Development of novel antipsychotic agents by inhibiting dopamine transporter – in silico approach

Dopamine transporter inhibition is deemed a promising schizophrenia treatment approach. This research paper outlines various QSAR modeling for molecules acting as dopamine transporter inhibitors. The SMILES notation and the local...

Pharmacotherapy of Primary Impulsive Aggression in Violent Criminal Offenders

Primary impulsive aggression (PIA) can be implicated as a common factor that results in an arrest, disciplinary, and restraint measures during confinement, and criminal recidivism after release. Evidence suggests that anti-impulsive aggression agents (AIAAs) can diminish or prevent impulsive aggression even when occurring with personality pathology such as borderline or antisocial personality disorder (ASPD), common conditions in offender populations. A previous review identified agents that have been subjected to controlled drug trials of sufficient quality, and subsequently, a decisional algorithm was developed for selecting an AIAA for individuals with IA. This selection process began with the five agents that showed efficacy in two or more quality studies from the earlier review. Today, 8 years after the quality review study, the present authors undertook this follow-up literature review. The aims of the present review were to survey the literature to identify and assess: (1) drug trials of comparable quality published since the 2013 review, including trials of the previously identified AIAAs as well as trials of agents not included in the earlier review; (2) severity of aggressive outbursts; (3) the materiality of risks or side-effects that are associated with individual AIAAs as well as antipsychotic agents commonly used to control clinical aggression; (4) efficacy of these agents in special populations (e.g., females); and (5) cost and convenience of each agent. Improved pharmacotherapy of PIA by addressing risks, side effects and practicality as well as the efficacy of AIAAs, should promote the rehabilitation and reintegration of some pathologically aggressive offenders back into the community.

Protocol on to Assess the Effectiveness of Planned Teaching on Knowledge Regarding to Adverse Effect of Antipsychotic Agents among Caregivers of Schizophrenia Patient

Background of the Study: The involvement of caregivers in treatment has been known as a vital part of mental health care. The enlarged emphasis on caregiver partaking has been to some extent driven by the shift from hospitals to primary provision of schizophrenia care in the community, where caregivers are more broadly involved in supporting consumers. Objectives: 1. To assess the pre-test knowledge regarding adverse effect of antipsychotic agent among caregivers of schizophrenia patients 2. To evaluate the effectiveness of planed teaching programme on knowledge regarding to antipsychotic agent among caregiver of schizophrenia patients. 3. To find out the association between post-test knowledge score with regards to adverse effect of antipsychotic agent regarding to adverse effect among caregivers of schizophrenia patients. Material and Methods: Pre-experimental, one group pretest and post-test design to assess the effectiveness of planed teaching on knowledge regarding adverse effect of antipsychotic agents and their response during the adverse effect among caregivers of schizophrenia patients. In this study total 100 caregivers of schizophrenia patient who full fill the inclusion criteria. Expected Results: This study is planned to assess the effectiveness of planed teaching on knowledge regarding to adverse effect of antipsychotic agents among caregivers of schizophrenia patients. There will be significant association between pre-test and post-test knowledge with regards to antipsychotic agents among schizophrenia patient’s caregivers. Conclusion: The conclusion will be drawn from the outcomes.

The More, the Merrier…? Antipsychotic Polypharmacy Treatment Strategies in Schizophrenia From a Pharmacology Perspective

Antipsychotic polypharmacy/drug combination treatment (APP) is a remarkably common practice in the schizophrenia context, given the lack of general support in treatment Guidelines. There is also a vast literature on APP outcomes, but a paucity of high-quality evidence-based data to guide and optimize adequate use of APP. This seems particularly true regarding many pharmacology-based considerations involved in APP treatment strategies. This paper first briefly summarizes clinical literature related to the use of APP. Against this backdrop, the pharmacological target profile features are then described of frequently used antipsychotic agents, in relation to estimated free plasma exposure levels at clinically efficacious dosing. APP strategies based on the properties of these drugs are then scrutinized and gauged within the background literature framework. The anticipated usefulness of APP from the pharmacological standpoint is detailed regarding efficacy, adverse effect (AE)/tolerability, and safety perspective, including why, when, and how it may be used to its advantage. For the purpose, a number of theoretically beneficial combinations as well as instances with suboptimal—and even futile—APP approaches are exemplified and discussed from the rational pharmacodynamic and pharmacokinetic pros and cons point-of-view. In this exposé, particular attention is paid to the utility and features of 3rd Generation Antipsychotic dopamine (DA) D2-D3 agonists within an APP setting.

Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

<p>Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by damage to the myelin sheaths that surround nerve axons. Inflammatory damage to the myelin sheath leads to severe physical disability in patients. Whereas approved disease modifying treatments are available for relapsing-remitting forms of MS, there are no approved treatments for the progressive stages, leaving approximately 50% of MS sufferers without treatment. Therefore, there is an urgent need for development of effective alternatives. Atypical antipsychotic agents used for treating schizophrenia have recently been recognized for their immune-modifying properties and our laboratory has shown previously that treating mice with risperidone or clozapine reduces the severity of disease in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Although atypical antipsychotic agents like clozapine have been used in the clinic for almost 60 years, there is very little experimental data that describes the mechanism by which atypical antipsychotic agents like clozapine are able to modify the immune response. This thesis aimed to describe the immunological mechanisms by which clozapine is able to reduce EAE disease and to determine the underlying cellular signalling alterations that occur during treatment to facilitate immune modifying properties. In vitro experiments showed that clozapine can impair induction of Th1 and Th17 cells while promoting the differentiation of iTreg and increasing Foxp3 expression. However, although clozapine effectively delayed disease onset and reduced the severity of EAE, the therapeutic effect of clozapine was not associated with impaired capacity to induce antigen specific Th1 or Th17 responses in the periphery. Moreover, Treg function was dispensable for disease protection by clozapine. Instead, disease protection by clozapine was associated with a suppressed state of activation in CNS resident microglia and infiltrating monocytes assessed by flow cytometric measurement of activation associated receptor expression. In vitro experiments using primary macrophage cell culture revealed that clozapine can alter the activation of activated macrophages towards a less inflammatory state directly. Interestingly, the altered state of activation in primary macrophages was not associated with detectable changes in cell signalling pathways known to mediate activation. This thesis demonstrated that clozapine treatment protects from EAE by a multi-faceted immunological mechanism that likely involves modifying multiple pathways and cell types during EAE and may be of therapeutic benefit to MS patients in the progressive stages of disease. Finally, this thesis also has relevance to psychiatry as it demonstrates that clozapine has potential to alter cellular immune responses.</p>

Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

<p>Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by damage to the myelin sheaths that surround nerve axons. Inflammatory damage to the myelin sheath leads to severe physical disability in patients. Whereas approved disease modifying treatments are available for relapsing-remitting forms of MS, there are no approved treatments for the progressive stages, leaving approximately 50% of MS sufferers without treatment. Therefore, there is an urgent need for development of effective alternatives. Atypical antipsychotic agents used for treating schizophrenia have recently been recognized for their immune-modifying properties and our laboratory has shown previously that treating mice with risperidone or clozapine reduces the severity of disease in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Although atypical antipsychotic agents like clozapine have been used in the clinic for almost 60 years, there is very little experimental data that describes the mechanism by which atypical antipsychotic agents like clozapine are able to modify the immune response. This thesis aimed to describe the immunological mechanisms by which clozapine is able to reduce EAE disease and to determine the underlying cellular signalling alterations that occur during treatment to facilitate immune modifying properties. In vitro experiments showed that clozapine can impair induction of Th1 and Th17 cells while promoting the differentiation of iTreg and increasing Foxp3 expression. However, although clozapine effectively delayed disease onset and reduced the severity of EAE, the therapeutic effect of clozapine was not associated with impaired capacity to induce antigen specific Th1 or Th17 responses in the periphery. Moreover, Treg function was dispensable for disease protection by clozapine. Instead, disease protection by clozapine was associated with a suppressed state of activation in CNS resident microglia and infiltrating monocytes assessed by flow cytometric measurement of activation associated receptor expression. In vitro experiments using primary macrophage cell culture revealed that clozapine can alter the activation of activated macrophages towards a less inflammatory state directly. Interestingly, the altered state of activation in primary macrophages was not associated with detectable changes in cell signalling pathways known to mediate activation. This thesis demonstrated that clozapine treatment protects from EAE by a multi-faceted immunological mechanism that likely involves modifying multiple pathways and cell types during EAE and may be of therapeutic benefit to MS patients in the progressive stages of disease. Finally, this thesis also has relevance to psychiatry as it demonstrates that clozapine has potential to alter cellular immune responses.</p>

Head-to-head comparison of various antipsychotic agents on genome-wide methylation in schizophrenia

Aim: To explore possible differences in genome-wide methylation between schizophrenia patients who consume various antipsychotics. Methods: We compared DNA methylation in leukocytes between the following cohorts: clozapine (n = 19) versus risperidone (n = 19), clozapine (n = 12) versus olanzapine (n = 12), clozapine (n = 9) versus quetiapine (n = 9) and clozapine (n = 33) versus healthy controls (n = 33). Subjects were matched for age, sex, ethnicity, smoking status and leukocyte proportions. Results: No single CpG site reached genome-wide significance for clozapine versus risperidone/olanzapine/quetiapine. For clozapine versus quetiapine, one significantly differentially methylated region was found – ch5: 176797920–176798049 (fwer = 0.075). Clozapine versus healthy controls yielded thousands of significantly differentially methylated CpG sites. Conclusions: Establishing antipsychotic induced genome-wide methylation patterns will further elucidate the biological and clinical effects of antipsychotic administration.

Exploring the kinetic selectivity of antipsychotics for dopamine D2 and 5-HT2A receptors: implications for the prevalence of EPS and receptor occupancy

Certain atypical antipsychotic drugs (APDs) used in the treatment of schizophrenia have been hypothesized to show reduced extrapyramidal side effects (EPS), due to their ability to promote nigrostriatal dopamine release through 5-HT2A receptor (5-HT2AR) blockade. The strength of this hypothesis is currently limited to a consideration of the relative receptor affinities of APDs for the 5-HT2AR and dopamine D2 receptor (D2R). Here we measure the 5-HT2AR kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay and correlate these properties with their observed EPS at therapeutic doses. For compounds with negligible affinity for 5-HT2AR, EPS is robustly predicted by a D2R specific rebinding model that integrates D2R association and dissociation rates to calculate the net rate of reversal of receptor blockade (kr). However, we show that for compounds with significant affinity for the 5-HT2AR, such as sertindole, higher relative 5-HT2A occupancy over time is an indicator for a reduced propensity to cause EPS. This study suggests that there is room for the development of novel kinetically optimised antipsychotic agents that modulate both serotonergic and dopamine function in a manner beneficial in the treatment of this chronic and debilitating disease.

Antipsychotic Medication and Risk of Incident Seizure in People with Autism Spectrum Disorder: Analyses with Cohort and Within Individual Study Designs

There are many case reports of seizures apparently associated with the prescription of antipsychotics. This study aimed to examine whether there is an association between the prescription of antipsychotics and incident seizures in individuals with autism spectrum disorder using retrospective data based on patients’ chart review. A cohort study was conducted to compare the rate of incident seizure between 3923 users of antipsychotics with 10,086 users of other psychotropics. This was followed by a self-controlled case series (SCCS) analysis of 149 patients to eliminate the effect of time-invariant confounders. The results showed no evidence of increased risk of seizure after exposure to antipsychotic agents (Hazard Ratio 1.28, 95% CI 0.74–2.19) compared to other psychotropics.