of PPARγ under physiological conditions. Communicated by Ramaswamy H. Sarma

The target of many drugs for the treatment of psychiatric disorders and other related neurological conditions are majorly relied on monoaminergic systems. In continuation of our previous study, computer-aided drug design approach was employed to design some new inhibitors of norepinephrine transporter as potential antipsychotic agents. The significant contribution of some descriptors (AlogP, AATS7i and ATSC3p) in the developed QSAR model and the result of molecular docking simulations from our previous study informed the selection of compound 2 as the lead compound for the design of some new inhibitors in the present study. Subsequently, ten (10) hypothetical inhibitors were designed that showed better pharmacological properties as potential antipsychotic agents when compared the results with an FDA approved antispychotic drug (Atomoxetine). The molecular docking analysis of the designed inhibitors revealed good biochemical interactions toward the active site of the biological target (receptor) with better binding affinities ranges from -7.2 to -7.6 kcal/mol compared to the binding affinity of the lead compound and the referenced drug (Atomoxetine) which were found to be 7.1 kcal/mol and 6.5 kcal/mol, respectively. An appreciable number of hydrogen bonds were associated between the amino acid residues of the protein target and all the designed inhibitors when compared the result to that of the lead compound. Likewise, the computed numerical values of all the descriptors in the designed inhibitors were significantly increased. These remarkable properties observed in the designed inhibitors could be ascribed to the structural modification via electrophilic substitutions (NH2, -OH, –OCH3, -CH3, NO2, -CF3, -F and Cl) at different positions of the lead compound owing to the influence of heteroatoms in the substituents as revealed by the descriptors in the developed QSAR model of our previous study. Similarly, drug-likeness and bioavailability evaluation showed that none of the designed inhibitors violates Lipinski's rule of five. The ADMET properties also revealed that all the designed inhibitors possessed excellent pharmacological attributes. Furthermore, toxicity risk assessments of some selected designed inhibitors showed that most of the selected inhibitors are non-AMES mutagenicity and none of these inhibitors is carcinogens. Against this background, the hypothetical designed inhibitors could be subjected to further experimental investigations and in vitro evaluations before it could be developed and optimized as novel antipsychotic agents/ drug candidates.

Syk and Src-targeted anti-inflammatory activity of aripiprazole, an atypical antipsychotic

Introduction: Prostate cancer (PC) ranks as the second most frequent type of cancer in men and is the fourth largest cause of mortality worldwide. Androgenic hormones such as testosterone and dihydrotestosterone are crucial for the development and progression of the prostate gland. Androgenic hormones bind to androgen receptors (AR) and trigger the synthesis of many genes that stimulate the growth of prostate cells, initiating PC growth. Apalutamide (APL) is a non-steroidal antiandrogen drug used to treat PC; however, it also causes a variety of toxicities and resistance during the treatment. Methods: The purpose of this study was to computationally identify new and safer analogues of APL, focusing on improved pharmacokinetic properties and reduced toxicity. Drug likeness (DL) and drug score (DS) were also calculated. Docking studies on the designed analogues were conducted to predict their binding affinities and compare their orientations with the ligands in the original crystal structure. Molecular dynamics (MD) simulation of docked ligands was done using Schrödinger suite. Results: We generated a total of 1,415 analogues for different groups of APL using the bioisosteric approach. We selected 80 bioisosteres based on pharmacokinetic profiles, DL and DS score predictions, and found that the designed APL bioisosteres were optimal to good compared to APL. Analogues APL19, APL35, APL43, APL76, and APL80, formed hydrogen bonds with protein (PDB ID: 5T8E) which is similar hydrogen bonding to the standard (APL). The MD simulation result confirmed that APL43 and APL80 complexes were stable during the 100nS run. Discussion: The results suggest that the APL analogues, particularly APL43 and APL80, are predicted to be potential antiandrogen drugs for the treatment of prostate cancer.

Background. Antipsychotic drugs (APDs) are used to manage traumatic brain injury (TBI)–induced behavioral disturbances, such as agitation and aggression. However, APDs exhibiting D2 receptor antagonism impede cognitive recovery after experimental TBI. Hence, empirical evaluation of APDs with different mechanistic actions is warranted. Aripiprazole (ARIP) is a D2 and 5-hydroxytryptamine1A (5-HT1A) receptor agonist; pharmacotherapies with these properties enhance cognition after TBI. Objective. To test the hypothesis that ARIP would increase behavioral performance and decrease histopathology after TBI. Methods. Adult male rats were subjected to either a controlled cortical impact (CCI) or sham injury and then randomly assigned to ARIP (0.1 or 1.0 mg/kg) or VEH (1.0 mL/kg, saline vehicle) groups. Treatments began 24 hours after surgery and were administered once daily for 19 days. Motor (beam-balance/beam-walk) and cognitive (Morris water maze) performance was assessed on postoperative days 1 to 5 and 14 to 19, respectively, followed by quantification of hippocampal CA1,3 neuron survival and cortical lesion volume. Results. Beam-balance was significantly improved in the CCI + ARIP (1.0 mg/kg) group versus CCI + ARIP (0.1 mg/kg) and CCI + VEH (P < .05). Spatial learning and memory retention were significantly improved in the CCI + ARIP (0.1 mg/kg) group versus the CCI + ARIP (1.0 mg/kg) and CCI + VEH groups (P < .05). Both doses of ARIP reduced lesion size and CA3 cell loss versus VEH (P < .05). Importantly, neither dose of ARIP impeded functional recovery as previously reported with other APDs. Conclusion. These findings support the hypothesis and endorse ARIP as a safer APD for alleviating behavioral disturbances after TBI.

Background: The development of atypical antipsychotics has markedly improved the treatment of schizophrenia; however, somnolence, metabolic syndrome, hyperprolactinemia and QTc prolongation are their main adverse events. Aripiprazole, the first D2 partial agonist effect antipsychotics, is proposed to reduce such adverse events. Furthermore, the 5HT1A partial agonist and 5HT2A antagonist effect may improve negative and cognitive symptoms. When patients are willing to switch from other antipsychotics to aripiprazole, “cross-tapering” are considered during the switching period. It may reduce the worsening psychosis and unpleasant side effects. Besides, the individual phenotype of CYP2D6 and CYP3A4 may influence the pharmacokinetics of aripiprazole. Objectives: To evaluate the efficacy and safety in different switching strategies and determine which strategy is more appropriate to implement in clinical practice. Methods: This was a block randomization, open-label, parallel assignment, phase IV and 8-week study conducted at 3 hospitals in Taiwan between September 2007 to July 2009. Patients with a primary DSM-IV diagnosis of schizophrenia and schizoaffective disorder were randomly assigned to either fast-switch or slow-switch group. Efficacy measurements included Positive and Negative Symptom Scales and Clinical Global Impressions. Safety measurements included Simpson-Angus Scale, Barnes Akathisia Rating Scale and abnormal Involuntary Movement Scale. Patients were also taken blood samples for the measurement of metabolic profile, drug concentration, and cytochrome P450 CYP2D6 and CYP3A4 genotypes. Results: In a total of 79 patients, 52 (66%) completed the 8-week trial. The fast switching group (n = 29) and the slow switching group (n = 23) were comparable in the demographic features and previous medications. PANSS negative score was significantly improved in both groups over the 8 weeks of treatment (both p < .05), Meanwhile, extrapyramidal symptom, metabolic profile, electrocardiogram and the prolactin level were maintained or somewhat improved as well. The prolactin level in almost all patients returned to normal range by the endpoint. After switching to aripiprazole from other antipsychotics, the symptoms of extrapyramidal symptoms did not increase. The serum concentrations of aripiprazole reached a stable level at day14, and did not significantly change at day 56 for both groups. After grouping by different CYP2D6 and CYP3A4 genotypes for all the subjects, only the CYP2D6*10 variant was associated with a lower serum concentration of aripiprazole as compared with those without the variant. Conclusions: This study provided empirical clinical experience in the treatment of switching patients to aripiprazole from other antipsychotics. Compared with the slow switching strategy, the fast switching strategy has similar efficacy and safety in the 8-week treatment of patients with schizophrenia.