Generation Antipsychotic Drugs Research Articles

Case Report: Experience with Cariprazine in Organic Delusional Disorder in an Elderly with Concomitant Somatic Pathology, Brief Report

Background: Organic disorder remains one of the most pressing issues in practical psychiatry, especially a disorder dominated by persistent or recurrent delusions. The difficulty for practitioners is often due to the older age of patients and the burden of concomitant therapeutic diseases. Modern and potentially promising pharmacological drugs developed in recent years include partial agonists of D2 and D3 receptors. Currently, there are insufficient publications of studies on Cariprazine use in various disorders that are not associated with endogenous pathology. Case Presentation: The author presented the results of the patient’s clinical examination with a complex of psychodiagnostic techniques, instrumental research methods, observation data in the department, and an analysis of the patient’s medical history. The paper describes the experience of treating a patient with the latest generation antipsychotic drug Cariprazine. Results: The author presents a case report on Cariprazine therapy in a 71-year-old female patient with a persistent organic delusional disorder with concomitant severe somatic illness. Conclusion: Cariprazine showed good efficacy in this case. Delusional symptoms were significantly reduced, and the author noted a reduction in negative symptoms. Mild side effects of the drug quickly resolved in the course of treatment. The key point is that the description of this case may be relevant to justify the need for further clinical studies on Cariprazine. Further clinical studies of the drug in the treatment of various mental pathologies may be in demand by specialists around the world.

Comparative study of performances of UHPLC-MS/MS and HPLC/UV methods for analysis of ziprasidone and its main impurities

AbstractZiprasidone is the second generation antipsychotic drug with unique multipotent G-protein-coupled (GPCR) receptor binding profile. Since ziprasidone is a highly lipophilic and unstable compound, development of efficient method for a concurrent assay of ziprasidone and its main impurities was a very challenging task.The UHPLC-MS/MS method that we developed for simultaneous determination of ziprasidone and its main impurities (BITP, Chloroethyl-chloroindolinone, Zip-oxide, Zip-dimer, and Zip-BIT) was compared with some other related HPLC-UV methods of our own and other authorship. An increase of the mobile phase pH value from 2.5 to 4.7 units in the examined analytical methods influenced elution order of the investigated compounds. It was found out that the UHPLC-MS/MS method is more selective and sensitive than the earlier developed HPLC-UV method. Similar to our earlier HPLC-UV method, the UHPLC-MS/MS method is linear with a correlation coefficient (r) above 0.99 for all the analysed compounds, but with a negligibly lower precision and accuracy. Finally, with shorter analysis time, smaller column size and reduction of solvent consumption, UHPLC-MS/MS is assumed as a greener method than HPLC-UV for the ziprasidone purity assay.After transfer of the UHPLC-MS/MS method to the UHPLC-DAD system, suitability of the UHPLC-DAD method for routine control of ziprasidone and its main impurities is examined and confirmed based on the retained good selectivity, resolution and short analysis time.

Brexpiprazole—Pharmacologic Properties and Use in Schizophrenia and Mood Disorders

In 2002, the first III generation antipsychotic drug was registered-aripiprazole. Its partial dopaminergic agonism underlies its unique mechanism of action and the potentially beneficial influence on the positive, negative, or cognitive symptoms. Due to its relatively high intrinsic activity, the drug could often cause agitation, anxiety, or akathisia. For this reason, efforts were made to develop a drug which would retain the positive favorable actions of aripiprazole but present a more advantageous clinical profile. This turned out to be brexpiprazole, which was registered in 2015. Its pharmacodynamic and pharmacokinetic profile (similarly to the other most recent antipsychotics, i.e., lurasidone or cariprazine) shows promise of increasing the effectiveness of schizophrenia treatment in the dimensions in which the previous antipsychotics were not sufficiently effective, including negative, depressive, or cognitive symptoms. Like other new antipsychotics, it can also be useful in the treatment of mood disorders, for instance drug-resistant depression. Previous reviews focused on the use of brexpiprazole in specific diagnostic groups. The aim of this article is to provide the readers with an overview of data on the mechanism of action, clinical effectiveness in all studied diagnostic groups, as well as potential drug-food interactions, and the safety of brexpiprazole.

The first generation and second generation antipsychotic drugs and their pharmacology in treatment of schizophrenia

In this review report, an attempt made to present an overview of schizophrenia & those drugs which are used in treatment of psychiatric disorders as well as some treatments for psychosis. In 1908, the schizophrenia word was coined by Eugen Bleuler (Swiss psychiatrist). The use antipsychotics as medication began from 1933 in France. Laborit and Huguenard administrated the aliphatic Phenothiazine, Chlorpromazine during surgery due to its potential anesthetic effect, in 1951. Thereafter, Hamon and Delay extended the use of this treatment in psychiatric patients. Due to abnormal brain structure & functioning occurs schizophrenia as well as psychotic disorders. Schizophrenia a condition in people unable to differentiate between real & imaginary world. In this article we all know about Schizophrenia & Antipsychotics drugs. In that include symptoms & their types, cause, risk factor, antipsychotics classification & their pharmacology etc. In that there are three types of symptoms namely positive, Negative, Cognitive. Exact causes of schizophrenia are unknown. In the treatment of Schizophrenia or psychotics disorders the physicians commonly used antipsychotic medicines or drugs to treat their symptoms. Antipsychotic drugs further divided into two major classes namely Typical & Atypical antipsychotics. Chlorpromazine is the first medicine or drug which is used to treat symptoms of schizophrenia and schizoaffective disorders. Clozapine is most effective or potent antipsychotics drug. Which is belongs to the atypical antipsychotics which are reducing the risk of schizoaffective patients. Physicians recommend a combination of antipsychotics along with psychotherapy. In this article we have covered Brahmyadiyoga is an Ayurvedic remedies.

The long-lasting effects of early antipsychotic exposure during juvenile period on adult behaviours – A study in a poly I:C rat model

Second generation antipsychotic drugs including aripiprazole, olanzapine and risperidone are prescribed increasingly (mostly off-label) to treat various mental disorders in children and adolescents. Early treatment with antipsychotics during this period may have long-lasting behavioural impacts, but to date there have been only limited investigations. Maternal infection could be implicated in the aetiology of various mental disorders including schizophrenia. Exposure of pregnant rodents to polyriboinosinic-polyribocytidylic acid (Poly I:C) causes schizophrenia-like behavioural abnormalities and neurodevelopmental conditions such as autism spectrum disorders in offspring. This study, using a Poly I:C rat model, investigated the long-lasting effects of early aripiprazole, olanzapine and risperidone treatment in the childhood/adolescent period (postnatal day 22–50) on adult behaviours of male rats. The study showed that early treatment with three antipsychotics had different effects on long-term behavioural changes in adults. Prenatal Poly I:C exposure (5 mg/kg) at gestation day 15 caused deficits in pre-pulse inhibition and social interaction, as well as cognitive impairments, that could be partially improved by early antipsychotic treatment in the juvenile period. Early antipsychotic treatment during the childhood-adolescent period resulted in similar long-lasting effects on pre-pulse inhibition, anxiety- and depressive-related behaviours in both Poly I:C and healthy (control) male rats. Overall, these results suggest that both prenatal Poly I:C exposure and early antipsychotic treatment in the childhood/adolescent period had long-lasting effects on adult behaviours of male rats, while early antipsychotic treatment could partly prevent the onset of behavioural abnormalities resulting from prenatal insult.

Antipsychotic drugs and QT interval prolongation

Prolongation of myocardial repolarization, i.e. lengthening of the QTc interval on surface electrocardiogram (ECG), with increased risk of cardiac arrhythmias, has been recognized as a side effect of many drugs. Most first and second generation antipsychotic drugs can cause dose-related prolongation of QTc, although there are important differences in the potency of individual agents. ECGs in 46 patients suffering from schizophrenic disorder and treated with different antipsychotic drugs one week after the admission to the psychiatric hospital were analyzed in this prospective observational study. Hearth rate, QT interval and QTc interval were assessed. The average daily dose of prescribed antipsychotic drugs was calculated. Average QTc interval was 417 msec, only 3 out of 46 (6,5%) patients had QTc over 450 msec and only one patient (2,2%) had QTc over 500 msec. No differences in QTc interval between patients who were treated either with first or second generation antipsychotic drug or with combination of both were found. Female participants had significantly longer OTc interval than male participants (p < 0,05). Results raise the question of the clinical relevance of a single ECG for diagnostics of cardiac complications in schizophrenia patients and suggest the need to conduct ECG monitoring in patients with high risk for cardiac complications during antipsychotic treatment.

Letter to the Editor: Rethinking The Cost Of Antipsychotic Treatment: The Average Cost Of The Drugs Used In Turkey In 2020.

Letter to the Editor: Rethinking The Cost Of Antipsychotic Treatment: The Average Cost Of The Drugs Used In Turkey In 2020.

Aripiprazole ameliorates scopolamine-induced amnesia in mice

Aripiprazole, a known third generation anti-psychotic drug. The drug has shown to have lesser side effects on extrapyramidal system and enhance memory when compared with the first-generation anti-psychotic drugs. However, studies on the impact of aripiprazole on scopolamine-induced memory impairment in mice have been poorly reported. This study was designed to investigate the impact of aripiprazole on scopolamine-induced amnesia in mice. Thirtysix (36) mice weighing between 20-23g were randomly divided into six groups. Group 1 was given 10 ml/kg distilled water. Group 2 received 3 mg/kg scopolamine alone. Group 3 was given 1 mg/kg donepezil. Group 4 received 0.5 mg/kg aripiprazole. Group 5 was given 0.3 mg/kg aripiprazole. Group 6 received 0.1mg/kg aripiprazole. Thirty minutes after administration of either aripiprazole or donepezil, scopolamine (3 mg/kg) was administered, intraperitoneally. The administration was for 7days, during which their memory was assessed using Morris water maze and Y-maze models. The results showed that the anti-amnesic effect of aripiprazole appeared to be dosedependent; the animals administered with 0.5 mg/kg aripiprazole showed the greatest improved memory performance against scopolamine-induced amnesia. The hippocampal and prefrontal cortex tissues displayed anti-amnesic potential of aripiprazole. Aripiprazole seems to improved memory performance against scopolamine-induced memory impairment in mice.
 Keywords: Aripiprazole; Anti-amnesic; Scopolamine; Memory

A ganglionic blocker and adrenoceptor ligands modify clozapine-induced insulin resistance

Clozapine is a second generation antipsychotic drug that has proven to be helpful in the management of patients with psychotic disorders that are resistant to other medications. Unfortunately, the majority of patients treated with clozapine develop metabolic dysregulation, including weight gain and insulin resistance. There are few treatments available to effectively counter these side-effects. The goal of the present study was to use an established animal model to better understand the nature of these metabolic side-effects and determine whether existing drugs could be used to alleviate metabolic changes. Adult female rats were treated with a range of doses of clozapine (2, 10 and 20 mg/kg) and subjected to the hyperinsulinemic-euglycemic clamp, to measure whole-body insulin resistance. Clozapine dose-dependently decreased the glucose infusion rate, reflecting pronounced insulin resistance. To reverse the insulin resistance, rats were co-treated with the ganglionic blocker mecamylamine (0.1, 1.0 and 5.0 mg/kg) which dose-dependently reversed the effects of 10 mg/kg clozapine. A 1.0 mg/kg dose of mecamylamine independently reversed the large increase in peripheral epinephrine caused by treatment with clozapine. To study the influence of specific adrenoceptors, rats were treated with multiple doses of α1 (prazosin), α2 (idazoxan), β1 (atenolol) and β2 (butoxamine) adrenoceptor antagonists after the onset of clozapine-induced insulin resistance. Both beta blockers were effective in attenuating the effects of clozapine, while idazoxan had a smaller effect; no change was seen with prazosin. The current results indicate that peripheral catecholamines may play a role in clozapine’s metabolic effects and be a target for future treatments.

Development of a New Polymeric Nanocarrier Dedicated to Controlled Clozapine Delivery at the Dopamine D2-Serotonin 5-HT1A Heteromers

Clozapine, the second generation antipsychotic drug, is one of the prominent compounds used for treatment of schizophrenia. Unfortunately, use of this drug is still limited due to serious side effects connected to its unspecific and non-selective action. Nevertheless, clozapine still remains the first-choice drug for the situation of drug-resistance schizophrenia. Development of the new strategy of clozapine delivery into well-defined parts of the brain has been a great challenge for modern science. In the present paper we focus on the presentation of a new nanocarrier for clozapine and its use for targeted transport, enabling its interaction with the dopamine D2 and serotonin 5-HT1A heteromers (D2-5-HT1A) in the brain tissue. Clozapine polymeric nanocapsules (CLO-NCs) were prepared using anionic surfactant AOT (sodium docusate) as an emulsifier, and bio-compatible polyelectrolytes such as: poly-l-glutamic acid (PGA) and poly-l-lysine (PLL). Outer layer of the carrier was grafted by polyethylene glycol (PEG). Several variants of nanocarriers containing the antipsychotic varying in physicochemical parameters were tested. This kind of approach may enable the availability and safety of the drug, improve the selectivity of its action, and finally increase effectiveness of schizophrenia therapy. Moreover, the purpose of the manuscript is to cover a wide scope of the issues, which should be considered while designing a novel means for drug delivery. It is important to determine the interactions of a new nanocarrier with many cell components on various cellular levels in order to be sure that the new nanocarrier will be safe and won’t cause undesired effects for a patient.

A Focused Review of the Metabolic Side-Effects of Clozapine.

The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation.

Treating Schizophrenia Thinking beyond the Choice of Antipsychotic

The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and non-dopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

Differential Effects of Acute Treatment With Antipsychotic Drugs on Peripheral Catecholamines

Antipsychotic drugs represent the most effective treatment for chronic psychotic disorders. The newer second generation drugs offer the advantage of fewer neurological side-effects compared to prior drugs, but many cause serious metabolic side-effects. The underlying physiology of these side-effects is not well-understood, but evidence exists to indicate that the sympathetic nervous system may play an important role. In order to examine this possibility further, we treated separate groups of adult female rats acutely with either the first generation antipsychotic drug haloperidol (0.1 or 1 mg/kg) or the second generation drugs risperidone (0.25 or 2.5 mg/kg), clozapine (2 or 20 mg/kg), olanzapine (3 or 15 mg/kg) or vehicle by intraperitoneal injection. Blood samples were collected prior to drug and then 30, 60, 120, and 180 mins after treatment. Plasma samples were assayed by HPLC-ED for levels of norepinephrine, epinephrine, and dopamine. Results confirmed that all antipsychotics increased peripheral catecholamines, although this was drug and dose dependent. For norepinephrine, haloperidol caused the smallest maximum increase (+158%], followed by risperidone (+793%), olanzapine (+952%) and clozapine (+1,684%). A similar pattern was observed for increases in epinephrine levels by haloperidol (+143%], olanzapine (+529%), risperidone (+617%) then clozapine (+806%). Dopamine levels increased moderately with olanzapine [+174%], risperidone [+271%], and clozapine [+430%]. Interestingly, levels of the catecholamines did not correlate strongly with each other prior to treatment at baseline, but were increasingly correlated after treatment as time proceeded. The results demonstrate antipsychotics can potently regulate peripheral catecholamines, in a manner consistent with their metabolic liability.

Pharmaceutical estimation of aripiprazole to assist in modern research: An upbeat review

Aripiprazole is second generation anti-psychotic drug. Numerous investigations that have been published previously; stating analytical methods. The reported investigations for aripiprazole in its medical preparation and biological matrices is in present report. The most widely employed approaches in analysis outlined, such as spectrometric, liquid chromatographic processes, liquid chromatography-mass spectrometry, voltammetry and gas chromatography (GC). Spectrometric methods for ARP alone and in combination are precisely stated. Which includes parameters like ? max, solvent, matrix etc. and HPLC methods for aripiprazole single and in combination are given in tabular form, to parameters like matrix, stationary phase, mobile phase composition detection wavelength etc. HPTLC methods are reported in tabular form contain parameters like mobile phase combination, stationary phase, Rf etc. LC-MS method of aripiprazole and metabolite including parameter like matrix, stationary phase, mobile phase, internal standard, flow rate, retention time etc. the statistical data regarding the utility of these methods for estimation of aripiprazole published during 2004 to 2019 is precisely presented herein assist in further analytical and formulation research in future. Keywords: Aripiprazole, Pharmaceutical, Analytical methods, Applications, Scope, Review.

Enhanced Pharmacokinetic Activity of Zotepine via Nanostructured Lipid Carrier System in Wistar Rats for Oral Application

Zotepine (ZT) is a substituted dibenzothiepine tricyclic molecule and second generation antipsychotic drug. It is available as the parenteral and oral solid dosage form, but, orally administered ZT has a poor oral bioavailability (10%) that might be due to either poor water solubility, high lipophilicity (Log P 4) and also first-pass hepatic metabolism. The oral bioavailability of ZT was improved by loading into a nanostructured lipid carriers (NLCs) system. Hot homogenization with probe sonication method was used for the preparation of ZT-NLCs formulations and characterized for an optimal system based on physicochemical characteristics and in vitro release. Differential scanning calorimetry (DSC), X-ray diffraction (XRD) analysis, and scanning electron microscopy (SEM) studies were used to confirm the crystalline nature and shape of the optimized ZT-NLC formulation. The physical stability of the optimized ZT-NLC formulation was evaluated at the refrigerator and room temperature over two months. Furthermore, in vivo pharmacokinetic (PK) studies of optimized ZT-NLC and ZT coarse suspension (ZT-CS) as control formulation, were conducted in male Wistar rats. The optimized formulation of ZT-NLC showed Z-avg, PDI, ZP of 145.8 ± 2.5 nm, 0.18 ± 0.05, -31.6 ± 1.8 mV, respectively. In vitro release studies indicated the sustained release of ZT. DSC and XRD studies revealed the conversion of ZT into an amorphous form. SEM studies showed the spherical shape of the ZT-NLC formulation. PK studies showed 1.8-folds improvement (p<0.05) in oral bioavailability when compared with ZTCS formulation. Overall, the results established that NLCs could be used as a new alternative delivery vehicle for the oral delivery of ZT.

Quality by Design Approach for Development and Characterisation of Solid Lipid Nanoparticles of Quetiapine Fumarate.

Background Quetiapine fumarate, a 2nd generation anti-psychotic drug has oral bioavailability of 9% because of hepatic first pass metabolism. Reports suggest that co-administration of drugs with lipids affects their absorption pathways, enhances lymphatic transport thus bypassing hepatic first-pass metabolism resulting in enhanced bioavailability.Objective The present work aimed at developing, and characterising potentially lymphatic absorbable Solid Lipid Nanoparticles (SLN) of quetiapine fumarate by Quality by Design approach.Methods Hot emulsification followed by ultrasonication was used as a method of preparation. Precirol ATO5, Phospholipon 90G and Poloxamer 188 were used as a lipid, stabilizer and surfactant respectively. A32 Central Composite design optimised the 2 independent variables, lipid concentration and stabilizer concentration and assessed their effect on percent Entrapment Efficiency (%EE: Y1). The lyophilized SLNs were studied for stability at 5 ±3οC and 25 ± 2οC/60 ± 5% RH for 3 months.Results The optimised formula derived for SLN had 270mg Precirol ATO5 and 107mg of Phospholipon 90G giving %EE of 76.53%. Mean particle size was 159.8nm with polydispersity index 0.273 and zeta potential -6.6mV. In-vitro drug release followed Korsmeyer-Peppas kinetics (R2=0.917) with release exponent n=0.722 indicating non-Fickian diffusion. Transmission electron microscopy images exhibited particles to be spherical and smooth. Fourier-transform infrared spectroscopy, differential scanning calorimetry and X-ray diffraction studies ascertained drug-excipient compatibility. Stability studies suggested 5οC as appropriate temperature for storage and preserving important characteristics within acceptable limits.Conclusion Development and optimisation by Quality by Design were justified as it yielded SLN having acceptable characteristics and potential application for intestinal lymphatic transport.

Risperidone and Hepatotoxicity in Children and Adolescent: A Literature Review

Risperidone is a second generation anti-psychotic drug that is commonly preferred in the treatment of schizophrenia, attention deficit hyperactivity disorder and bipolar disorders. Risperidone-associated hepatic adverse effects have long been investigated and continues to be unclear. In this review, our aim is to establish the possible hepatic adverse effects linked to risperidone treatment in children and adolescent in terms of severities and reversibility. We performed literature search via electronic databases (PubMed, Embase and the Cochrane Library) in August 2019. Risperidone treatment may lead to alterations in liver function test (LFT), mostly asymptomatic and reversible with the discontinuation or normalizes with time. Furthermore, there are few cases reporting risperidone-induced cholestatic hepatitis and immunoallergic hepatitis. Although exact mechanism of action of risperidone on liver remains unknown, there are growing evidences that link alterations of fatty acid biosynthesis to hepatic adverse effects. We recommend physicians to take basal LFT prior to risperidone treatment and monitor LFT during treatment. Additionally, physicians should be aware that most alterations at LFT associated with risperidone use are asymptomatic and reversible. However, more comprehensive studies investigating risperidone-associated hepatic adverse effects should be performed to reach a definitive outcome.

Repurposing of Iloperidone: Antihypertensive and ocular hypotensive activity in animals

PurposeIloperidone, second generation antipsychotic drug, reported in clinical trial to produce orthostatic hypotension as side effect. It was claimed to be antagonistic at alpha adrenergic receptor in central nervous system. We evaluated effect of Iloperidone on peripheral alpha 1 adrenoreceptor by in silico and in vitro methods while in vivo hypotensive, antihypertensive and ocular hypotensive activity was evaluated in animals. MethodsPharmacological activity prediction of Iloperidone was done using PASSOnline and SwissTargetPrediction softwares and molecular docking with Alpha 1A adrenoreceptor using AutoDock Vina. Hypotensive activity in normotensive and antihypertensive activity against DOCA-salt induced hypertension in rats were evaluated at doses 0.03 mg/Kg and 0.1 mg/Kg, i.p of Iloperidone. Blood pressure was measured by invasive blood pressure measurement technique using PowerLab 4/30 and intraocular pressure was measured using digital tonometer. ResultsIloperidone (0.1 mg/Kg) showed significant decrease in blood pressure (38.96 ± 1.1%) in normotensive rats, while in DOCA salt induced hypertensive rats, systolic blood pressure was found to be decreased by 29.04 ± 1.45% and 31.43 ± 1.21% in 0.03 mg/Kg and 0.1 mg/Kg treated rats respectively. Iloperidone prevented rise in systolic BP with adrenaline. Intraocular pressure was found to be decreased by 36.66 ± 3.15% in rabbits after 1 h of instillation of 0.1% Iloperidone. ConclusionIloperidone exerted hypotensive and/or anti-hypertensive activity in rats and ocular hypotensive activity in rabbits.

Serum sickness-like reaction to a second generation antipsychotic drug

Introduction: Serum sickness is a type III hypersensitivity reaction. Immune complex deposition activates complement pathways resulting in fever, vasculitic rash, arthritis and lymphadenopathy. Medications are known to trigger serum sickness-like reactions which clinically resemble serum sickness, however, are not thought to involve circulating immune complexes. The full pathophysiology is not clear. Risperidone is an atypical antipsychotic drug commonly used in the paediatric population. Aim: To describe the diagnosis, disease course and outcome of a patient who developed serum sickness-like reaction secondary to risperidone. Methods: Review of patient chart and medical interview in accordance with institutional research ethics board approval. Results: The patient, a 7 year old male with Attention Deficit Hyperactivity Disorder, was started on risperidone 0.25 mg once daily. Within a week the dose was increased to 0.5 mg once daily. During the third week after initiation of medication, the patient developed generalized purpuric, confluent, maculopapular rash. Although the patient did not have any signs and symptoms of a viral illness, he was diagnosed with viral-induced exanthema and continued on risperidone. On day 28, he developed significant, bilateral swelling of upper and lower extremities, facial angioedema, lymphadenopathy, arthralgia and arthritis in ankles, knees, hands and elbows without fever. Investigations showed normal complement C3 and C4 levels. C1 esterase inhibitor, anti-nuclear antibody and urinalysis were normal. Erythrocyte sedimentation rate, C-reactive protein and leukocyte levels were elevated. The diagnosis of serum sickness-like reaction to risperidone was made and the patient subsequently treated with cetirizine, hydrocortisone, and prednisone for 1 week with significant improvement. Skin biopsy was declined by the patients’ parents and therefore was not performed. Provocative oral challenge to risperidone was not considered because of clear suggestive history and ethical consideration. Conclusion: Psychotropic medications are known to cause cutaneous eruptions. Serum sickness-like reactions can happen upon exposure to risperidone. Clinicians should be aware of this potential adverse reaction that can develop weeks after therapy initiation, and be encouraged to discontinue risperidone when the suggestive symptoms emerges. Statement of novelty: We describe a case of serum sickness-like reaction to risperidone in a paediatric patient. To our knowledge, this is the first case of serum sickness-like reaction to risperidone.

A comparison of the effects of clozapine and its metabolite norclozapine on metabolic dysregulation in rodent models

RationaleThe second generation antipsychotic drug clozapine is a psychotherapeutic agent with superior efficacy for treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of neurological side-effects, but a high propensity to induce weight gain and metabolic dysregulation. The primary metabolite of clozapine is norclozapine (N-Desmethylclozapine), which has psychoactive properties itself, but its effects on metabolic function remains unknown. The goal of the present study was to determine whether directly administered norclozapine could cause metabolic dysregulation, similar to clozapine. MethodsAdult female rats were treated with a range of doses of clozapine and norclozapine (0.5, 2, 8 & 20 mg/kg, i.p.) and then subjected to the intraperitoneal glucose tolerance test (IGTT), where glucose levels were recorded for 2 h following a glucose challenge. In parallel, rats were tested with two doses of clozapine and norclozapine (2 & 20 mg/kg, i.p.) in the hyperinsulinemic-euglycemic clamp (HIEC), to measure whole body insulin resistance. ResultsIn the IGTT, clozapine demonstrated dose-dependent effects on fasting glucose levels and total glucose area-under-the-curve following the glucose challenge, with the two highest doses strongly increasing glucose levels. Only the highest dose of norclozapine increased fasting glucose levels, and caused a non-significant increase in glucose levels following the challenge. By contrast, both doses of clozapine and norclozapine caused a potent and long-lasting decrease in the glucose infusion rate in the HIEC, indicating that both compounds cause whole body insulin resistance. AbstractWhile not as potent as its parent compound, norclozapine clearly exerts acute metabolic effects, particularly on insulin resistance.This article is part of the issue entitled ‘Special Issue on Antipsychotics’.