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Ziprasidone is widely used in the treatment of psychiatric disorders. Despite its prevalence, there is a notable lack of population pharmacokinetics (PPK) studies on ziprasidone in serum, both domestically and internationally. This study aimed to comprehensively investigate the various factors influencing the PPK characteristics of Ziprasidone, thereby providing a scientific basis for personalized treatment strategies in clinical settings. This is a retrospective study. A non-linear mixed-effects modeling method was used for data analysis, with the ziprasidone PPK model established using the Phoenix NLME 8.1 software. Model evaluation employed goodness-of-fit plots, visual predictive checks, and Bootstrap methods to ensure reliability and accuracy. To further validate the model's applicability, data from an additional 30 patients meeting the same inclusion criteria but not included in the final model were collected for external validation. Simulations were performed to explore the personalized dosage regimens. This retrospective analysis collected 547 drug concentration data points from 185 psychiatric disorder patients, along with related medical records. The data included detailed demographic information (such as age, gender, weight), dosing regimens, laboratory test results, and concomitant medication details. In the final model, Ka was fixed at 0.5 h -1 based on literature, and the population typical values for ziprasidone clearance (CL) and volume of distribution (V) were 18.74 L/h and 110.24 L, respectively. Co-administration of lorazepam and valproic acid significantly influenced the clearance of ziprasidone. Moreover, the model evaluation indicated good stability and predictive accuracy. A simple to use dosage regimen table was derived based on the results of simulations. This study successfully established and validated a PPK model for ziprasidone in Chinese patients with psychiatric disorders. The model provides a scientific reference for individualized dosing of ziprasidone and holds the potential to optimize treatment strategies, thereby enhancing therapeutic efficacy and safety., Competing Interests: Declarations. Ethics approval: This study was conducted following the Declaration of Helsinki. This research was carried out at the Beijing Anding Hospital, Capital University, with the official endorsement of the hospital’s institutional ethics committee [Ethical Approval No. (2022) Research No. 154]. Consent to participate: The data of this retrospective study are anonymous, and the requirement for informed consent was therefore waived. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: There is no consensus on the optimal antipsychotic for acute agitation. Whereas haloperidol is frequently used and has proven efficacy, second generation antipsychotics show similar efficacy and improved safety and tolerability. This study aimed to determine the effectiveness of short-acting intramuscular (IM) haloperidol versus other IM antipsychotics for acute agitation in adults admitted to an inpatient psychiatry unit., Methods: This was a retrospective medical record review of patients who received 1 or more doses of a short-acting IM antipsychotic, including chlorpromazine, haloperidol, olanzapine, or ziprasidone. The primary endpoint was the need for subsequent IM antipsychotic(s) or physical restraint within 2 hours of the initial IM antipsychotic. Secondary endpoints assessed outcomes at 24 hours and adverse events., Results: One hundred six patients were included. Four patients in the haloperidol group and 0 patients in the other antipsychotic group received an additional IM antipsychotic or required physical restraints within 2 hours (5.3% versus 0%, p  = .319). More patients in the other antipsychotic group required an additional dose of IM antipsychotic within 24 hours compared with the haloperidol group ( p  = .0096). More adverse events were seen in patients who received haloperidol., Discussion: Haloperidol was used more frequently than other short-acting IM antipsychotics. Whereas the effectiveness at 2 hours was not significantly different between groups, patients who received haloperidol were more likely to experience adverse events and were more often subjected to polypharmacy with benzodiazepines and/or diphenhydramine. This study further supports the use of olanzapine and ziprasidone for acute agitation in patients hospitalized in inpatient psychiatry., (© 2024 AAPP. The Mental Health Clinician is a publication of the American Association of Psychiatric Pharmacists.)

This case report details an intentional overdose attempt utilizing tricyclic antidepressants (TCAs) and atypical antipsychotics with significant neurologic, pulmonary, and cardiac toxicity. In conjunction with the local poison control center, progression of the clinical toxidrome was anticipated, aggressively managed, and successfully treated. This case highlights the dangers of significant TCA toxicity, peak onset of toxicity within six hours, and the amplification of clinical toxidromes with co-ingestions., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: HCA Healthcare Disclaimer This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare-affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities., (Copyright © 2024, Foresteire et al.)

Background: Cognitive impairment is a core symptom of schizophrenia and is associated with functional outcomes. Improving cognitive function is an important treatment goal. Studies have reported beneficial cognitive effects of the second-generation antipsychotic (SGA) ziprasidone. Reducing the dose of first-generation antipsychotics (FGA) might also improve cognitive function. This study compared the cognitive effects in long-stay patients who were randomized to groups who underwent FGA dose reduction or switched to ziprasidone. Methods : High-dose FGA was reduced to an equivalent of 5 mg of haloperidol in 10 patients (FGA-DR-condition), and 13 patients switched to ziprasidone 80 mg b.i.d. (ZIPRA condition). Five domains of cognitive function were assessed before dose reduction or switching (T0) and after 1 year (T1). This study was approved by the ethics committee of the Open Ankh (CCMO number 338) and registered at the Netherlands Trial Register (code 5864). Results : Non-significant deterioration was seen in all cognitive domains studied in the FGA-DR condition, whereas there was a non-significant improvement in all cognitive domains in the ZIPRA condition. The most robust difference between conditions, in favor of ziprasidone, was in executive function. Conclusions : In patients with severe chronic schizophrenia, ziprasidone had a non-significant and very modest beneficial effect on cognitive function compared with FGA dose reduction. Larger trials are needed to further investigate this effect.

Quetiapine, a pharmacological agent within the class of atypical antipsychotics, is characterized by its efficacy in mood stabilization and its role in the modulation of serotonergic and dopaminergic pathways. Its therapeutic utility is broad, encompassing the management of acute psychotic episodes, schizophrenia, bipolar disorder, and treatment-resistant depressive states. Quetiapine's effectiveness extends to depressive disorders that do not exhibit classic psychotic features, with a side effect profile that is less burdensome than many alternative psychotropic medications. Its versatility in addressing a range of psychiatric conditions is useful in the psychopharmacological management of mood and thought disorders. However, like all drugs, quetiapine may have different effects relative to the individual. It is imperative to approach the administration of quetiapine carefully, ensuring any adverse effects are ameliorated for beneficial therapeutic outcomes. In this case report, we present a psychosis-naive 42-year-old male who developed psychotic symptoms after beginning a quetiapine regimen in order to manage major depressive disorder with suicidal ideation. Clinical suspicion of quetiapine-induced psychosis was a diagnosis considered due to symptom remission secondary to ziprasidone in the place of quetiapine. The determination of a suspected adverse drug reaction can utilize the Naranjo scale to demonstrate the likelihood of an adverse drug reaction. This patient scored a three on the Naranjo scale, indicating a possible adverse effect from quetiapine. Other potential etiologies of psychosis include medication-induced psychosis, major depressive disorder exacerbation, cocaine use/withdrawal, and brief psychotic disorder. Quetiapine-induced psychosis has not been described in the current literature, and therefore, this case report is solely based on clinical evaluation and is intended for educational purposes due to possible confounding factors and etiologies., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Valentine et al.)

Neuroleptic malignant syndrome (NMS) is a severe adverse reaction associated with neuroleptic or antipsychotic drugs. This case report discusses a 43-year-old man with a history of bipolar disorder and polysubstance abuse who presented with altered mental status, autonomic dysfunction, and muscular rigidity. The patient had recently started on ziprasidone, a second-generation antipsychotic, leading to an atypical presentation of NMS. Unlike classic findings associated with NMS induced by first-generation antipsychotics, this case lacked high fever, lead pipe rigidity, or elevated creatine kinase levels greater than 1000 on initial presentation. The delay in diagnosis was attributed to the milder symptoms and absence of typical findings, resulting in extensive diagnostic workup and interventions. The patient responded positively to treatment with lorazepam based on the Woodbury severity stage guidelines. This case underscores the complexity of diagnosing NMS induced by second-generation antipsychotics and highlights the need for awareness and tailored treatment approaches for atypical presentations., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

On the example of a patient with a mixed affective episode within the framework of bipolar affective disorder, the clinical features of this psychopathological condition, the difficulties of diagnosis and selection of therapy in mixed states are presented. The use of the modern atypical antipsychotic ziprasidone in this category of patients is argued.

In this study, an AQbD-compliant chaotropic chromatography method for ziprasidone and the determination of its five impurities was developed. The influence of critical method parameters (initial and final methanol fraction in the mobile phase, gradient duration) on the set of selected critical method attributes ( t _imp. V , t _imp. V - t _imp. I , S and USP > ) was studied by Box-Behnken design. The errors resulting from the calculation of the model coefficients were propagated to the selected responses by Monte Carlo simulations, and their predictive distribution was obtained. The design space was computed (π ≥ 80%), and a working point was selected: initial methanol fraction 38.5%, final methanol fraction 77.5%, and gradient duration 16.25 min. Furthermore, the quantitative robustness of the developed method was tested using the Plackett-Burman design. P _imp II and P _imp V were found to be significantly affected, the first by mobile phase flow rate and the second by gradient duration. Finally, the method was validated, and its reliability for routine quality control in capsules was confirmed.

The feasibility of using lipid-polymer hybrid (LPH) nanocarriers as a potential platform for the intranasal delivery of ziprasidone (ZP), a second-generation antipsychotic, was explored. Different ZP-loaded LPH composed of a PLGA core and cholesterol-lecithin lipid coat were prepared using a single step nano-precipitation self-assembly technique. Modulation of polymer, lipid and drug amounts, as well as stirring-speed-optimized LPH with a particle size of 97.56 ± 4.55 nm and a ZP entrapment efficiency (EE%) of 97.98 ± 1.22%. The brain deposition and pharmacokinetics studies proved the efficiency of LPH to traverse the blood-brain barrier (BBB) following intranasal delivery with a 3.9-fold increase in targeting efficiency compared to the intravenous (IV) ZP solution with a direct nose-to-brain transport percentage (DTP) of 74.68%. The ZP-LPH showed enhanced antipsychotic activity in terms of animals' hypermobility over an IV drug solution in schizophrenic rats. The obtained results showed that the fabricated LPH was able to improve ZP brain uptake and proved its antipsychotic efficiency.

Introduction: Schizophrenia usually begins with prodromal symptoms in adolescence. In 39% of patients, onset of psychotic symptoms occurs prior to age 19. Advances in the treatment of psychosis with medications over the last decade are reviewed in this paper., Areas Covered: Understanding how to prescribe antipsychotics early in schizophrenia requires an understanding of the pathophysiology of the disease. The current structure of the dopamine hypothesis is reviewed. Risperidone, paliperidone, olanzapine, quetiapine, and aripiprazole have become established treatments prior to 2012. Since 2012, lurasidone (2017) and brexpiprazole (2022) have also been approved. Lurasidone was approved based on placebo-controlled studies, but brexpiprazole has been approved on the bases of open safety trials. In comparative trials, aripiprazole was better tolerated and less likely to cause hyperprolactinemia and metabolic abnormalities., Expert Opinion: Antipsychotics can induce adaptive changes in the brain that predispose patients to future problems such as tardive dyskinesia and supersensitivity psychosis. When pathophysiology of schizophrenia, and a clear understanding of the pharmacology of existing antipsychotics are included in the evidence-based analysis, use of partial agonists, which are less likely to induce adaptive changes in the brain and less likely to induce metabolic and prolactin side effects, become the preferred agents.

Packed with hemoglobin, an essential protein for oxygen transport, human erythrocytes are a suitable model system for testing the pleiotropic effects of lipophilic drugs. Our study investigated the interaction between antipsychotic drugs clozapine, ziprasidone, sertindole, and human hemoglobin under simulated physiological conditions. Analysis of protein fluorescence quenching at different temperatures and data obtained from the van't Hoff diagram and molecular docking indicate that the interactions are static and that the tetrameric human hemoglobin has one binding site for all drugs in the central cavity near αβ interfaces and is dominantly mediated through hydrophobic forces. The association constants were lower-moderate strength (~10 4 M -1 ), the highest observed for clozapine (2.2 × 10 4 M -1 at 25 °C). The clozapine binding showed "friendly" effects: increased α-helical content, a higher melting point, and protein protection from free radical-mediated oxidation. On the other hand, bound ziprasidone and sertindole had a slightly pro-oxidative effect, increasing ferrihemoglobin content, a possible "foe". Since the interaction of proteins with drugs plays a vital role in their pharmacokinetic and pharmacodynamic properties, the physiological significance of the obtained findings is briefly discussed.

Background: Ziprasidone mesylate injection is an atypical antipsychotic drug which is recently approved in China. In combination with its oral formulation, sequential therapy with ziprasidone brings new interventions to patients with agitation in the acute phase of schizophrenia. The purpose of this 7-day multicenter study conducted in China was to evaluate the efficacy and safety of ziprasidone sequential treatment through intramuscular/oral routes in agitated patients with schizophrenia., Methods: A total of 95 patients were enrolled from three centers in this study. The study duration was 7 days. In the first 3 days, subjects were administered an intramuscular injection of ziprasidone 10-40 mg daily and started sequentially with oral ziprasidone 40-80 mg at dinner (or lunch) from the day of the last intramuscular injection. In the following 4 days, according to the severity of the symptoms and the drug response, 120-160 mg of ziprasidone was orally administered daily. In total, six visits were scheduled to assess the Positive and Negative Syndrome Scale (PANSS), the Behavioral Activity Rating Scale (BARS), the Clinical Global Impression of Severity (CGI-S), and Improvement (CGI-I) scores throughout the procedure. Lastly, adverse events were recorded during treatment., Results: Out of the 95 patients that were enrolled, 83 cases were effectively completed. Visits 3, 4, 6, PANSS, and PANSS-excited component (PANSS-EC) subscale points, and Visit 2-Visit 6 viewpoints, BARS scale points, and baseline scores denote a progressive downward trend (P < 0.001). In this study, 62 adverse events were reported. The most common adverse events were extrapyramidal symptoms (EPS) (23 cases) and excessive sedation(10 cases), and 13 cases of prolonged QTc interval were reported., Conclusions: Ziprasidone IM demonstrated significant and rapid reduction in agitation, and sequential oral formulation keep stability and continuation of the treatment can further ensure efficacy. Ziprasidone sequential therapy may provide a new approach to acute agitation in schizophrenic patients., Trial Registration: The Chinese Clinical Trials Registry; URL: https://www.chictr.org.cn : ChiCTR-OIC-16007970., (© 2023. The Author(s).)

A systematic study was performed into the degradation of ziprasidone in simulated postmortem blood. Fifteen potential degradation products not previously reported in the literature were observed. Four resulted from degradation in human blood, whereas the remaining products resulted from reaction with solvents: four from alkaline degradation, four from reaction with acetaldehyde, and three from reaction with acetone. To identify possible degradation products, a liquid chromatograph-diode array detector (LC-DAD) and liquid chromatograph quadrupole-time-of-flight mass spectrometer (LC-QTOF-MS) operating in auto-MS/MS mode were used. It was indicated from red-shifted UV-Vis spectra, accurate mass data, mass fragmentation data, and a deuteration experiment that the site of ziprasidone degradation, in the in vitro blood experiments, was the methylene carbon of the oxindole moiety. The major in vitro blood degradation products were proposed to be E/Z isomers of 3-ethylidene-ziprasidone. Further, another in vitro degradation product in microbially inoculated blood specimens was proposed to be 3-ethyl-ziprasidone. 3-Ethylidene-ziprasidone was hypothesized to form from the reaction of ziprasidone with acetaldehyde derived from the ethanol used to spike ziprasidone into the in vitro blood experiments. Data from two postmortem investigations were available for retrospective reanalysis. Attempts were made to detect degradation products of ziprasidone, but none were found., (© 2022 John Wiley & Sons Ltd.)

Background: Ziprasidone is a second-generation antipsychotic drug commonly used to treat schizophrenia and bipolar disorder. Acne is a common inflammatory disease of sebaceous glands in adolescents that is often co-morbid with anxiety and depression, which may reduce treatment compliance. Through unknown mechanisms, ziprasidone may cause a range of inflammatory responses. Whether ziprasidone can cause acne in young patients with bipolar disorder has not been reported., Case Summary: We report a 23-year-old woman with a 5-year history of bipolar disorder who experienced acne during use of ziprasidone. She was admitted to our hospital during 1-month aggravation of her symptoms and was diagnosed with bipolar I disorder (current or most recent episode of depression) with psychotic features. She was given ziprasidone and soon developed acne, which she never had before; the rash worsened substantially when the ziprasidone dose was increased. At the same time, levels of inflammatory factors increased. The rash resolved after ziprasidone therapy was stopped., Conclusion: When prescribing ziprasidone to young people with bipolar disorder, clinicians should consider the potential for adverse skin reactions. It may be useful to assay levels of inflammatory markers during ziprasidone therapy and adjust the dose if necessary in order to ensure treatment compliance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yuan, Li, Jiang, Li, Ou and Li.)

Objective: To describe the longer-term effectiveness, safety, and tolerability of open-label ziprasidone in children and adolescents with bipolar I disorder (BD-I). Methods: A subset of 23 participants aged 10-17 years, who were previously treated in a multi-site, 4-week randomized controlled trial received open-label ziprasidone (20-80 mg twice a day) for up to 26 weeks. Results: The most common adverse events (AEs) were fatigue (30%), somnolence (17%), and nausea (13%). Effects on weight, body mass index, and metabolic parameters (glucose, cholesterol, and triglycerides) were minimal. No participant had a Fridericia-corrected QT interval ≥ 460 msec or a change from baseline of ≥60 msec, and there were no cardiac-related AEs. Both the participants who continued ziprasidone and those who initiated ziprasidone in the open-label extension showed improvements in their symptoms of mania. Conclusions: The overall findings of the study are consistent with the accumulating knowledge on the safety profile of ziprasidone in the acute and long-term treatment of children and adolescents with BD-I, in the midst of a manic episode. ClinicalTrial.gov ID: NCT03768726.

Background: Patients with severe agitation are frequently encountered in the emergency department (ED). At times, these patients are physically restrained and given calming medications; however, little is known about the effects of medications and other predictors on restraint duration., Objective: Our aim was to compare restraint duration when haloperidol or ziprasidone was used as the primary antipsychotic with or without concomitant medications, and to identify predictors of restraint duration., Methods: We performed a review of a retrospective cohort of physically restrained ED patients between January 1, 2013 and November 30, 2017. An unadjusted analysis and adjusted linear regression model were used to evaluate the effect of antipsychotic choice on restraint duration, controlling for sex, age, race, homelessness, arrival in restraints, re-restraint during visit, concomitant medications (i.e., benzodiazepines or anticholinergics), additional medications given during restraint, time of day, and patient disposition., Results: In 386 patients (319 haloperidol, 67 ziprasidone), the average restraint duration was 2.4 h (95% confidence interval [CI] 2.2 to 2.6 h). There were no differences in physical restraint times between ziprasidone and haloperidol groups in the unadjusted (mean difference 0.12 h; 95% CI -0.42 to 0.66 h) or adjusted analyses (-12.7%; 95% CI -33.9% to 8.6%). Haloperidol given with diphenhydramine alone was associated with decreased restraint duration (-30.8%; 95% CI -50.6% to -11.1%) The largest association with restraint duration was administration of additional sedating medications during restraint, prolonging restraint by 62% (95% CI 27.1% to 96.9%). In addition, compared with White patients, Black patients spent significantly more time restrained (mean difference 33.9%; 95% CI 9.0% to 58.9%)., Conclusions: Restraint duration of agitated ED patients was similar when haloperidol or ziprasidone was used as the primary antipsychotic. However, race and additional medications given during restraint were significantly associated with restraint duration., (Copyright © 2021. Published by Elsevier Inc.)

Treatment-resistant schizophrenia (TRS) is a prevalent clinical problem with heterogeneous presentations. However, the clinical trial designs for new treatments are still lacking. This study aimed to assess the efficacy of ziprasidone plus sertraline in TRS patients as compared to ziprasidone monotherapy. We conducted a 24 weeks, randomized, controlled, double-blinded clinical research trial. 62 treatment-resistant patients with acute exacerbation SZ were randomly allocated to receive a usual dose of ziprasidone (120-160 mg/d) monotherapy (Control group) and 53 TRS inpatients were to receive a low dose of ziprasidone (60-80 mg/d) in combination with sertraline (ZS group). Treatment outcomes were measured by the Positive and Negative Syndrome Scale (PANSS), the Hamilton Depression Rating Scale (HAMD), CGI-Severity (CGI-S) and Personal and Social Performance Scale (PSP) at baseline, week 4, 8, 12, and 24. Relative to control group, the patients in ZS group showed greater reductions in the following: PANSS positive symptom, negative symptom, total score, and HAMD total score. Additionally, the patients in ZS group had a greater increase in PSP total score. Notably, the reduction in HAMD was positively correlated with the reduction in PANSS total score. The reduction in CGI-S was a predictor for the improvement of psychosocial functioning in patients. Furthermore, the ZS group had a lower rate of side effects compared to the control group. Our findings suggest that a low dose of ziprasidone in combination with sertraline is an effective therapy for the clinical symptoms as compared to a usual dose of ziprasidone in the treatment-resistant patients with acute exacerbation SZ. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04076371., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shi, Xu, Lang, Wu, Xiu and Zhang.)

Objective: To evaluate the acute efficacy, safety, and tolerability of flexibly dosed ziprasidone in children and adolescents with Bipolar I Disorder (BD-I). Methods: Participants, 10-17 years of age, meeting The Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria, were randomized 1:1 in a 4-week double-blind (DB) study, to receive ziprasidone (20-80 mg/twice a day) or placebo. Some were then enrolled in a 26-week open-label extension (OLE) study. The primary efficacy measure was the Young Mania Rating Scale (YMRS) total score. Results: A total of 171 participants entered this randomized DB study and 23 continued into the OLE study. The mean (SD) age of the combined sample was 13.4 (2.1) years, 44.4% were male, and 66.7% were white. The demographic characteristics of participants who received ziprasidone ( n  = 86) or placebo ( n  = 85) were similar. The primary objective was met: the mean difference for ziprasidone versus placebo in the YMRS total score was -4.23 (95% confidence interval: -7.14 to -1.32; p  = 0.005) indicating an effect size of 0.58. The most common adverse events (AEs) in the ziprasidone group were somnolence (31.4%), fatigue (22.1%), and nausea (14%). The mean Fridericia-corrected QT interval (QTcF) intervals in the ziprasidone group were moderately prolonged relative to the placebo group at all study visits. No participants had QTcF intervals ≥480 msec or an increase from baseline ≥60 msec. No AEs indicative of QT prolongation occurred. Weight, body mass index (BMI), and BMI z -scores, and metabolic measures were similar in both treatment groups. The data from the OLE study will be reported separately. Conclusions: Ziprasidone was effective in children and adolescents with BD-I in a manic episode, replicating the results of a previous study with a similar design (Findling et al. 2013). Overall, ziprasidone was safe and well tolerated with no meaningful effects on weight or metabolic parameters. Trial registration: ClinicalTrials.gov. NCT02075047 and NCT03768726.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignant tumor whose effective treatment has not been found. The redox state and proliferative activity of PDAC cells are maintained by the conversion of aspartic acid in the cytoplasm into oxaloacetate though aspartate aminotransferase 1 (GOT1). Therefore, GOT1 inhibitors as a potential approach for treating PDAC have attracted more attention of researchers. Ziprasidone effectively inhibited GOT1 in a non-competitive manner. The potential cytotoxicity and anti-proliferation effects of ziprasidone against PDAC cells in vitro and in vivo were evaluated. Ziprasidone can induce glutamine metabolism disorder and redox state imbalance of PDAC cells by targeting GOT1, thereby inhibiting proliferation, preventing migration, and inducing apoptosis. Ziprasidone displayed significant in vivo antitumor efficacy in SW1990 cell-derived xenografts. What's more, knockdown of GOT1 in SW1990 reduced the anti-proliferative effects of ziprasidone. As a novel GOT1 inhibitor, ziprasidone may be a lead compound for the treatment of PDAC. KEY MESSAGES: Small molecule inhibitors targeting GOT1 may provide a therapeutic target in PDAC. Ziprasidone effectively inhibited GOT1 enzyme in a non-competitive manner. Ziprasidone repressed glutamine metabolism and inhibited the growth of tumor in vivo. Knockdown of GOT1 decreased the anti-proliferative effects of ziprasidone., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Many patients with schizophrenia (SCZ) discontinue antipsychotics, frequently due to dose-related multiple and severe adverse effects. We hypothesized that a low-dose ziprasidone plus sertraline would reduce serious side effects without affecting treatment efficacy. Therefore, this clinical trial was designed to investigate the efficacy, safety, and tolerability of adding sertraline to ziprasidone in order to substantially reduce ziprasidone dose and potential side effects in first-episode and drug-naive (FEDN) patients with SCZ. This 24-week randomized, double-blinded, controlled clinical trial randomly allocated 452 FEDN SCZ patients to receive a usual dose of ziprasidone (control group) or half the dose of ziprasidone in combination with sertraline (ZS group). Treatment outcome included the Positive and Negative Syndrome Scale (PANSS), the Hamilton Depression Rating Scale (HAMD), CGI-Severity (CGI-S) and the Personal and Social Performance Scale (PSP) at baseline and weeks 2, 4, 8, 12, and 24. Repeated measures ANCOVA showed significant treatment by time interactions on the PANSS general psychopathology and total scores, as well as CGI-S, HAMD, and PSP scores (all p < 0.05). Furthermore, the ZS group had greater reductions in PANSS general psychopathology, total scores, HAMD, and CGI-S (all p < 0.05) and greater increases in the PSP total score (p < 0.01) than the control group. Importantly, adverse effects were lower in the ZS than control group. The reduction in PANSS, CGI-S, or HAMD scores was not correlated with the increase in PSP. Sex and duration of disease predicted PSP improvement from baseline to week 24 in the ZS group. Our FEDN patients with SCZ were effectively treated for their psychotic and depressive symptoms while experiencing significantly fewer adverse effects using half the usual ziprasidone dose when combined with sertraline. ClinicalTrials.gov, NCT04076371., (© 2022. The American Society for Experimental NeuroTherapeutics, Inc.)

The objective was to develop a model to a priori identify the most suitable depot technology for a candidate based upon its therapeutic index (TI), pharmacokinetics (PK), and physical chemical properties. A depot map of release rates needed to achieve target PK in TI against release rates predicted based on intrinsic dissolution rate (IDR) and particle size (PS) clearly identified three zones: (a) products and candidates around the line of identity for which suspension is the appropriate depot technology, (b) area to the right of line of identity in which depot candidates would require a controlled release technology such as PLGA microspheres since in vivo release rate needed for PK in TI is significantly lower than predicted based on IDR and PS, and (c) area to the left of the line of identity where IDR is not sufficient to achieve target in vivo release rate for PK in TI and hence enhanced dissolution is needed such as with nanoparticles. Dose-solubility technology map of approved depot products and candidates showed clusters of products around a depot technology such as suspensions and microspheres, for drugs with high dose/low solubility and low dose/high solubility compounds, respectively. Novel PK-based computational tool showed how all combinations of depot doses and release rate constants for a candidate can be calculated to achieve plasma levels within the TI bounded by minimum effective and minimum toxic concentrations (MEC and MTC). The PK predictions for several drugs such as estradiol, risperidone, medroxyprogesterone acetate (MPA), and ziprasidone showed how these predictions can guide scientists to target specific depot doses and release rates into the depot formulation. In parallel, IDR of depot compounds clearly showed differentiation of compounds by successful depot technologies to achieve target dose and duration. For drugs with IDR between 0.1 and 1 mg/h/cm 2 , aqueous suspension has successfully delivered depot PK profile, while for candidates with IDRs greater than 1 mg/h/cm 2 , controlled release technology such as microsphere or in situ gel was required. The framework, prediction tools, and depot map will reduce the need for semi-empirical formulation work and preclinical studies to design depot formulations. Graphical Abstract., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background and Objectives: Patients taking opioids are at risk of developing dependence and possibly abuse. Given the role of the mesolimbic dopamine system in opioid reward, blocking dopamine D2 receptors should limit the abuse liability of opioid analgesics. This pilot study evaluates the analgesic efficacy of oxycodone combined with an atypical antipsychotic (dopamine D2 receptor antagonist)., Methods: A randomized, double-blind, within-subjects, controlled trial in healthy volunteers was conducted at UT Health SA Pain Clinic. Fifteen volunteers with previous medical exposure to opioids were enrolled. Risperidone (2 mg) or ziprasidone (80 mg) in combination with oxycodone (5, 10, 15 mg) was administered. Pain intensity using the cold pressor test, Current Opioid Misuse Measure (COMM), Addiction Research Center Inventory (ARCI, opioid subscale), Drug likability with drug effects questionnaire (DEQ) were assessed., Results: Oxycodone produced dose dependent increases in thermal analgesia on the cold pressor test that was significant at 10 and 15 mg ( t = 3.087, P = 0.017). The combination did not significantly alter thermal analgesia. There was no significant effect of the combination on the ARCI or the POMS., Discussion and Conclusion: The combination of an atypical antipsychotic with oxycodone does not alter analgesic response or increase the incidence of adverse effects when compared to oxycodone alone. Such information is critical for the development of drug combinations for the treatment of pain and provide the foundation for future studies of abuse potential in drug users., Scientific Significance: This intervention in chronic pain patients is unique because it utilizes FDA approved drugs in combination to reduce abuse liability. The first step, and aim of this study, is to confirm the drug combination does not interfere with analgesic efficacy. The next step is to examine the combination in recreational drug users to assess the potential to block the euphoric effects of oxycodone. Ultimately, if this combination is effective, this approach could be beneficial in management of chronic pain., Competing Interests: DL and AF have a patent filed on this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nagpal, Lodge, Potter, Frazer, Tragus, Curtis, Boley and Eckmann.)

Ziprasidone hydrochloride is a second-generation antipsychotic drug employed for the treatment of schizophrenia and acute mania or mixed episodes associated with bipolar disorder. During the scale-up of ziprasidone hydrochloride, an unknown impurity was observed in the batches ranging from 0.10% to 0.15% by HPLC-UV analysis. The structure of an unknown impurity was proposed as 3,3'-methylenebis(5-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloroindolin-2-one) which is named as methylene ziprasidone dimer (MZD impurity). It was isolated from an enriched sample by preparative HPLC, and its structure was elucidated by comprehensive analysis of HRMS, 1D NMR ( 1 H, 13 C), DEPT-135, 2D NMR (COSY, HSQC, HMBC) spectroscopy. A plausible mechanism for the formation of isolated impurity is proposed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflict of interest The authors report no declarations of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: The current study focused on the evaluation of the cytotoxic effect and permeability of ziprasidone hydrochloride monohydrate (ZHM) nanocrystals on Caco-2 cells., Materials and Methods: ZHM nanocrystals were prepared by the microfluidization method in the presence of polyvinylpyrrolidone as a stabilizer. Particle size (PS), particle size distribution (PDI), and zeta potential (ZP) values were measured in characterization studies. In vitro cytotoxic effects of ZHM nanocrystals were investigated using the 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Caco-2 transport studies were conducted with formulations of ZHM coarse powder and nanocrystals., Results: Nanocrystals were obtained with 400-600 nm PS, 0.1-0.4 PDI, and >20 mV ZP values. The cell viability remained 100% for all sample groups. The permeability value of ZHM nanocrystals through Caco-2 cells increased 2.3-fold in comparison with ZHM coarse powder. Cumulative drug transport also increased at the end of the sampling period., Conclusion: Nanocrystal technology helps to increase the permeability of drug particles by increasing the saturation solubility.

Neuroleptic malignant syndrome (NMS) is a well-recognized neurologic emergency. It presents with classic features including hyperthermia, autonomic instability, muscle hypertonia, and mental status changes. The syndrome is potentially fatal and is associated with significant morbidity due to complications such as rhabdomyolysis, acute kidney injury, and ventricular arrhythmias due to the trans-cellular electrolyte shift. NMS is conventionally associated with the first-generation antipsychotic agents, however, has been described with the use of atypical and novel antipsychotics including Ziprasidone. A case of NMS with Ziprasidone use at the therapeutic dose is reported here., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Sedhai YR et al.)

Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-moderate hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment.

Introduction: Despite the paucity of studies evaluating short-acting parenteral second-generation antipsychotics in the medically ill, their use in this population has increased. The purpose of this study was to characterize the use of IM olanzapine and ziprasidone in the medically ill at an academic medical center., Methods: This is a retrospective medical record review of all patients who received IM olanzapine or ziprasidone on nonpsychiatric inpatient units at a large academic medical center from August 1, 2015 to July 31, 2017. The primary endpoint characterized the indication for use. Secondary endpoints included safety, effectiveness, and prescribing patterns., Results: After exclusion criteria, a total of 100 patients were included in this study, predominantly white males with a mean age of 56 years. Seventy-four percent of patients received IM ziprasidone and 26% received IM olanzapine. The most common indications for use were agitation of nonpsychotic origin (40%) and delirium (33%). Patients received IM olanzapine and ziprasidone when their use was contraindicated (26.9% vs 9.5%, respectively)., Discussion: Intramuscular second-generation antipsychotics are increasingly being used in the medically ill for delirium and agitation. Our study confirms these were the most common indications for IM second-generation antipsychotic use in this population. Additionally, their use appeared to be well-tolerated, and no patient developed Torsades de Pointes even when combined with other agents that putatively increase QTc. Given the retrospective, single-center, nonrandomized design of this study, the safety and effectiveness of these parenteral second-generation antipsychotics in common causes of acute agitation should continue to be further evaluated., Competing Interests: Disclosures: The authors have no potential conflicts of interest or sources of funding to disclose with regards to the conducted research and prepared article., (© 2021 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.)

Schizophrenia is a severe, chronic mental illness characterized by delusions, hallucinations, negative symptoms, and cognitive dysfunction. Recently, several studies have demonstrated that the pathogenesis of schizophrenia involves mitochondrial dysfunction and oxidative stress. However, the effect of antipsychotic drugs for these events has been poorly investigated. In the present study, we evaluated the neuroprotective effect of an atypical antipsychotic drug, ziprasidone (ZPD), on rotenone (ROT)-induced neurotoxicity involving oxidative stress in PC12 cells. Our data showed that ZPD treatment promoted the translocation of NF-E2-related factor-2 (Nrf2) from cytoplasm to nucleus and activated the expression of its target genes NAD(P)H quinone oxidoreductase (NQO-1), catalase (CAT), and heme oxygenase (HO-1). Additionally, ZPD prevented ROT-induced cell death and intracellular reactive oxygen species production. Interestingly, the use of serotonin 5-HT 1A receptor antagonist 1-(2-methoxyphenyl)-4 (4-(2-phtalimido) butyl) piperazine (NAN-190) completely blocked the protective effect of ZPD against ROT-induced cell death. Our results demonstrate the neuroprotective effect of ZPD against ROT-induced neurotoxicity and suggest that ZPD may be a potential candidate for the prevention of mitochondrial dysfunction and oxidative stress in schizophrenia.

Some psychiatric diseases are associated with disruptions in the circadian clock system. Ziprasidone (ZIP), a second-generation antipsychotic, is widely used for psychiatry-related pharmacotherapy but its mechanism has not been clearly elucidated. We measured clock gene fluctuation patterns in the hippocampus and the amygdala in ZIP-treated mice. ZIP significantly increased Per1, Per2, and Bmal1 mRNA 2 h after the lights were turned off (ZT14) in the hippocampus, but not in the amygdala. These results suggest that ZIP might affect clock gene regulation, which could represent the pathway underlying symptom amelioration., Competing Interests: Declaration of Competing Interest The authors indicate no potential conflicts of interest., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Oculogyric crisis is a rare ocular dystonia first appearing at the turn of the last century in postencephalitic patients. In the modern era, they were most frequently associated with first-generation D1 dopaminergic receptor blocking antipsychotic medication. We present an unusual case of acute oculogyric crisis in a 74-year-old woman with long-standing Parkinson disease following exposure to the second-generation neuroleptic ziprasidone, which has dopaminergic (D2) and serotoninergic (5-HT2A) receptor blocking effects and is used for severe delusions and psychosis. To the best of our knowledge, there are no other published reports., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Wilson et al.)

Restless legs syndrome (RLS) is a common sleep-related movement disorder characterised by an uncomfortable urge to move the legs that occurs during periods of inactivity. Although there have been many case reports on antipsychotic-induced RLS, ziprasidone has never been reported as a cause of RLS. We present a case of a female patient with schizophrenia who presented with symptoms of RLS following the administration of high doses of ziprasidone added to quetiapine and valproate. The patient's symptoms of RLS occurred following the administration and titration of ziprasidone to 160 mg, and were relieved upon reducing the dose to 120 mg/day. Other potential causative medications and differential diagnoses that could have caused similar symptoms were excluded. Clinicians should be aware of the potential for ziprasidone-induced RLS. Dopamine and serotonin interaction could be the mechanism underlying ziprasidone-induced RLS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The purpose of this study was to develop and evaluate a new formulation of ziprasidone (ZIP) for improved fasted state absorption and sustained drug release. ZIP solid dispersions were produced via spray drying using Soluplus®, an amphiphilic polymer, as the solubility enhancer. Physicochemical analysis proved that ZIP presented at amorphous state in the spray-dried microparticles and the dissolution rate of ZIP from the Soluplus®-ZIP composite microparticles was significantly increased compared with that of the physical mixtures. Commonly used encapsulation materials including Eudragit® RL, Eudragit® S100 and Ethyl Cellulose were incorporated into the solid dispersions to regulate the drug release kinetics. The formulation containing ethyl cellulose provided the most sustained release behaviors. Pharmacokinetic studies in beagle dogs confirmed that there was no significant difference in oral bioavailability of the microparticles under fasted and fed states, and a prolonged T max value was simultaneously achieved compared with the commercial ZIP capsules.

Acute agitation is a common presenting symptom in the emergency ward and is also dealt with on a routine basis in psychiatry. Usually a symptom of an underlying mental illness, it is considered urgent and immediate treatment is indicated. The practice of treating agitation on an acute care basis is also referred to as rapid tranquilization. A variety of psychotropic drugs and combinations thereof can be used. The decision is usually made based on availability and the clinician's experience, with the typical antipsychotic haloperidol (alone or in combination with antihistaminergic and anticholinergic drugs such as promethazine), the benzodiazepines lorazepam, diazepam and midazolam as well as a variety of atypical antipsychotics being used for this purpose. Haloperidol is associated with extrapyramidal symptoms (which can be controlled by co-administration of promethazine) and may control agitation without inducing sedation, while benzodiazepines have a more pronounced sedating activity. The atypical antipsychotics aripiprazole and ziprasidone are better tolerated, while olanzapine is also a powerful sedative. Clinical trials evaluating the efficacy of different treatment options have been conducted but they are extremely heterogenous and most have numerous methodological flaws, leading to a poor overall quality of evidence upon which guidelines for the appropriate treatment could be based. The combination of haloperidol and promethazine, which combines the sedative properties of the antihistamine with the more selective calming action of haloperidol (with a reduced risk of extrapyramidal effects compared to haloperidol alone because of the anticholinergic properties of promethazine) may be the best choice based on empirical evidence., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Zareifopoulos et al.)

Vlad, not his real name, a 15 year old boy with an autism spectrum disorder and intellectual disability, was referred for psychiatric consultation due to aggression and other behavioural problems. He presented for initial psychiatric consultation on five psychotropic medications with associated severe obesity. A systematic deprescribing and cross-tapering plan was implemented, removing all five psychotropic medications (which included olanzapine and quetiapine) and introducing ziprasidone. These changes were associated with a 44.8kg weight loss with no behavioral deterioration and overall lower rates of aggression. Vlad's case may typify important deficiencies in the service system which create a context that allows for aggressive psychotropic polypharmacy without apparent concomitant increase in sophistication of behavioral management design and support, while also tolerating substantial treatment adverse effects (e.g., medication induced severe obesity) within a member of a vulnerable population (e.g., a youth with developmental disability in care). Suggestions to address some of these contextual factors are outlined., (Copyright © 2019 Canadian Academy of Child and Adolescent Psychiatry.)

Antipsychotic drugs interfere with the antioxidant defense system provoking complex and often toxicological effects. Here we examined differences in plasma albumin reduced free thiol (SH) group content and its reactivity as a consequence of clozapine (CLZ) and ziprasidone (ZIP) binding. Chronic administration of CLZ reduced, whereas treatment with ZIP increased albumin-SH content in rats. Regardless of the ratio of stearic acid (SA) bound to protein, in vitro binding of ZIP to human serum albumin (HSA) increased both the SH group level and reactivity. In contrast, the effect of CLZ on HSA-SH reactivity was dependent on HSA to SA molar ratio. CLZ binding was accompanied by an increase in HSA-SH reactivity in samples with normal, but a reduction of its reactivity level with higher SA/HSA ratio, compared to drug-free samples. We demonstrate by steady-state fluorescence quenching studies that an increase in SA binding to HSA is associated with a significant reduction of binding constant for both antipsychotics. In addition, this is the first report of quantitative characterization of ZIP binding to HSA. Our findings suggest that albumin-SH content and reactivity is modulated by ZIP towards an increased antioxidant defense capacity in circulation, as opposed to CLZ, which can contribute to the safer, more effective treatment of schizophrenia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Pregnancy is associated with physiological changes that alter the pharmacokinetics (PK) of drugs. The aim of this study was to predict the PK of ziprasidone in pregnant women., Methods: A full physiologically-based pharmacokinetic (PBPK) model of ziprasidone was developed and validated for the non-pregnant population (healthy adults, paediatrics, geriatrics), and this was extended to the pregnant state to assess the change in PK profile of ziprasidone throughout pregnancy., Results: The PBPK model successfully predicted the ziprasidone disposition in healthy adult volunteers, wherein the predicted and observed AUC, C max and t max were within the fold-difference of 0.94-1.09, 0.89-1.40 and 0.80-1.08, respectively. The paediatric and geriatric population, also showed predicted AUC, C max and t max within a two-fold range of the observed values. The simulated exposure in pregnant women using a p-PBPK model showed no significant difference when compared to non-pregnant women., Conclusions: The PBPK model predicted the impact of physiological changes during pregnancy on PK and exposure of ziprasidone, suggesting that dose adjustment is not necessary in this special population., (© 2019 The British Pharmacological Society.)

Objectives: An increasing number of pediatric patients with psychiatric chief complaints present to emergency departments (EDs) nationwide. Many of these patients require treatment with antipsychotic medications to treat agitation. We sought to examine the use of antipsychotic medications in pediatric patients presenting to a tertiary care pediatric ED., Methods: We performed a retrospective electronic medical record review of patients presenting to a tertiary care pediatric hospital from January 2009 through February 2016 with a psychiatric chief complaint who received an antipsychotic medication in the ED., Results: A total of 229 patients were identified, 54.1% of whom were male. Mean age was 14.4 ± 2.6 years. Commonly administered medications included olanzapine (51.1%), aripiprazole (26.6%), haloperidol (24.0%), and risperidone (11.8%). Eighty-seven patients (38.0%) were given at least 1 intravenous or intramuscular dose of antipsychotic medication. A total of 113 patients (49.3%) received only 1 antipsychotic medication, 65 (28.4%) received 2, 30 (13.1%) received 3, and 21 (9.2%) received 4 or more antipsychotics. Median length of stay (minutes) increased significantly with increasing number of medications administered (p < 0.001). Length of stay was significantly shorter in patients given only oral medications (675.6 minutes, IQR 418-1194) compared to those given at least one intramuscular or intravenous dose (951 minutes, IQR 454-1652) (p = 0.014)., Conclusions: In this retrospective series, the majority of patients were treated with newer oral antipsychotics. Administration of multiple medications was associated with a significantly longer length of stay in the ED, as was parenteral administration of antipsychotics.

The separation and characterization of the unknown degradation product of second-generation antipsychotic drug ziprasidone are essential for defining the genotoxic potential of the compound. The aim of this study was to develop a simple UHPLC method coupled with tandem mass spectrometry (MS/MS) for chemical characterization of an unknown degradant, and the separation and quantification of ziprasidone and its five main impurities (I-V) in the raw material and pharmaceuticals. Chromatographic conditions were optimized by experimental design. The MS/MS fragmentation conditions were optimized individually for each compound in order to obtain both specific fragments and high signal intensity. A rapid and sensitive UHPLC-MS/MS method was developed. All seven analytes were eluted within the 7 min run time. The best separation was obtained on the Acquity UPLC BEH C 18 (50 × 2.1 mm × 1.7 μm) column in gradient mode with ammonium-formate buffer (10 mm; pH 4.7) and acetonitrile as mobile phase, with the flow rate of 0.3 mL min -1 and at the column temperature of 30°C. The new UHPLC-MS/MS method was fully validated and all validation parameters were confirmed. The fragmentation pathways and chemical characterization of an unknown degradant were proposed and it was confirmed that there are no structural alerts concerning genotoxicity., (© 2018 John Wiley & Sons, Ltd.)

Background: Over 10 million Chinese are affected by schizophrenia. The annual cost of schizophrenia in China was estimated at US$2586 per patient., Aims: The study has two aims: (1) to conduct a targeted literature review of the economic literature on oral ziprasidone in China, and (2) to develop an inpatient economic model that compared the cost of intramuscular ziprasidone with other regimens including electroconvulsive therapy (ECT) for the management of acute agitation in patients with schizophrenia from a hospital's perspective in China., Methods: A targeted literature review was conducted using PubMed and the Chinese literature databases for studies published between January 2007 and December 2017. Studies that assessed costs associated with oral ziprasidone treatment for schizophrenia in China were summarised. In the inpatient economic model, cost measures included hospital room and board, antipsychotics, ECT and medications for the management of extrapyramidal symptoms (EPS). Input for standard antipsychotic regimens and unit cost were obtained from the literature. Hospital length of stay (LOS), utilisation of ECT and incidence of EPS were derived from the literature and supplemented/validated with a survey of psychiatrists in China. Cost was presented in 2017 Chinese yuan., Results: The average estimated LOS was 29 days with ziprasidone, 33 days with risperidone+benzodiazepine, 32 days with olanzapine, 35 days with haloperidol and 29 days with ECT. The cost of antipsychotics was ¥1260 with ziprasidone, ¥137 with risperidone+benzodiazepine, ¥913 with olanzapine and ¥210 with haloperidol; ECT treatment cost ¥785. The base-case analysis suggested that higher antipsychotic cost with ziprasidone was offset by savings with shorter LOS. Using intramuscular ziprasidone for acute management was associated with a total cost of ¥11 157, the lowest among all antipsychotic regimens (¥11 424 with risperidone+benzodiazepine, ¥11 711 with olanzapine and ¥11 912 with haloperidol) and slightly higher than ECT (¥10 606). The cost of antipsychotics and ECT accounted for 1 %-11 % of the total cost. Varying LOS between the lower and upper bounds of the 95% CI, the total cost was comparable between these regimens., Conclusions: Overall, the cost for the management of acute agitation was similar between intramuscular ziprasidone and other antipsychotics. Compared with other antipsychotics, the higher medication cost of intramuscular ziprasidone can be offset by savings with shorter hospital stay. The results from this economic analysis were complementary to the findings in the published literature assessing the economic outcomes of oral ziprasidone., Competing Interests: Competing interests: Y-CY, FD and XG are paid consultants of Pfizer Investment. DL and LY are employees of Pfizer Investment.

Background: Agitation is very common in patients with acute stage schizophrenia, and injection of antipsychotics and clonazepam is widely used. Network meta-analysis of these comparisons among three injection treatments has been seldom reported., Aim: To compare the efficacy and safety of various injections for agitation symptoms in Chinese patients with schizophrenia., Methods: Searches were made in PubMed, Embase and Web of Knowledge, Cochrane Library, Wanfang data, CNKI, SinoMed and VIP databases up to 18 February 2018. Standard search strategies were performed by two reviewers according to the Cochrane Review Group. The Consolidated Standards of Reporting Trials statement was used to assess the methodological quality of the studies. STATA was used to perform meta-analysis. The Cochrane Grades of Recommendation, Assessment, Development and Evaluation (GRADE) was used to assess the strength of evidence., Results: A total of 15 studies were included in the network meta-analysis. There were 11 studies comparing ziprasidone with haloperidol, and four studies comparing haloperidol with clonazepam. The results showed that ziprasidone is more effective than haloperidol and clonazepam (sucra: 77.2, 72.8 and 0) in the treatment of agitation symptoms. There was the effect size (standardised mean difference (SMD)) in the three groups: haloperidol: SMD=2.278, 95% CI 1.836 to 2.719; ziprasidone: SMD=2.536, 95% CI 2.082 to 2.990; and clonazepam: SMD=1.360, 95% CI 0.127 to 2.593. The acceptability was assessed by the incidence of excessive sedation, which showed that ziprasidone and haloperidol were similar with both being superior to clonazepam (sucra: 0.3, 0.7 and 99.0). Ziprasidone had significantly less adverse effects than haloperidol in effects of extrapyramidal system (EPS) ( z =5.01, p <0.001). There were no statistically significant differences between haloperidol and ziprasidone in tachycardia and abnormal ECG ( z =1.69, p =0.091; z =0.87, p =0.386; respectively). Based on GRADE, the strength of the evidence for primary outcome was 'medium'., Conclusion: Our results suggested that ziprasidone was more suitable than haloperidol and clonazepam in the treatment of agitation symptoms in Chinese patients with schizophrenia, according to the efficacy and acceptability of these three intramuscular injection medications., Competing Interests: Competing interests: None declared.

Long-stay patients with severe schizophrenia are frequently treated with high doses of first-generation antipsychotics (FGA). Dose reduction or switching to ziprasidone may reduce the severity of negative symptoms and side effects. We investigated in a randomized double-blind trial whether a dose-reduction strategy to achieve an adequate dose of a FGA (5 mg/day haloperidol equivalents, n = 24) or switching to ziprasidone (160 mg/day, n = 24) in treatment resistant patients would decrease negative symptoms after 1 year of treatment. We found that negative symptoms did not change significantly in either condition. Positive symptoms, excited symptoms, and emotional distress worsened over time with ziprasidone, resulting in a significant difference between conditions in favour of FGA dose reduction. Relapse and treatment failure, defined as a prolonged or repeated relapse, occurred more often with ziprasidone than with FGA (45.8% versus 20.8%, and 25.0% versus 16.7%, respectively). Treatment with ziprasidone was superior for extrapyramidal symptoms. Our study establishes that lowering high FGA doses to an equivalent of 5 mg/day haloperidol or switching to ziprasidone is feasible in the vast majority of patients but does not improve negative or other symptoms. Neither FGA dose reduction nor switching to ziprasidone is an adequate alternative to clozapine for long-stay patients with severe treatment resistant schizophrenia., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

The synergistic effect of nanosizing and lipid-based drug delivery systems (LBDDS) was explored to enhance formulation drug loading levels and improve drug solubilisation in the gastrointestinal environment. A novel formulation combining drug nanocrystals and silica-lipid hybrid (SLH) microparticles as a solid-state LBDDS was developed for the challenging poorly water-soluble drug, ziprasidone. A ziprasidone nanosuspension was fabricated via high-pressure homogenisation, achieving a mean particle size of 280 nm. In vitro dissolution studies revealed the nanosuspension to exhibit a significant 2.4-fold increase in the extent of drug dissolution, relative to pure drug. Novel ziprasidone nanocrystal-loaded SLH microparticles (ncSLH) were formulated by freeze-drying a precursor drug-loaded emulsion with drug nanocrystals and silica nanoparticles. Drug loading levels were increased at least 17-fold relative to conventional SLH microparticles, resulting in an increase in crystalline drug content and a change in surface atomic composition. The in vitro performance was evaluated by quantifying solubilisation levels during simulated intestinal lipolysis studies. Novel ncSLH significantly improved the in vitro fasted state solubilisation of ziprasidone (up to 4.7-fold), thus indicating the potential for such a formulation to overcome some of the various challenges faced by poorly water-soluble, brick-dust drug molecules., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Antipsychotic drugs are used to treat schizophrenia and other psychiatric disorders. However, most of these drugs present side effects causing obesity and other serious metabolic alterations that correlate with grade of chronic inflammation. In contrast, ziprasidone's (ZIP) metabolic side effects are attenuated relative to those of other antipsychotic drugs, but some reports suggest that this drug could cause allergic, hypersensitive reactions in susceptible patients. At present, the mechanism of ZIP's effect on peripheral inflammatory metabolism is not well characterized. We conducted an in vitro study to evaluate the effect of ZIP on a macrophage cell line (RAW 264.1). Our results showed that in non-activated macrophage cells, ZIP exposure initiated macrophage spreading; increased cellular proliferation, as evaluated by MTT and flow cytometry assays; and presented higher levels of oxidant molecules involved in the inflammatory response (nitric oxide, superoxide, reactive oxygen species), and proinflammatory cytokines (IL-1, IL-6, TNFα, INFγ). Levels of IL-10, an anti-inflammatory cytokine were lower in ZIP-exposed cells. These effects were less potent than those caused by the positive control for inflammation induction (phytohemagglutinin), and more intense than the effects of lithium (LI), which was used as an anti-inflammatory molecule. ZIP also modulated cytokine gene expression. Taken together, these data suggest that ZIP can produce a peripheral inflammatory response, and this response may explain the allergen-inflammatory response observed in some patients treated with this antipsychotic drug., (Copyright © 2017. Published by Elsevier Ltd.)

So far, demographic variables have not consistently been found to predict clinical response to antipsychotics. This study examines some differences in response to ziprasidone, which has been shown to be effective, with a better metabolic side effect profile, but was little used in New York State Hospitals. The aim was to study state hospital patients switched to ziprasidone. The results led to questions about different responses in different groups. Subjects from state hospitals who needed a change of antipsychotic participated in this open-label, 8-week trial of up to 240-mg ziprasidone. Analyses included comparisons of the very different results from two sites. Of the 36 study subjects, 12 terminated early. The 17 outpatients from Buffalo, who were older and on lower doses of antipsychotics pre-study, improved significantly. The 19 inpatients from the Bronx, overall younger and on higher pre-study doses, barely changed. Improvements in PANSS total score were significantly associated with older age, greater baseline severity, and lower doses of antipsychotics pre-study. The subjects improved on metabolic parameters. The results suggest that ziprasidone may be just as effective as previous antipsychotics taken by these severely mentally ill patients, and with fewer metabolic side effects. Note: The study described here includes a dosage of ziprasidone that has not been approved by the U.S. Food and Drug Administration (FDA). The FDA has approved daily doses of ziprasidone no greater than 100 mg PO bid.

More than 40 years of research and clinical practice have proven the effectiveness of dopamine receptor antagonists in the pharmacological treatment of tics. A blockade of the striatal dopamine-D2 receptors is mainly responsible for their tic-reducing effect. A broad spectrum of dopamine-modulating agents, such as typical and atypical antipsychotics, but also dopamine receptor agonists are used with an immanent discord between experts about which of them should be considered as first choice. The present Review outlines the state of the art on pharmacological treatment of tics with dopamine-modulating agents by giving an systematic overview of studies on their effectiveness and a critical discussion of their specific adverse effects. It is considered as an update of a previous review of our research group published in 2013. The Review closes with a description of the current resulting treatment recommendations including the results of a first published revised survey on European expert's prescription preferences. Based on the enormously growing evidence on its effectiveness and safety, aripiprazole currently seems to be the most promising agent in the pharmacological treatment of tics. Furthermore, benzamides (especially tiapride), which are commonly used in Europe, have proven their excellent effectiveness-tolerability profile over decades in clinical practice and are therefore also highly recommended for the treatment of tics. Nevertheless, pharmacological treatment of tics remains an indiviual choice depending on each patient's own specific needs.