Synthesis and Evaluation of Aryl Substituted Propyl Piperazines for Potential Atypical Antipsychotic activity

2019 ◽  
Vol 15 ◽  
Author(s):  
Shalu Singh ◽  
Alka Bali ◽  
Tania Peshin
Keyword(s):  
Atypical Antipsychotic ◽  
Physicochemical Parameters ◽  
Negative Symptoms ◽  
Atypical Antipsychotics ◽  
Lead Compounds ◽  
Antipsychotic Activity ◽  
Barrier Penetration ◽  
Good Potential ◽  
Log Bb ◽  
Online Software

Background: Schizophrenia is a disorder with complex etiology with hyperdopaminergia as the main underlying cause. Atypical antipsychotics are the agents which do not give rise to significant extrapyramidal side effects and are more effective against negative symptoms of schizophrenia. Introduction: A new series of chloro-substituted substituted aryloxypiperazine derivatives and their indole based derivatives was designed and evaluated for atypical antipsychotic activity based on established models for combined dopaminergic and serotonergic antagonism. Method: The present series of compounds were designed based on 3D similarity studies, synthesized and evaluated for atypical antipsychotic activity in animal models for combined dopaminergic and serotonergic antagonism. The blood brain barrier penetration potential was assessed from theoretical log BB values computed through an online software program. Results: Theoretical ADME profiling of the designed compounds based on selected physicochemical parameters suggested an excellent compliance with Lipinski’s rules. The log BB values obtained for the compounds suggested a good potential for brain permeation. Indole substitution contributed towards an improved efficacy over aryloxy analogs. Lead compounds showed a potential for combined dopaminergic and serotonergic antagonism. Conclusion: The 5-methoxy indole based compounds 16 and 17 were identified as the lead compounds displaying a potential atypical antipsychotic profile.

One Pot Synthesis and Pharmacological Evaluation of Aryl Substituted Imidazoles as Potential Atypical Antip

2020 ◽  
Vol 17 ◽  
Author(s):  
Arshjyoti Singh ◽  
Alka Bali ◽  
Pooja Kumari
Keyword(s):  
Atypical Antipsychotic ◽  
In Silico ◽  
Negative Symptoms ◽  
Atypical Antipsychotics ◽  
Docking Studies ◽  
D2 Receptors ◽  
One Pot ◽  
In Silico Docking ◽  
One Pot Synthesis ◽  
Antipsychotic Activity

Background: Second generation or ‘‘atypical’’ antipsychotics demonstrate an improved therapeutic profile over conventional neuroleptics. These are effective in both positive and negative symptoms of the disease and have a lower propensity to induce adverse symptoms. Objective: Main objective of the research was in silico design and synthesis of potential atypical antipsychotics with combined antiserotonergic / antidopaminergic effect. Method: A one pot synthesis of aryl substituted imidazole derivatives was carried out in green solvent PEG-400 and the prepared compounds were evaluated for atypical antipsychotic activity in animal models for dopaminergic and serotonergic antagonism. The compounds were designed based on their 3D similarity studies to standard drugs and in silico (docking studies) with respect to 5-HT2A and D2 receptors. Results and Discussion: Results from the docking studies with respect to 5-HT2A and D2 receptors suggested a potential atypical antipsychotic profile for the test compounds. Theoretical ADME profiling of the compounds based on selected physicochemical parameters suggested an excellent compliance with Lipinski’s rules. The potential of these compounds to penetrate the blood brain barrier (log BB) was computed through an online software program and the values obtained for the compounds suggested a good potential for brain permeation. Reversal of apomorphine induced mesh climbing behaviour coupled with inactivity in the stereotypy assay indicates antidopaminergic effect and a potential atypical profile for the test compounds 1-5. Further, activity of compounds in DOI assay indicated a 5-HT2 antagonistic profile (5-HT2 antagonism). Conclusion: Compound 5 emerged as important lead compound showing combined antidopaminergic and antiserotonergic (5-HT2A) activity with potential atypical antipsychotic profile.

Synthesis and evaluation of amide, sulfonamide and urea – benzisoxazole derivatives as potential atypical antipsychotics

MedChemComm ◽  
2015 ◽  
Vol 6 (5) ◽  
pp. 831-838 ◽  
Author(s):  
Yin Chen ◽  
Yu Lan ◽  
Xudong Cao ◽  
Xiangqing Xu ◽  
Juecheng Zhang ◽  
...  
Keyword(s):  
Atypical Antipsychotic ◽  
Atypical Antipsychotics ◽  
Antipsychotic Activity ◽  
Amide Derivatives ◽  
Derivatives Of

A series of amide derivatives of benzisoxazole has been synthesized and the target compounds evaluated for atypical antipsychotic activity in vitro and vivo.

scholarly journals Review of the efficacy of placebo in comparative clinical trials between typical and atypical antipsychotics

2009 ◽  
Vol 31 (1) ◽  
pp. 52-56 ◽  
Author(s):  
Irismar Reis de Oliveira ◽  
Paulo Menezes Nunes ◽  
Domingos Macedo Coutinho ◽  
Eduardo Pondé de Sena
Keyword(s):  
Clinical Trials ◽  
Atypical Antipsychotic ◽  
Atypical Antipsychotics ◽  
Rating Scale ◽  
Study Drug ◽  
Typical Antipsychotic ◽  
The Difference ◽  
Psychiatric Rating Scale ◽  
Efficacy Parameters ◽  
Typical Antipsychotics

OBJECTIVE: To review the efficacy of placebo in comparison with atypical and typical antipsychotics for the treatment of schizophrenia and schizoaffective disorder and to evaluate the pertinence of using placebo in clinical trials with antipsychotics. METHOD: Trials in which the atypical antipsychotics were compared with typical antipsychotics and placebo were included. A search was conducted using the terms "amisulpride", "aripiprazole", "clozapine", "olanzapine", "quetiapine", "risperidone", "sertindole", "ziprasidone" and "zotepine". Main efficacy parameters were calculated using the proportion of "events" (defined as a deterioration or lack of improvement by at least 20% in Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale) and the pooled relative risk with random effects, with their respective 95% confidence intervals. We also calculated the necessary sample sizes in studies in which the study drug is compared to a typical antipsychotic or placebo. RESULTS: The pooled efficacy rates observed were 40.8%, 34.9% and 21.3% for the atypical antipsychotics, typical antipsychotics and placebo, respectively. One hundred and sixty six patients would have to be included when a new drug is compared with placebo if calculation is based on a difference of 20% found between the atypical antipsychotic and placebo and 2,054 if the difference sought were that found between the atypical antipsychotic and the typical antipsychotic, i.e. 6%. The estimated therapeutic failures would be 115 of the 166 patients when the study drug is compared with placebo, and 1,274 failures in the 2,054 patients when the study drug is compared to the typical antipsychotic. CONCLUSIONS: Placebo controlled studies may reduce the number of individuals exposed to the harmful effects of ineffective drugs.

Psychopharmacology of olanzapine

1999 ◽  
Vol 174 (S38) ◽  
pp. 52-58 ◽  
Author(s):  
C. M. E. Stephenson ◽  
L. S. Pilowsky
Keyword(s):  
Side Effects ◽  
Atypical Antipsychotic ◽  
Antipsychotic Drug ◽  
Therapeutic Efficacy ◽  
Atypical Antipsychotics ◽  
Extrapyramidal Side Effects ◽  
Atypical Antipsychotic Drug ◽  
Blood Monitoring

The development of atypical antipsychotics has revolutionised the treatment of schizophrenia, as well as providing new insights into its cause. The archetypal atypical antipsychotic is clozapine, which has therapeutic advantages over traditional antipsychotics, as well as a low potential for producing extrapyramidal side-effects (EPS) (Kane et al, 1988). However, clozapine causes agranulocytosis in 1% of patients, and there has consequently been a search for novel atypical antipsychotics, as efficacious as clozapine, but without the need for intensive blood monitoring. There has been much discussion of the definition and characteristics of an atypical antipsychotic drug, and an operational understanding seems to have been agreed upon, that atypical drugs have therapeutic efficacy in treating schizophrenia, without producing EPS (Deutch et al, 1991; Kerwin, 1994).

Lithium vs valproate in the maintenance treatment of bipolar I disorder: A post- hoc analysis of a randomized double-blind placebo-controlled trial

2019 ◽  
Vol 54 (3) ◽  
pp. 298-307
Author(s):  
Mehar G Kang ◽  
Hong Qian ◽  
Kamyar Keramatian ◽  
Trisha Chakrabarty ◽  
Gayatri Saraf ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Atypical Antipsychotic ◽  
Maintenance Treatment ◽  
Atypical Antipsychotics ◽  
Controlled Trial ◽  
Hazard Ratio ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Post Hoc Analysis ◽  
Post Hoc

Objective: Lithium and valproate are commonly used either in monotherapy or in combination with atypical antipsychotics in maintenance treatment of bipolar I disorder; however, their comparative efficacy is not well understood. This study aimed to compare the efficacy of valproate and lithium on mood stability either in monotherapy or in combination with atypical antipsychotics. Methods: We performed a post hoc analysis using data from a 52-week randomized double-blind, placebo-controlled trial, that recruited 159 patients with recently remitted mania during treatment with lithium or valproate and adjunctive atypical antipsychotic therapy. Patients were randomized to discontinue adjunctive atypical antipsychotic at 0, 24 or 52 weeks. Results: No significant differences in efficacy were observed between valproate and lithium (hazard ratio: 0.99; 95% confidence interval: [0.66, 1.48]) in time to any mood event. Valproate with 24 weeks of atypical antipsychotic was significantly superior to valproate monotherapy in preventing any mood relapse (hazard ratio: 0.46; 95% confidence interval: [0.22, 0.97]) while lithium with 24 weeks of atypical antipsychotic was superior to lithium monotherapy in preventing mania (hazard ratio: 0.27; 95% confidence interval: [0.09, 0.85]) but not depression. Conclusion: Overall, this study did not find significant differences in efficacy between the two mood-stabilizing agents when used as monotherapy or in combination with atypical antipsychotics. However, study design and small sample size might have precluded from detecting an effect if true difference in efficacy existed. Further head-to-head investigations with stratified designs are needed to evaluate maintenance therapies.

scholarly journals Lurasidone compared to other atypical antipsychotic monotherapies for adolescent schizophrenia: a systematic literature review and network meta-analysis

2019 ◽  
Vol 29 (9) ◽  
pp. 1195-1205
Author(s):  
Celso Arango ◽  
Daisy Ng-Mak ◽  
Elaine Finn ◽  
Aidan Byrne ◽  
Antony Loebel
Keyword(s):  
Weight Gain ◽  
Literature Review ◽  
Atypical Antipsychotic ◽  
Systematic Literature Review ◽  
Atypical Antipsychotics ◽  
Meta Analysis ◽  
Similar Efficacy ◽  
Binary Outcomes ◽  
Schizophrenia Spectrum Disorders ◽  
Credible Intervals

AbstractThis network meta-analysis assessed the efficacy and tolerability of lurasidone versus other oral atypical antipsychotic monotherapies in adolescent schizophrenia. A systematic literature review identified 13 randomized controlled trials of antipsychotics in adolescents with schizophrenia-spectrum disorders. A Bayesian network meta-analysis compared lurasidone to aripiprazole, asenapine, clozapine, olanzapine, paliperidone extended-release (ER), quetiapine, risperidone, and ziprasidone. Outcomes included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), weight gain, all-cause discontinuation, extrapyramidal symptoms (EPS), and akathisia. Results were reported as median differences for continuous outcomes and odds ratios (ORs) for binary outcomes, along with 95% credible intervals (95% CrI). Lurasidone was significantly more efficacious than placebo on the PANSS (− 7.95, 95% CrI − 11.76 to − 4.16) and CGI-S (− 0.44, 95% CrI − 0.67 to − 0.22) scores. Lurasidone was associated with similar weight gain to placebo and statistically significantly less weight gain versus olanzapine (− 3.62 kg, 95% CrI − 4.84 kg to − 2.41 kg), quetiapine (− 2.13 kg, 95% CrI − 3.20 kg to − 1.08 kg), risperidone (− 1.16 kg, 95% CrI − 2.14 kg to − 0.17 kg), asenapine (− 0.98 kg, 95% CrI − 1.71 kg to − 0.24 kg), and paliperidone ER (− 0.85 kg, 95% CrI − 1.57 kg to − 0.14 kg). The odds of all-cause discontinuation were significantly lower for lurasidone than aripiprazole (OR = 0.28, 95% CrI 0.10–0.76) and paliperidone ER (OR = 0.25, 95% CrI 0.08–0.81) and comparable to other antipsychotics. Rates of EPS and akathisia were similar for lurasidone and other atypical antipsychotics. In this network meta-analysis of atypical antipsychotics in adolescent schizophrenia, lurasidone was associated with similar efficacy, less weight gain, and lower risk of all-cause discontinuation compared to other oral atypical antipsychotics.

scholarly journals Antipsychotic Effects on Cortical Morphology in Schizophrenia and Bipolar Disorders

2020 ◽  
Vol 14 ◽  
Author(s):  
Ruiqi Feng ◽  
Fay Y. Womer ◽  
E. Kale Edmiston ◽  
Yifan Chen ◽  
Yinshan Wang ◽  
...  
Keyword(s):  
Atypical Antipsychotic ◽  
Cortical Thickness ◽  
Atypical Antipsychotics ◽  
Structural Changes ◽  
Middle Temporal Gyrus ◽  
Antipsychotic Treatment ◽  
Illness Duration ◽  
Cortical Thinning ◽  
Age Related

Background: Previous studies of atypical antipsychotic effects on cortical structures in schizophrenia (SZ) and bipolar disorder (BD) have findings that vary between the short and long term. In particular, there has not been a study exploring the effects of atypical antipsychotics on age-related cortical structural changes in SZ and BD. This study aimed to determine whether mid- to long-term atypical antipsychotic treatment (mean duration = 20 months) is associated with cortical structural changes and whether age-related cortical structural changes are affected by atypical antipsychotics.Methods: Structural magnetic resonance imaging images were obtained from 445 participants consisting of 88 medicated patients (67 with SZ, 21 with BD), 84 unmedicated patients (50 with SZ, 34 with BD), and 273 healthy controls (HC). Surface-based analyses were employed to detect differences in thickness and area among the three groups. We examined the age-related effects of atypical antipsychotics after excluding the potential effects of illness duration.Results: Significant differences in cortical thickness were observed in the frontal, temporal, parietal, and insular areas and the isthmus of the cingulate gyrus. The medicated group showed greater cortical thinning in these regions than the unmediated group and HC; furthermore, there were age-related differences in the effects of atypical antipsychotics, and these effects did not relate to illness duration. Moreover, cortical thinning was significantly correlated with lower symptom scores and Wisconsin Card Sorting Test (WCST) deficits in patients. After false discovery rate correction, cortical thinning in the right middle temporal gyrus in patients was significantly positively correlated with lower HAMD scores. The unmedicated group showed only greater frontotemporal thickness than the HC group.Conclusion: Mid- to long-term atypical antipsychotic use may adversely affect cortical thickness over the course of treatment and ageing and may also result in worsening cognitive function.

Switching Antipsychotic Therapies

2000 ◽  
Vol 34 (2) ◽  
pp. 200-207 ◽  
Author(s):  
Prakash S Masand ◽  
Sarah L Berry
Keyword(s):  
Adverse Effect ◽  
Atypical Antipsychotic ◽  
Atypical Antipsychotics ◽  
Psychotic Symptoms ◽  
Double Blind ◽  
Medline Search ◽  
Mood Symptoms ◽  
Conventional Antipsychotics ◽  
Hospitalization Rates ◽  
Study Selection

BACKGROUND: Atypical antipsychotics are superior to conventional antipsychotics in improving positive and negative psychotic symptoms. Atypical antipsychotics do not exacerbate mood symptoms, and may improve mood symptoms and cognitive functioning; additionally, they have better adverse effect profiles than conventional antipsychotics. OBJECTIVE: To review the benefits of switching patients with schizophrenia or schizoaffective disorder from a conventional to an atypical antipsychotic, or from one atypical antipsychotic to another. In spite of the higher acquisition cost of atypical antipsychotics, overall treatment costs may decrease due to lower relapse and hospitalization rates. DATA SOURCES: A MEDLINE search (January 1977–January 1999) was conducted for articles written in English about efficacy, adverse effects, compliance, and pharmacoeconomics for atypical and conventional antipsychotics. STUDY SELECTION: Large, multicenter, double-blind, controlled studies were used for efficacy, safety, tolerability, and pharmacoeconomic data. Where appropriate, recent review articles were also used. RESULTS: Atypical antipsychotics are superior to conventional antipsychotics in the treatment of schizophrenia. Atypical and conventional antipsychotics have different adverse effect profiles, costs, and compliance rates. CONCLUSIONS: Some patients may benefit by switching from a conventional to an atypical antipsychotic, from an atypical to a conventional antipsychotic, or from one atypical antipsychotic to another. Methods of switching antipsychotic therapies include tapering and cross-over strategies.

3-[[(Aryloxy)alkyl]piperidinyl]-1,2-Benzisoxazoles as D2/5-HT2 Antagonists with Potential Atypical Antipsychotic Activity: Antipsychotic Profile of Iloperidone (HP 873)

1995 ◽  
Vol 38 (7) ◽  
pp. 1119-1131 ◽  
Author(s):  
Joseph T. Strupczewski ◽  
Kenneth J. Bordeau ◽  
Yulin Chiang ◽  
Edward J. Glamkowski ◽  
Paul G. Conway ◽  
...  
Keyword(s):  
Atypical Antipsychotic ◽  
Antipsychotic Activity

Glucose Disturbances and Atypical Antipsychotic Use in the Intensive Care Unit

2016 ◽  
Vol 29 (6) ◽  
pp. 534-538 ◽  
Author(s):  
Amy Bishara ◽  
Stephanie V. Phan ◽  
Henry N. Young ◽  
T. Vivian Liao
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Patient Outcomes ◽  
Atypical Antipsychotic ◽  
Atypical Antipsychotics ◽  
Apache Ii Score ◽  
Icu Patients ◽  
Acute Hyperglycemia ◽  
The Impact ◽  
Chronic Use

Purpose: Chronic use of atypical antipsychotics may lead to metabolic abnormalities including hyperglycemia. Although evidence supports acute hyperglycemic episodes associated with atypical antipsychotic use, the acute use of atypical antipsychotics in the intensive care unit (ICU) setting has not been studied. The purpose of this study is to evaluate the occurrence of hyperglycemia in ICU patients receiving newly prescribed atypical antipsychotic. Summary: Of the 273 patient charts reviewed, 50 patients were included in this study. Approximately 45% of patients experienced at least 1 hyperglycemic episode (blood glucose >180 mg/dL) after the initiation of an atypical antipsychotic in the ICU. Of the patients experiencing at least 1 hyperglycemic episode, 60% experienced multiple distinct hyperglycemic episodes. In this study, quetiapine was the most commonly used atypical antipsychotic, 19 (38%) patients were discharged from the ICU on the atypical antipsychotic, 6 (12%) patients died in the ICU, and 31 (62%) patients were treated with an antihyperglycemic agent. Logistic regression analysis showed that women and ICU patients with a higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score were significantly more likely to have multiple hyperglycemic episodes. Conclusion: Patients admitted to the ICU and initiated on an atypical antipsychotic may develop hyperglycemia independent of other glucose-elevating factors. The direct correlation of these agents to resulting acute hyperglycemia is unknown. Further studies are needed to investigate the link between atypical antipsychotics and acute hyperglycemia and the clinical significance of the impact on patient outcomes.

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