Antipsychotic Activity Research Articles

A Comprehensive Review on the Screening Models for the Pharmacological Assessment of Antipsychotic Drugs

Background: Psychosis is a debilitating mental disorder characterized by a profound disconnection from reality, manifesting in symptoms such as hallucinations, delusions, and disorganized thinking. The pathophysiology of psychosis is multifaceted, involving an interplay of neurobiological, genetic, and environmental factors. Neurobiologically, dysregulation of neurotransmitter systems particularly dopaminergic, serotonergic, and glutamatergic pathways-plays a central role, with excessive dopaminergic activity linked to positive symptoms and glutamatergic dysfunction implicated in cognitive impairments. Genetic predisposition, evidenced by significant heritability and associations with specific genetic variants, intersects with environmental factors such as stress, trauma, and substance use to influence the onset and progression of psychosis. Cognitive disruptions, including deficits in attention, memory, and executive function, exacerbate the disorder’s impact. This phenomenon has led to short-term as well as long-term psychosocial and mental health implications for all. Objective: To determine the antipsychotic activity of pharmaceuticals, numerous antipsychotic screening models are available. Determining the optimal animal model for measuring antipsychotic activity is the primary goal of this study. Methods: A search for literature was carried out using several keywords, including "Antipsychotic," "In-vivo models," "In-vitro models," and "Behavior models," on the databases Science Direct and PubMed. For the purpose of obtaining the most appropriate articles to fulfil the goal of this review article, the search was customized by using the necessary filters. Results: Research and review articles based on neuroleptic screening models are available to determine the antipsychotic activity of novel pharmacological compounds. Conclusion: Following our research, we identified several helpful models for evaluating the antipsychotic activity of pharmaceuticals and proposed that combining invitro and in-vivo techniques with behavioral methodologies might yield the most appropriate results for our field of study.

Classical psychedelics’ action on brain monoaminergic systems

The study of the mechanism of action of classical psychedelics has gained significant interest due to their clinical potential in the treatment of several psychiatric conditions, including major depressive and anxiety disorders. These drugs bind 5-hydroxytryptamine receptors (5-HTR) including 5-HT1AR, 5-HT2AR, 5-HT2BR, and/or 5-HT2CR, as well as other targets. 5-HTRs regulate the activity of ascending monoaminergic neurons, a mechanism primarily involved in the action of classical antidepressant drugs, antipsychotics, and drugs of abuse. Sparse neurochemical data have been produced on the control of monoaminergic neuron activity in response to classical psychedelics. Here we review the available data in order to determine whether classical psychedelics have specific neurochemical effects on serotonergic, dopaminergic, and noradrenergic neurons. The data show that these drugs have disparate effects on each monoaminergic system, demonstrating a complex response with state-dependent and region-specific effects. For instance, several psychedelics inhibit the firing of serotonergic neurons, although this is not necessarily associated with a decrease in serotonin release in all regions. Noradrenergic neuron spontaneous activity also appears to be inhibited by psychedelics, also not necessarily associated with a decrease in noradrenaline release in all regions. Psychedelics influence on dopaminergic systems is also complex as the above-mentioned 5-HTRs may have opposing effects on dopaminergic neuron activity, in a state-dependent manner. There is an apparent lack of clear neuronal signature induced by psychedelics on monoaminergic neuron activity despite specific recurrent mechanisms. This review provides a current summary of the action of psychedelics on monoamine neuromodulators serotonin, dopamine and noradrenaline, compiling reoccurring and contradictory findings demonstrating that a monoamine signature of psychedelics, if applicable, would be state- and region-dependant.

Recent Trends in Chemistry and Biological Activity of Antipsychotics

Abstract: Several novel antipsychotics have been outlined in this review. Different synthetic methods for the synthesis of promising antipsychotics have been summarized. There are different starting materials from which we can start to prepare the proposed antipsychotics. Also, the final nucleus of the proposed antipsychotics is different e.g. 8-azabicyclo[3.2.1]oct-3β-yl-amide 8a-w, 3-aminoethyl tetralones 19, 3-fluourobenzoyl-propionic acid 22, 6,7-dihydrobenzo[b]thiophen- 4(5H)-one derivative 26, 3,4-dihydronaphthalen-1(2H)-one derivative 30, Benzocycloalkanone derivative 36, 3-methyl-6,7-dihydrobenzo[d]isoxazol-4(5H)-one derivative 55, 1,5,6,7- tetrahydro-4H-indazol-4-one derivative 61, 2-methyl-1,5,6,7-tetrahydro-4H-benzo[d]imidazol-4- one derivative 66. Different antipsychotic activities of the prepared compounds are summarized.

Thermal behavior and determination of physicochemical properties of novel candidates for antipsychotic drugs

Treatment of schizophrenia with currently available drugs is often ineffective or results in several adverse reactions. In previous studies focusing on the search for new antipsychotic drugs, we designed and obtained a series of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptor ligands that were pharmacologically evaluated and showed promising antipsychotic activity. Evaluation of ADMET parameters is an important issue in drug development and should be performed at its early stage to avoid developing molecules with poor pharmacokinetics, that are unlikely to enter the market. For this reason, in this work we focused on the assessment of physicochemical parameters of selected compounds from the series we obtained to assess their drug-like potential. The results of thermal analysis showed that most of the tested compounds are thermally stable above 200 °C, with one compound stable up to 190 °C. Permeability through biological membranes assessed in the parallel artificial membrane permeability assay indicated that all tested compounds effectively migrate through biological membranes by means of passive diffusion. The solubility of the tested compounds was determined in PBS, reflecting physiological pH, and 0.01 M HCl, indicating their low to moderate solubility in PBS, which was significantly improved in acidic environment. The lipophilicity of the studied compounds expressed as LogD falls within the range of 1.84–2.80, what suggest that they would show good oral absorption and the ability to cross lipid barriers. The studies were supplemented with in silico prediction of ADMET parameters, which also indicate the probable high drug-likeness of the tested compounds.

Antipsychotics possess anti-glioblastoma activity by disrupting lysosomal function and inhibiting oncogenic signaling by stabilizing PTEN

The repurposing of medications developed for central nervous system (CNS) disorders, possessing favorable safety profiles and blood-brain barrier permeability, represents a promising strategy for identifying new therapies to combat glioblastoma (GBM). In this study, we investigated the anti-GBM activity of specific antipsychotics and antidepressants in vitro and in vivo. Our results demonstrate that these compounds share a common mechanism of action in GBM, disrupting lysosomal function and subsequently inducing lysosomal membrane rupture and cell death. Notably, PTEN intact GBMs possess an increased sensitivity to these compounds. The inhibition of lysosomal function synergized with inhibitors targeting the EGFR-PI3K-Akt pathway, leading to an energetic and antioxidant collapse. These findings provide a foundation for the potential clinical application of CNS drugs in GBM treatment. Additionally, this work offers critical insights into the mechanisms and determinants of cytotoxicity for drugs currently undergoing clinical trials as repurposing agents for various cancers, including Fluoxetine, Sertraline, Thioridazine, Chlorpromazine, and Fluphenazine.

Understanding the Therapeutic Action of Antipsychotics: From Molecular to Cellular Targets With Focus on the Islands of Calleja.

The understanding of the pathophysiology of schizophrenia as well as the mechanisms of action of antipsychotic drugs remains a challenge for psychiatry. The demonstration of the therapeutic efficacy of several new atypical drugs targeting multiple different receptors, apart from the classical dopamine D2 receptor as initially postulated unique antipsychotic target, complicated even more conceptualization efforts. Here we discuss results suggesting a main role of the islands of Calleja, still poorly studied GABAergic granule cell clusters in the ventral striatum, as cellular targets of several innovative atypical antipsychotics (clozapine, cariprazine, and xanomeline/emraclidine) effective in treating also negative symptoms of schizophrenia. We will emphasize the potential role of dopamine D3 and M4 muscarinic acetylcholine receptor expressed at the highest level by the islands of Calleja, as well as their involvement in schizophrenia-associated neurocircuitries. Finally, we will discuss the implications of new data showing ongoing adult neurogenesis of the islands of Calleja as a very promising antipsychotic target linking long-life neurodevelopment and dopaminergic dysfunction in the striatum.

Anti-psychotic effects of leaf extracts of <i>Palisota hirsute</i> (Thunb.) K. Schum. (Commelinaceae) and <i>Costus afer</i> Ker-Gawl (Zingiberaceae) on ketamine-induced psychotic mice

This study assessed the anti-psychotic activity of the methanol leaf extracts of Palisota hirsute (Thunb.) K. Schum. (Commelinaceae) and Costus afer Ker-Gawl (Zingiberaceae) in Ketamineinduced psychotic mice. Antipsychotic activity of the two plant extracts (Palisota hirsuta and Costus afer) at different doses were assessed using the Ketamine animal model of psychosis. Locomotor and stereotype behaviours were studied in an open-field and transparent chambers, while the force swim test was investigated in a cylindrical glass containing water. From the locomotion test, both doses of the plant extracts tested for activity showed a significant reduction in hyperactivity. Palisota hirsuta and Costus afer (500 mg/kg) antagonised the stereotypy effect induced by Ketamine in the mice. Furthermore, the two doses of Palisota hirsuta (250 and 500 mg/kg) and Costus afer at 500 mg/kg had high anti-depressant activity in that the immobility time recorded during the force swim test was reduced significantly. Palisota hirsuta extract had a good anti-psychotic effect at both the higher (500 mg/kg) and lower doses (250 mg/kg), whereas Costus afer extract had a greater anti-psychotic effect at a higher dose of 500 mg/kg than at a lower dose and these results are similar to those of the positive control drug (Haloperidol).

The use of antipsychotics in obsessive compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic disease with a prevalence in the general population of around 2%-3%, generally accompanied by a severe impairment of functioning and quality of life. A consistent subgroup of patients may not achieve adequate symptom remission with first-line treatments (i.e., cognitive behavioral therapy, selective serotonin reuptake inhibitors [SSRIs]). The most validated option for treatment-resistant cases relies on the augmentative use of antipsychotics to SSRIs, preferably of the 'second generation'. Indeed, dopamine appears to be crucially involved in OCD neuropathology due to its implication in systems relating to goal-directed behaviour and maladaptive habits. Nevertheless, the mechanism of action of antipsychotics in OCD symptom improvement is still unclear. Risperidone, aripiprazole, and haloperidol seem to be the most useful medications, whereas 'first generation' antipsychotics may be indicated in case of comorbidity with tics and/or Tourette Syndrome. Antipsychotic augmentation may be also related to side-effects, particularly in the long term (e.g., alteration in metabolic profile, sedation, extrapyramidal symptoms). The present mini-review sought to provide the most updated evidence on augmentative antipsychotic use in treatment-resistant patients with OCD, providing a road map for clinicians in daily practice and shedding light on avenues for further research.

A Profound Insight into the Structural Modification of Natural Bioactive Compounds Containing Piperazine Moiety: A Comprehensive Review

Abstract: Piperazine is the heterocyclic nucleus and exhibits significant biological potential such as antipsychotic, antidepressant, antihistamine, anticancer, anti-anginal, cardioprotective, antiviral, and anti-inflammatory activity. As a result, it had been considered a crucial structural component in the majority of the therapeutic medications that were already on the market. Other issues that limit its use include solubility, limited bioavailability, cost-effectiveness, and a mismatch between the drug's pharmacokinetic and pharmacodynamic profiles. Literature describes structural modification in the piperazine moiety to create novel derivatives or analogues to solve the issues with currently marketed medications. Nature provides various bioactive components having piperazine nuclei in their core structure. The present review describes the potential of the piperazine nucleus present in natural bioactive components. So the study concludes that it is vital to concentrate on the structural characteristics of this scaffold, which opens the way for future research and may benefit pharmaceutical companies as well as medicinal chemists.

The Natural Protoalkaloid Methyl-2-Amino-3-Methoxybenzoate (MAM) Alleviates Positive as well as Cognitive Symptoms in Rat and Mouse Schizophrenia Models.

The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.

Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia.

Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia. Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical. Results: In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094. Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.

Анализ эффективности антипсихотической терапии у больных параноидной шизофренией с несуицидальной аутоагрессией и дефицитарными личностными изменениями

Aim. A comparative analysis of the effectiveness of neuroleptics in patients with paranoid schizophrenia with deficit changes at the personal level and non-suicidal auto-aggressive actions (NAA) who are on compulsory treatment. Design. Full-scale non-randomized longitudinal study Materials and methods. The study included 237 patients with paranoid schizophrenia during maintenance therapy: 76 people were on risperidone monotherapy, 61 patients received quetiapine, and 100 patients took haloperidol. The clinical effectiveness of therapy was determined by comparative analysis of the frequency of exacerbation of psychotic symptoms, the severity of negative disorders, the frequency of acts of non-suicidal auto-aggression and the level of social functioning. In addition to clinical observation, the Scale of Negative Psychopathology (SANS) and the Social Functioning Scale (PSP) were used. Fisher's test and ANOVA analysis of variance were used to statistically evaluate the data. Results. All drugs helped reduce the incidence of exacerbation of psychotic disorders, while only with the use of risperidone and haloperidol positive changes in antipsychotic activity were statistically significant (p < 0.01). All drugs helped reduce the severity of negative disorders. When taking risperidone, a statistically significant decrease in disorders associated with flattening and rigidity of affect and attention was noted (p ≤ 0.05). Haloperidol caused a decrease in flattening and rigidity of affect, attention and speech disorders, and apato-abulic syndrome (p ≤ 0.05). All drugs statistically significantly reduced the risk of NAA (p ≤ 0.05), and also contributed to an increase in the level of social functioning of patients, and in patients taking haloperidol, statistically significant changes in this indicator appeared earlier. By the end of the study, while taking each of the drugs included in the study, statistically significant positive changes in the studied parameters were noted (p ≤ 0.05). Conclusion. The first-line drug for patients with paranoid schizophrenia with deficient personality changes and NAA who are on compulsory treatment is haloperidol. An alternative treatment method for this group of patients may be the administration of risperidone. Keywords: schizophrenic defect at the personal level, neuroleptics, paranoid schizophrenia, non-suicidal auto-aggression.

Recent progress in therapeutic applications of fluorinated five-membered heterocycles and their benzo-fused systems.

Heterocyclic derivatives grafted with fluorine atom(s) have attracted the attention of scientists due to the unique physicochemical properties of the C-F bond. The inclusion of fluorine atom(s) into organic compounds often increases their lipophilicity and metabolic stability, enhancing their bioavailability and affinity for target proteins. Therefore, it is not surprising to find that more than 20% of the medications on the market contain fluorine, and nearly 300 fluorine-containing drugs have been officially approved for use as medicines. In this review article, we are interested in classifying and describing the reports comprising varied therapeutic activities of the directly fluorinated five-membered heterocycles and their fused systems during the last two decades. These therapeutic activities included antiviral, anti-inflammatory, enzymatic inhibitory, antimalarial, anticoagulant, antipsychotic, antioxidant, antiprotozoal, histamine-H3 receptor, serotonin receptor, chemokine receptor, prostaglandin-D2 receptor, and PBR inhibition activities. In many cases, the activities of fluorinated azoles were almost equal to or exceeded the potency of reference drugs.

Antipsychotic Activity of Ethanolic Extracts of Crinum asiaticum and Crinum defixum in Animal Models.

The current study examined the antipsychotic properties of ethanolic extracts of Crinum asiaticum (EECA) and Crinum defixum (EECD). The effects of the extracts on rodents' ketamine-induced hyperactivity, amphetamine-induced stereotypy, forced swim test, conditioned avoidance response, and catalepsy were assessed. According to the findings, EECA and EECD both significantly outperformed typical antipsychotic medications in antipsychotic-like behaviours across a variety of behavioural paradigms. The extracts exhibited a 50-75% reduction in ketamine-induced hyperactivity, indicating a possible impact on glutamatergic signalling. Additionally, they greatly reduced amphetamine-induced stereotypy, suggesting a potential antagonistic interaction with the dopamine D2 receptor. Similar to haloperidol, EECD at 400 mg/kg dramatically decreased avoidance behaviour in the conditioned avoidance response test. Though less so than with haloperidol, both extracts caused catalepsy in rodents. The reversal of ketamine's effect in the forced swim test suggests that it may be effective in preventing psychosis's negative symptoms. Given that oxidative stress is a contributing factor to psychotic disorders, the antipsychotic effect of these extracts may be associated with their anti-inflammatory and antioxidant characteristics. These results bolster the long-standing usage of Crinum species in the treatment of mental illnesses and imply that they could be rich sources of new antipsychotic chemicals. To determine the active ingredients, clarify the mechanisms of action, and assess the safety and effectiveness of clinical trials, more study is necessary.

In-Vivo Evaluation of Some Novel Chromen- 2 One Based on Pharmacological Activity of Antipsychotic Drug

Most neuroleptics block the emesis hyper activity and aggression induced by apomorphine and other dopaminergic agonists. In higher doses, most neoroleptics induce characteristic cataleptic immobility that allows the animal to be placed in abnormal postures that persists, the aim of this project work was to carry out preliminary pharmacological screening of 2-[(4-methyl-2-oxo-2H-chromen-7-yl) oxy-(aryl)] acetamide. preliminary pharmacological screening of the synthesized compounds for the antipsychotic activity. The screening was limited to in vivo models only. The synthesized compounds were converted to their hydrochloride salts in order to make them water-soluble. These hydrochloride salts were used for the pharmacological testing purpose. The experiments were performed on Swiss albino mice (male) and the route of administration was intra peritoneal.

Pharmacoencephalographic Assessment of Antiphyschotic Agents’ Effect Dose-Dependency in Rats

Pharmacoencephalography (pharmaco-EEG) is a prominent instrument for the pharmacological screening new psychoactive molecules. This experimental approach has not remained a vestige of neurobiological studies, and can be used successfully to complete today’s research objectives. The development and rise to universal use of machine learning techniques opens up novel prospects for the use of pharmaco-EEG data to solve the problems of classification and prognosis. We have previously shown that naïve Bayes classifier (NBC) combined with the principal component analysis (PCA) can be used to differentiate between antipsychotic and sedative drug effects as well as to distinguish among the antipsychotics’ effects. In the present study, we evaluated the possibility to employ this method to assess the dose-dependency of antipsychotic effects. The experiments were carried out in white outbred male rats with chronically implanted electrocorticographic electrodes. As the agents of interest, we chose two drugs with antipsychotic activity, chlorpromazine and promethazine, in three doses each (0.1, 1, 10 mg/kg and 0.5, 5 and 20 mg/kg, respectively). The training set, used as a reference to determine the pharmacological effects of the agents of interest, included the D2-dopamine receptor blocker haloperidol, M-cholinergic receptor blocker tropicamide, H1-histamine receptor blocker chloropyramine, the sedative dexmedetomidine, and the anxiolytic phenazepam. We have shown that the lowest chlorpromazine dose (0.1 mg/kg) can be characterized as antipsychotic with a marked histaminolytic effect, while the highest one (10 mg/kg) exhibits predominantly antipsychotic activity with a cataleptogenic effect. All the doses demonstrated anticholinergic activity, which increased with the dose. For promethazine, we observed a clear dose-dependent transition from antipsychotic action to cataleptogenic, alongside a notable antimuscarinic effect of all doses. None of promethazine doses showed any resemblance to chloropyramine, which probably indicates its anti-dopaminergic and antimuscarinic effects being able to mask its H1-antihistamine effect in the used dose range. In summary, our results demonstrate that NBC coupled with PCA can be used to determine the dose-dependency of antipsychotic agents’ effects based on their impact on electrocorticogram parameters. Further development of this method as well as expansion of psychotropic agent electropharmacogram library would allow for more precise prognosis of pharmacological activity of the agents of interest.

The Janus face of antipsychotics in glial cells: Focus on glioprotection.

Antipsychotics are commonly prescribed to treat several neuropsychiatric disorders, including schizophrenia, mania in bipolar disorder, autism spectrum disorder, delirium, and organic or secondary psychosis, for example, in dementias such as Alzheimer's disease. There is evidence that typical antipsychotics such as haloperidol are more effective in reducing positive symptoms than negative symptoms and/or cognitive deficits. In contrast, atypical antipsychotic agents have gained popularity over typical antipsychotics, due to fewer extrapyramidal side effects and their theoretical efficacy in controlling both positive and negative symptoms. Although these therapies focus on neuron-based therapeutic schemes, glial cells have been recognized as important regulators of the pathophysiology of neuropsychiatric disorders, as well as targets to improve the efficacy of these drugs. Glial cells (astrocytes, oligodendrocytes, and microglia) are critical for the central nervous system in both physiological and pathological conditions. Astrocytes are the most abundant glial cells and play important roles in brain homeostasis, regulating neurotransmitter systems and gliotransmission, since they express a wide variety of functional receptors for different neurotransmitters. In addition, converging lines of evidence indicate that psychiatric disorders are commonly associated with the triad neuroinflammation, oxidative stress, and excitotoxicity, and that glial cells may contribute to the gliotoxicity process. Conversely, glioprotective molecules attenuate glial damage by generating specific responses that can protect glial cells themselves and/or neurons, resulting in improved central nervous system (CNS) functioning. In this regard, resveratrol is well-recognized as a glioprotective molecule, including in clinical studies of schizophrenia and autism. This review will provide a summary of the dual role of antipsychotics on neurochemical parameters associated with glial functions and will highlight the potential activity of glioprotective molecules to improve the action of antipsychotics.

Adverse Effects of Antipsychotic Drugs - A Review

Antipsychotic drugs which are also known as Neuroleptics are group of psychotropic drugs or psychopharmacological agents1 that are primarily used to manage psychoses including delusions, hallucinations, paranoia, or disordered thought. Besides their antipsychotic action, they had been reported to have some adverse effects which can be seen in Cardiovascular system, Metabolic system, Skeletal and Muscular system, Cognitive and Emotional side effects, and Sexual dysfunction. These adverse effects were mainly observed when they used for longer duration or taken in larger doses or with sudden change in their dose. Keywords: Antipsychotic drugs, Adverse events, Side effects, Extrapyramidal symptoms

Pharmacological animal models of schizophrenia for antipsychotic drug discovery and development

Schizophrenia is a chronic psychoneurological condition that encompasses a wide variety of neurochemical, morphological, bioelectrical and behavioural changes. Comprehension of the mechanisms underlying schizophrenia and psychosis cannot be fully acquired in clinical studies with humans. For this reason, a number of experimental animal models of schizophrenia have been developed. Although none of the existing models of schizophrenia fully reproduces the complete spectrum of schizophrenia, critical aspects of pathology processes can be experimentally recapitulated. In this review we summarise the pathological features, advantages and limitations of the major pharmacological animal models of schizophrenia, including maternal immune activation. Commonly used pharmacological models of schizophrenia are useful for the preclinical evaluation of antipsychotic drugs and involve the dysfunction of various neurotransmitter systems, including dopamine, glutamate, serotonin. The review also describes maternal immune activation and neurodevelopmental rat models of schizophrenia. Positive, negative, and cognitive symptoms vary in degree and combination depending on the type of model used. A greater understanding of the strengths and weaknesses of various animal models of schizophrenia and the use of more than one model to evaluate antipsychotic activity would help to improve the efficiency of the drug discovery process and therapy translation from preclinical studies to patients.

Clozapine-loaded nanocapsules improve antipsychotic activity in rats: building a sequential PopPK/PD model to discriminate nanocarriers in the preformulation step.

We investigated the impact of nanoformulations on the dose-exposure-response relationship of clozapine (CZP), a low-solubility antipsychotic with serious adverse effects, using a popPK/PD approach. We evaluated the pharmacokinetics and PK/PD profiles of three coated polymeric CZP-loaded nanocapsules functionalized with polysorbate 80 (NCP80), polyethylene glycol (NCPEG), and chitosan (NCCS). Data on in vitro CZP release by dialysis bag, plasma pharmacokinetic profiles in male Wistar rats (n = 7/group, 5 mg kg-1, i.v.), and percentage of head movements in a stereotyped model (n = 7/group, 5 mg kg-1, i.p.) were integrated using a sequential model building approach (MonolixSuiteTM-2020R1-Simulation Plus). A base popPK model developed with CZP solution data collected after the i.v. administration of CZP was expanded to describe the changes in drug distribution caused by nanoencapsulation. Two additional compartments were inserted into the NCP80 and NCPEG models, and a third compartment was included in the NCCS model. The nanoencapsulation showed a decrease in the central volume of distribution for NCCS (V1NCpop = 0.21 mL), while for FCZP, NCP80, and NCPEG, it was ~1 mL. The peripheral distribution volume was higher for the nanoencapsulated groups (19.1 and 129.45 mL for NCCS and NCP80, respectively) than for FCZP. The popPK/PD model showed a formulation-dependent plasma IC50, with 20-, 50-, and 80-fold reductions compared to the CZP solution (NCP80, NCPEG, and NCCS, respectively). Our model discriminates the coatings and describes the peculiar PK and PD behavior of nanoencapsulated CZP, especially NCCS, making it an exciting tool for evaluating the preclinical performance of nanoparticles.