Gynura procumbens and selected metabolites: Amelioration of depressive-like behaviors in mice and risperidone-induced hyperprolactinemia in rats.

Gynura procumbens (Lour.) Merr., utilized in traditional Chinese medicine, is known for its liver-protective, liver-soothing, and depression-alleviating properties. This research examines the antidepressant and anti-hyperprolactinemia potentials of an ethanol extract from G. procumbens stems (EEGS) and specific metabolites. To model depression and hyperprolactinemia, chronic unpredictable mild stress (CUMS) was induced in mice and risperidone was administered to rats, respectively. Treatments involved administering low (5 mg/kg), medium (25 mg/kg), and high (125 mg/kg) doses of EEGS and certain metabolites to both models. Behavioral assessments were conducted in the CUMS-induced mice, while the CA3 neuronal damage in mice and histopathological alterations in rat mammary glands were evaluated using Nissl and Hematoxylin & Eosin staining techniques, respectively. EEGS decreased immobility times in the forced swimming and tail suspension tests in mice, enhancing their exploration of the central zone. It elevated the serum levels of 5-hydroxytryptamine, norepinephrine, estradiol, luteinizing hormone (LH), and testosterone in mice. Moreover, EEGS restored the neuronal cell arrangement in the CA3 area, reduced interleukin-1beta mRNA production, and increased the expression of interleukin-10 and beta-catenin mRNA. In the context of risperidone-induced hyperprolactinemia, EEGS lowered blood prolactin levels, reduced the dimensions of rat nipples, and enhanced LH, progesterone, and dopamine levels, alongside mitigating mammary hyperplasia. Among the EEGS selected metabolites, the combined effect of chlorogenic acid and trans-p-coumaric acid was found to be more effective than the action of each compound in isolation. Collectively, the findings indicate that EEGS and its selected metabolites offer promising antidepressant benefits while counteracting hyperprolactinemia.

Neurobehavioral Differences of Valproate and Risperidone on MK-801 Inducing Acute Hyperlocomotion in Mice.

OBJECTIVE: The glutamate system plays a major role in the development of neuropsychiatric disorders such as addiction, epilepsy, dementia, and psychosis. MK-801 (dizocilpine), an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, could increase locomotor activity and stereotyped neurobehaviors mimicking schizophrenic-like features in the mouse model. The study would explore the neuropharmacological differences of risperidone and valproic acid on the MK-801-induced neurobehavioral changes. METHODS: The subjects were male C57BL/6J mice obtained from the National Laboratory Animal Center. Drug effects were assessed using the open field with a video-tracking system and gaiting tests. After habitation, risperidone (0, 0.1 mg/kg) or valproic acid (0, 200 mg/kg) was injected and ran locomotion for 30 mins. Sequentially, mice were followed by intraperitoneal injection (i.p.) with MK-801 (0, 0.2 mg/kg) and ran locomotion for 60 mins. Gaiting behaviors such as step angles, stride lengths, and stance widths were measured following the study drugs. RESULTS: The results showed that risperidone and valproic acid alone could not alter the locomotor activities. Following the MK-801 injection, the travelled distance and speed in the entire open field dramatically increased. The dose 0.1 mg/kg of risperidone could totally inhibit the MK-801-induced hyperlocomotion compared with that of the saline-injected group (p < 0.001). The valproic acid (200 mg/kg) partially suppressed the hyperlocomotion which is induced by MK801. CONCLUSION: The more dominant effect of risperidone to rescue MK-801 induced hyperlocomotion compared with that of valproic acid. The partial suppression of valproic acid may imply the psychopharmacological evidence as adjuvant effect to treat psychotic patients through tuning glutamatergic neurotransmission.

Effects of Venlafaxine, Risperidone and Febuxostat on Cuprizone-Induced Demyelination, Behavioral Deficits and Oxidative Stress.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.

The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain.

Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine-another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice.

A 16-week randomized placebo-controlled trial investigating the effects of omega-3 polyunsaturated fatty acid treatment on white matter microstructure in recent-onset psychosis patients concurrently treated with risperidone.

We examined the impact of treatment with fish oil (FO), a rich source of omega-3 polyunsaturated fatty acids (n-3 PUFA), on white matter in 37 recent-onset psychosis patients receiving risperidone in a double-blind placebo-controlled randomized clinical trial. Patients were scanned at baseline and randomly assigned to receive 16-weeks of treatment with risperidone + FO or risperidone + placebo. Eighteen patients received follow-up MRIs (FO, n = 10/Placebo, n = 8). Erythrocyte levels of n-3 PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA) were obtained at both time points. We employed Free Water Imaging metrics representing the extracellular free water fraction (FW) and fractional anisotropy of the tissue (FA-t). Analyses were conducted using Tract-Based-Spatial-Statistics and nonparametric permutation-based tests with family-wise error correction. There were significant positive correlations of FA-t with DHA and DPA among all patients at baseline. Patients treated with risperidone + placebo demonstrated reductions in FA-t and increases in FW, whereas patients treated with risperidone + FO exhibited no significant changes in FW and FA-t reductions were largely attenuated. The correlations of DPA and DHA with baseline FA-t support the hypothesis that n-3 PUFA intake or biosynthesis are associated with white matter abnormalities in psychosis. Adjuvant FO treatment may partially mitigate against white matter alterations observed in recent-onset psychosis patients following risperidone treatment.

A potential role for adjunctive omega-3 polyunsaturated fatty acids for depression and anxiety symptoms in recent onset psychosis: Results from a 16 week randomized placebo-controlled trial for participants concurrently treated with risperidone.

Omega-3 treatment studies for multi-episode schizophrenia or clinical high risk for conversion to psychosis states have had variable, and often negative, results. To examine adjunctive omega-3 treatment for recent onset psychosis, participants aged 15-40 years with recent onset schizophrenia-spectrum (n = 46) or bipolar (n = 4) disorders and current psychotic symptoms were treated for 16 weeks with risperidone and randomly-assigned omega-3 (EPA 740 mg and DHA 400 mg daily) or matching placebo. The primary outcome measure was the Brief Psychiatric Rating Scale (BPRS) total score. Mean lifetime antipsychotic exposure was 18.1 days. Length of time in treatment, risperidone dose and number of omega-3/placebo capsules taken did not differ between conditions. Longitudinal analysis of the total BPRS score revealed a trend level (p = 0.0826) treatment effect favoring omega-3 treatment. Lorazepam was an allowed concomitant medication. Among the subgroup (N = 23) who did not receive lorazepam, the treatment effect on BPRS total scores favoring omega-3 was significant (p = 0.0406) and factor scores analyses revealed a substantial decrease in depression-anxiety with omega-3 but no change with placebo (treatment-by-time interaction, p = 0.0184). Motor side effects did not differ between conditions. Analysis of Systematic Assessment for Treatment Emergent Events assessments revealed fewer adverse events overall with omega-3 compared with placebo with the largest differences between conditions (all favoring omega-3) on confusion, anxiety, depression, irritability, and tiredness/fatigue. These results suggest that omega-3 adjuvant treatment is a potential option for depression and anxiety symptoms of people with recent onset psychosis. Further research is needed to confirm this potential. Clinical trial registration: NCT01786239.

Tropisetron enhances recognition memory in rats chronically treated with risperidone or quetiapine.

While impairments of cognition in schizophrenia have the greatest impact on long-term functional outcome, the currently prescribed treatments, antipsychotic drugs (APDs), do not effectively improve cognition. Moreover, while more than 20 years have been devoted to the development of new drugs to treat cognitive deficits in schizophrenia, none have been approved to date. One area that has not been given proper attention at the preclinical or clinical stage of drug development is the chronic medication history of the test subject. Hence, very little is known about how chronic treatment with drugs that affect multiple receptors like APDs influence the response to a potential pro-cognitive agent. Therefore, the purpose of this study was to evaluate the α7 nicotinic acetylcholine receptor (α7 nAChR) partial agonist, tropisetron in rats chronically treated with APDs with distinct pharmacological profiles. Rats were treated orally with either risperidone (2.5 mg/kg/day) or quetiapine (25.0 mg/kg/day) for 30 or 90 days and then an acute injection of vehicle or tropisetron (3.0 mg/kg) was administered before training in a novel object recognition (NOR) task. After a 48 h delay (when recollection of the familiar object was impaired in vehicle-treated animals) neither 30 nor 90 days of risperidone or quetiapine treatment improved NOR performance. In contrast, tropisetron markedly improved NOR performance in rats treated with either APD for 30 or 90 days. These animal data reinforce the argument that two commonly prescribed APDs are not pro-cognitive agents and that α7 nAChR ligands like tropisetron have potential as adjunctive treatments in schizophrenia.

Risperidone-induced metabolic dysfunction is attenuated by Curcuma longa extract administration in mice.

Antipsychotics, such as risperidone, increase food intake and induce alteration in glucose and lipid metabolism concomitantly with overweight and body fat increase, these biological abnormalities belong to the metabolic syndrome definition (high visceral adiposity, hypertriglyceridemia, hyperglycemia, low HDL-cholesterol and high blood pressure). Curcumin is a major component of traditional turmeric (Curcuma longa) which has been reported to improve lipid and glucose metabolism and to decrease weight in obese mice. We questioned the potential capacity of curcumin, contained in Curcuma longa extract (Biocurcuma™), to attenuate the risperidone-induced metabolic dysfunction. Two groups of mice were treated once a week, for 22 weeks, with intraperitoneal injection of risperidone (Risperdal) at a dose 12.5 mpk. Two other groups received intraperitoneal injection of the vehicle of Risperdal following the same schedule. Mice of one risperidone-treated groups and of one of vehicle-treated groups were fed a diet with 0.05% Biocurcuma™ (curcumin), while mice of the two other groups received the standard diet. Curcumin limited the capacity of risperidone to reduce spontaneous motricity, but failed to impede risperidone-induced increase in food intake. Curcumin did not reduce the capacity of risperidone to induce weight gain, but decreased visceral adiposity and decreased the risperidone-induced hepatomegaly, but not steatosis. Furthermore, curcumin repressed the capacity of risperidone to induce the hepatic over expression of enzymes involved in lipid metabolism (LXRα, FAS, ACC1, LPL, PPARγ, ACO, SREBP2) and decreased risperidone-induced glucose intolerance and hypertriglyceridemia. Curcumin decreased risperidone-induced increases in serum markers of hepatotoxicity (ALAT, ASAT), as well as of one major hepatic pro-inflammatory transcription factor (NFκB: p105 mRNA and p65 protein). These findings support that nutritional doses of curcumin contained in Curcuma longa extract are able to partially counteract the risperidone-induced metabolic dysfunction in mice, suggesting that curcumin ought to be tested to reduce the capacity of risperidone to induce the metabolic syndrome in human.

The Screening of Anticholinergic Accumulation by Traditional Chinese Medicine.

Many Western drugs can give rise to serious side effects due to their ability to bind to acetylcholine receptors in the brain. This aggravates when they are combined, which is known as anticholinergic accumulation (AA). Some bioactives in Traditional Chinese Medicine (TCM) are known to block acetylcholine receptors and thus potentially cause AA. The AA of TCM was screened by quantifying the displacement of [³H] pirenzepine on acetylcholine receptors in a rat brain homogenate. We used a new unit to express AA, namely the Total Atropine Equivalents (TOAT). The TOAT of various herbs used in TCM was very diverse and even negative for some herbs. This is indicative for the broadness of the pallet of ingredients used in TCM. Three TCM formulas were screened for AA: Ma Huang Decotion (MHD), Antiasthma Simplified Herbal Medicine intervention (ASHMI), and Yu Ping Feng San (YPFS). The TOAT of ASHMI was indicative for an additive effect of herbs used in it. Nevertheless, it can be calculated that one dose of ASHMI is probably too low to cause AA. The TOAT of YPFS was practically zero. This points to a protective interaction of AA. Remarkably, MHD gave a negative TOAT, indicating that the binding to the acetylcholine receptors was increased, which also circumvents AA. In conclusion, our results indicate that TCM is not prone to give AA and support that there is an intricate interaction between the various bioactives in TCM to cure diseases with minimal side effects.

The Effects of Prenatal Iron Deficiency and Risperidone Treatment on the Rat Frontal Cortex: A Proteomic Analysis.

Prenatal iron deficiency (pID) has been described to increase the risk for neurodevelopmental disorders such as autism and schizophrenia; however, the precise molecular mechanisms are still unknown. Here, we utilized high-throughput MS to examine the proteomic effects of pID in adulthood on the rat frontal cortex area (FCA). In addition, the FCA proteome was examined in adulthood following risperidone treatment in adolescence to see if these effects could be prevented. We identified 1501 proteins of which 100 were significantly differentially expressed in the FCA at postnatal day 90. Pathway analysis of proteins affected by pID revealed changes in metabolic processes, including the tricyclic acid cycle, mitochondrial dysfunction, and P13K/Akt signaling. Interestingly, most of these protein changes were not present in the adult pID offspring who received risperidone in adolescence. Considering the link between pID and several neurodevelopmental disorders such as autism and schizophrenia these presented results bring new perspectives to understand the role of iron in metabolic pathways and provide novel biomarkers for future studies of pID.

Formulation by design based risperidone nano soft lipid vesicle as a new strategy for enhanced transdermal drug delivery: In-vitro characterization, and in-vivo appraisal.

The present study was designed to formulate and optimize transdermal risperidone soft lipid vesicles. The formulation optimized with phospholipid, safranal and ethanol were incorporated as permeation and absorption enhancers. The optimized risperidone soft lipid vesicle was further evaluated for skin irritation study, in-vivo pharmacokinetic study and locomotor activity. Three factor three level Box-Behnken design (BBD) was used to statistically optimize soft lipid vesicle using safranal (A), ethanol (B)and phospholipid (C) as independent variable, while their effect was observed for vesicle size (Y1), entrapment efficiency (Y2) and flux (Y3). The optimized risperidone soft lipid vesicle (Ris-opt) showed nanometric vesicle size, high entrapment efficiency and marked enhancement in transdermal flux. The extent of absorption from Ris-opt was greater when compared to oral suspension with relative bioavailability of 177%. The histopathological evaluation revealed developed formulation did not showed skin irritation compared to standard irritant. The significant findings presented here encourage further studies with risperidone soft lipid vesicles for treatment of schizophrenia.

3-month parenteral PLGA microsphere formulations of risperidone: Fabrication, characterization and neuropharmacological assessments.

The study aims at formulation and characterization of three months parenteral risperidone loaded polymeric microspheres (p-RLPMs) as a sustained delivery system and established their in vitro and in vivo assessments. The p-RLPMs formulations were prepared by solvent extraction and diffusion method. The optimized p-RLPMs (batch RPLGA-1) formulation demonstrated favorable different physicochemical properties such as mean particle size (104±5.34µm), percent porosity (44.56±3.11%) and percent drug loading (38.42±2.67%). The physical state characterization, Fourier transformed infrared spectroscopy analysis showed no changes in the chemical structure of risperidone (RPD) in the batch RPLGA-1 formulation and differential scanning calorimetry study confirmed, pure RPD retained its crystallinity in the batch RPLGA-1 formulation. The SEM micrographs of the all p-RLPMs formulations revealed the irregular shapes and indentations. The GC/MS results showed that the residual organic solvent content in the batch RPLGA-1 formulation was below the limits. Pharmacokinetic parameters revealed that optimized RPLGA-1 formulation exhibited an initial burst followed by an excellent sustained release as compared to pure RPD as well as other formulations. Furthermore, in vivo studies of the batch, RPLGA-1 formulation showed an antipsychotic effect that was significantly prolonged over that of pure RPD solution for up to 72h with fewer extrapyramidal side effects. Thus, results of this study prove the suitability of using poly(lactic-co-glycolic acid) copolymer to develop sustained release p-RLPMs formulations that can tailor in vivo behavior and enhance the pharmacological effectiveness of the RPD.

Celecoxib and omega-3 fatty acids alone and in combination with risperidone affect the behavior and brain biochemistry in amphetamine-induced model of schizophrenia.

The implications of oxidative stress and neuro-inflammation in the pathogenesis of schizophrenia have been elucidated. Despite their effectiveness against positive symptoms of schizophrenia, antipsychotics have limited effectiveness against negative and cognitive symptoms and are associated with remarkable adverse effects. The use of celecoxib or omega-3 in schizophrenia may have beneficial effects. This study aimed to evaluate the possible efficacies of celecoxib, omega-3 or the combination of celecoxib+risperidone and omega-3+ risperidone compared to risperidone on the behavior and brain biochemistry in rats. In the present study, an amphetamine-induced model of schizophrenia in adult male rats was used to evaluate the effects of celecoxib, omega-3, celecoxib+risperidone and omega-3+ risperidone on the behavior of animals and on brain lipid peroxidation or tumor necrosis factor-alpha. In the water maze task, celecoxib, omega-3, celecoxib+risperidone, omega-3+ risperidone significantly decreased the latency time compared to amphetamine-treated group. Celecoxib, omega-3, celecoxib+risperidone, omega-3+risperidone also significantly reversed the decreased spontaneous alternation induced by amphetamine in the Y-maze task. In the social interaction task, groups treated with celecoxib, omega-3, celecoxib+risperidone, omega-3+ risperidone spent less time to recognize foreign animals than animals in the amphetamine-treated group. Increased brain MDA and TNF-α levels due to amphetamine were significantly reduced in groups treated with celecoxib+risperidone or omega-3+ risperidone. The present findings showed that celecoxib or omega-3 can attenuate amphetamine- induced behavioral impairment and these effects may be associated with their ability to decrease lipid peroxidation and cytokine release. Celecoxib or omega-3 may be promising candidates as adjuvant therapy for schizophrenia.

Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology.

Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients.

Development of Nutraceutical Emulsions as Risperidone Delivery Systems: Characterization and Toxicological Studies.

Emulsions are gaining increasing interest to be applied as drug delivery systems. The main goal of this work was the formulation of an oil/water nutraceutical emulsion (NE) for oral administration, enriched in omega 3 (ω3) and omega 6 (ω6), and able to encapsulate risperidone (RISP), an antipsychotic drug widely used in the treatment of autism spectrum disorders (ASD). RISP has low solubility in aqueous medium and poor bioavailability because of its metabolism and high protein binding. Coadministration of ω3, ω3, and vitamin E complexed with RISP might increase its bioavailability and induce a synergistic effect on the treatment of ASD. Here, we developed an easy and quick method to obtain NEs and then optimized them. The best formulation was chosen after characterization by particle size, defects of the oil-in-water interface, zeta potential (ZP), and in vitro drug release. The formulation selected was stable over time, with a particle size of around 3 µm, a ZP lower than -20 mV and controlled drug release. To better understand the biochemical properties of the formulation obtained, we studied in vitro toxicity in the Caco-2 cell line. After 4 h of treatment, an increase in cellular metabolism was observed for all RISP concentrations, but emulsions did not change their metabolic rate, except at the highest concentration without drug (25 µg/mL), which showed a significant reduction in metabolism respect to the control. Additionally, locomotor activity and heart rate in zebrafish were measured as parameters of in vivo toxicity. Only the highest concentration (0.625 µg/mL) showed a cardiotoxic effect, which corresponds to the decrease in spontaneous movement observed previously. As all the materials contained in the formulations were US FDA approved, the NE selected would be good candidate for clinical trials.

Vitamin D deficiency exacerbates atypical antipsychotic-induced metabolic side effects in rats: involvement of the INSIG/SREBP pathway.

Metabolic syndrome is a major concern in psychotic patients receiving atypical antipsychotics. Recent evidence suggests that sterol regulatory element-binding proteins (SREBPs) and insulin-induced genes (INSIGs) are implicated in the antipsychotic-induced metabolic side-effects. Vitamin D (VD) deficiency, a highly prevalent phenomenon among patients with psychosis, might also predispose individuals to metabolic syndrome Considering that VD has modulating effects on the INSIG/SREBP pathway, it is possible that VD may have a role in the antipsychotic-induced metabolic disturbances involving its effects on the INSIG/SREBP system. Thus, the present study aimed to evaluate the effects of VD deficiency and VD supplementation on antipsychotic-induced metabolic changes in rats. After 4-week administration, clozapine (10mg/kg/d) and risperidone (1mg/kg/d) both caused glucose intolerance and insulin resistance in VD deficient rats, but not in rats with sufficient VD status. Antipsychotic treatments, especially clozapine, elevated serum lipid levels, which were most apparent in VD deficient rats, but alleviated in VD-supplemented rats. Additionally, antipsychotic treatments down-regulated INSIGs and up-regulated SREBPs expression in VD deficient rats, and these effects were attenuated when VD status was more sufficient. Collectively, this study disclose the novel findings that antipsychotic-induced metabolic disturbances is exacerbated by VD deficiency and can be alleviated by VD supplementation, providing new evidence for the promising role of VD in prevention and treatment of metabolic disorders caused by antipsychotic medications. Furthermore, our data also suggest the involvement of INSIG/SREBP pathway in the antipsychotic-induced hyperlipidemia and beneficial effects of VD on lipid profile.

Effects of risperidone treatment on the expression of hypothalamic neuropeptide in appetite regulation in Wistar rats.

Although the use of atypical antipsychotic drugs has been successful in the treatment of schizophrenia, they can cause some complications in the long-term use, including weight gain. Patients using these drugs tend to disrupt treatment primarily due to side effects. The atypical antipsychotic mechanism of action regulates a number of highly disrupted neurotransmitter pathways in the brains of psychotic patients but may also cause impairment of neurohormonal pathways in different brain areas. In this study, we investigated the circulating levels of hypothalamic neurohormones, which are related to appetite regulation; neuropeptide Y (NPY); alpha melanocyte stimulating hormone (α-MSH); cocaine and amphetamine regulated transcript (CART); agouti-related peptide (AgRP); and leptin in male Wistar rats, which were treated with risperidone, a serotonin antagonist, for four weeks. Alterations in the mRNA expression levels of these candidate genes in the hypothalamus were also analyzed. We hypothesized that risperidone treatment might alter both hypothalamic and circulating levels of neuropeptides through serotonergic antagonism, resulting in weight gain. Gene expression studies revealed that the mRNA expression levels of proopiomelanocortin (POMC), AgRP, and NPY decreased as well as their plasma levels, except for NPY. Unexpectedly, CART mRNA levels increased when their plasma levels decreased. Because POMC neurons express the serotonin receptor (5HT2C), the serotonergic antagonism of risperidone on POMC neurons may cause an increase in appetite and thus increase food consumption even in a short-term trial in rats.

Influence of aripiprazole, risperidone, and amisulpride on sensory and sensorimotor gating in healthy 'low and high gating' humans and relation to psychometry.

Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making.

Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone.

The efficacy of oral risperidone treatment in prevention of schizophrenia is well known. However, oral side effects and patient compliance is always a problem for schizophrenics. In this study, risperidone was formulated into matrix transdermal patches to overcome these problems. The formulation factors for such patches, including eudragit RL 100 and eudragit RS 100 as matrix forming polymers, olive oil, groundnut oil and jojoba oil in different concentrations as enhancers and amount of drug loaded were investigated. The transdermal patches containing risperidone were prepared by solvent casting method and characterized for physicochemical and in vitro permeation studies through excised rat skin. Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug. Neuroleptic efficacy of transdermal formulation was assessed by rota-rod and grip test in comparison with control and marketed oral formulations with no skin irritation. This suggests the transdermal application of risperidone holds promise for improved bioavailability and better management of schizophrenia in long-term basis.