Behavioural effects of chronic haloperidol and risperidone treatment in rats

The therapeutic properties of typical antipsychotic drugs (APDs) such as haloperidol in schizophrenia treatment are mainly associated with their ability to block dopamine D2 receptors. This blockade is accompanied by side effects such as extrapyramidal symptoms (EPS). Atypical APDs such as risperidone have superior therapeutic efficacy possibly due to their activity at multiple receptors (in particular 5-HT2A receptors). Although the risk of EPS is significantly lower in atypical than in typical APDs, it is not negligible. To investigate and compare the behavioural profile and EPS-asssociated side effects of haloperidol and risperidone APD treatment we applied a multi-tiered, comprehensive behavioural phenotyping approach. Sprague-Dawley rats were treated chronically (28 days) with supratherapeutic EPS-inducing doses of haloperidol and risperidone using osmotic minipumps. Domains such as motor activity, exploration, memory, and anxiety were analysed together with EPS assessment ("early onset" vacuous chewing movements and catalepsy). Both APDs produced diminished motor activity and exploration, impaired working memory performances, and increased anxiety levels. These effects were more pronounced in haloperidol-treated animals. Chronic APD treatment also caused a time-course dependent elevation of EPS-like symptoms. Risperidone-treated animals showed a catalepsy-like phenotype, which differed to that of haloperidol-treated rats, indicating that processes other than the anticipated dopaminergic mechanisms are underlying this phenomenon. These EPS-related phenotypes are consistent with reported EPS-inducing D2 receptor occupancies of around 80%. Differences in the behavioural profile of haloperidol and risperidone, which were revealed by a comprehensive phenotyping strategy, are likely due to the unique receptor activation profiles of these APDs.     

Aripiprazole: review of its pharmacology and therapeutic use in psychiatric disorders.

The discovery of antipsychotic medications has revolutionized the treatment of schizophrenia and other psychotic disorders. However, side effects such as extrapyramidal symptoms (EPS) and tardive dyskinesia (TD), electrocardiogram (ECG) changes, weight gain, and metabolic disturbances indicate the continued need to develop new agents. The introduction of atypical drugs such as clozapine, risperidone, olanzapine, quetiapine, and ziprasidone has widened our choices. This article provides an overview of the pharmacology, efficacy, and techniques for the clinical use of aripiprazole, a novel agent with a unique pharmacological profile.     

Distinct neurobehavioral consequences of prenatal exposure to sulpiride (SUL) and risperidone (RIS) in rats

Antipsychotic treatment during pregnancy is indicated when risk of drug exposure to the fetus is outweighed by the untreated psychosis in the mother. Although increased risk of congenital malformation has not been associated with most available antipsychotic drugs, there is a paucity of knowledge on the subtle neurodevelopmental and behavioral consequences of prenatal receptor blockade by these drugs. In the present study, antipsychotic drugs, sulpiride (SUL, a selective D2 receptor antagonist) and risperidone (RIS, a D2/5HT2 receptor antagonist) were administered to pregnant Sprague-Dawley dams from gestational day 6 to 18. Both RIS and SUL prenatal exposed rats had lower birth body weights compared to controls. RIS exposure had a significant main effect to retard body weight growth in male offspring until postnatal day (PND) 60. Importantly, water maze tests revealed that SUL prenatal exposure impaired visual cue response in visual task performance (stimulus-response, S-R memory), but not place response as reflected in hidden platform task (spatial memory acquisition and retention). In addition, prenatal SUL treatment reduced spontaneous activity as measured in open field. Both behavioral deficits suggest that SUL prenatal exposure may lead to subtle disruption of striatum development and related learning and motor systems. RIS exposure failed to elicit deficits in both water maze tasks and increased rearing in open field test. These results suggest prenatal exposure to SUL and RIS may produce lasting effects on growth, locomotion and memory in rat offspring. And the differences may exist in the effects of antipsychotic drugs which selectively block dopamine D2 receptors (SUL) as compared to second generation drugs (RIS) that potently antagonize serotonin and dopamine receptors.     

Neurotoxic/neuroprotective activity of haloperidol, risperidone and paliperidone in neuroblastoma cells

The neurotoxicity of antipsychotic (AP) drugs seems to be linked with neurological side effects like extrapyramidal symptoms (EPS). On the other hand, neuroprotective effects can mitigate or slow the progressive degenerative structural changes in the brain leading to improved outcome of schizophrenia. First and second-generation antipsychotics may differ in their neurotoxic and neuroprotective properties. The aim of this study was to compare the neurotoxic/neuroprotective activity of haloperidol, a first-generation antipsychotic, and risperidone, a second-generation one, with paliperidone, a relatively new second-generation antipsychotic, in SK-N-SH cells. Haloperidol, risperidone and paliperidone (10, 50, 100 μM) were administered, either alone or in combination with dopamine (100 μM), to human neuroblastoma SK-N-SH. We examined the effects of the drugs on cell viability (measured by alamarBlue®), caspase-3 activity (measured by fluorimetric assay) and cell death (by measuring the externalization of phosphatidylserine). Haloperidol significantly decreased cell viability and increased caspase-3 activity and cell death. Risperidone and paliperidone did not affect cell viability or cell death. Both second-generation APs decreased caspase-3 activity, especially paliperidone. In cells treated with dopamine in combination with antipsychotics, only paliperidone (10 μM) induced a slight improvement in cell viability. While haloperidol potentiated the dopamine-induced increase in caspase-3 activity, risperidone and paliperidone reduced this effect. The results indicate that haloperidol induces apoptosis, whereas risperidone and paliperidone may afford protection against it. Of the APs tested, paliperidone always showed the strongest neuroprotective effect. The different antipsychotic effects on survival and cell death might be related to differences in their capacity to induce EPS.     

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

Atypical antipsychotic drugs offer several notable benefits over typical antipsychotics, including greater improvement in negative symptoms, cognitive function, prevention of deterioration, and quality of life, and fewer extrapyramidal symptoms (EPS). However, concerns about EPS have been replaced by concerns about other side effects, such as weight gain, glucose dysregulation and dyslipidemia. These side effects are associated with potential long-term cardiovascular health risks, decreased medication adherence, and may eventually lead to clinical deterioration. Despite a greater understanding of the biochemical effects of these drugs in recent years, the pharmacological mechanisms underlying their various therapeutic properties and related side effects remain unclear. Besides dopamine D(2) receptor antagonism, a characteristic feature of all atypical antipsychotic drugs, these agents also bind to a range of non-dopaminergic targets, including serotonin, glutamate, histamine, alpha-adrenergic and muscarinic receptors. This review examines the potential contribution of different receptors to metabolic side effects associated with atypical antipsychotic treatment for all seven agents currently marketed in the United States (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone and clozapine) and another agent (bifeprunox) in clinical development at the time of this publication.     

Neuroleptic malignant syndrome and atypical antipsychotic drugs

OBJECTIVE: The incidence of neuroleptic malignant syndrome (NMS) is not known, but the frequency of its occurrence with conventional antipsychotic agents has been reported to vary from 0.02% to 2.44%. DATA SOURCES: MEDLINE search conducted in January 2003 and review of references within the retrieved articles. DATA SYNTHESIS: Our MEDLINE research yielded 68 cases (21 females and 47 males) of NMS associated with atypical antipsychotic drugs (clozapine, N = 21; risperidone, N = 23; olanzapine, N = 19; and quetiapine, N = 5). The fact that 21 cases of NMS with clozapine were found indicates that low occurrence of extrapyramidal symptoms (EPS) and low EPS-inducing potential do not prevent the occurrence of NMS and D(2) dopamine receptor blocking potential does not have direct correlation with the occurrence of NMS. One of the cardinal features of NMS is an increasing manifestation of EPS, and the conventional antipsychotic drugs are known to produce EPS in 95% or more of NMS cases. With atypical antipsychotic drugs, the incidence of EPS during NMS is of a similar magnitude. CONCLUSIONS: For NMS associated with atypical antipsychotic drugs, the mortality rate was lower than that with conventional antipsychotic drugs. However, the mortality rate may simply be a reflection of physicians' awareness and ensuing early treatment.     

Efficacy of flupentixol and risperidone in chronic schizophrenia with predominantly negative symptoms

The study investigated the non-inferiority of flupentixol compared to risperidone in the treatment of negative symptoms. In addition, the effects of flupentixol on mood and cognitive symptoms were explored. In a randomized, double-blind multicenter study, 144 non-acute schizophrenia patients with predominant negative symptoms were treated with a flexible dose of either flupentixol (4-12 mg/d) or risperidone (2-6 mg/d) for up to 25 weeks. In addition to a non-inferiority analysis, a principal component analysis (PCA) of the PANSS was performed post hoc. Regarding negative symptoms, flupentixol proved to be non-inferior to risperidone. Both drugs improved depressed mood with effect sizes favoring flupentixol. PCA suggested a five-factor structure. Effect sizes for the cognitive factor were up to 0.74 for flupentixol and up to 0.80 for risperidone. EPS scores were rather low and Parkinsonism improved in both groups, but anticholinergic drugs were prescribed significantly more frequently in the flupentixol group, which generally showed significantly more adverse events. Results indicate that the 1st generation antipsychotic flupentixol improves negative, affective and cognitive symptoms in chronic schizophrenia comparable to risperidone. Further studies should confirm the latter using neuropsychological performance tests and should investigate whether tolerability improves with a markedly lower dose range.     

A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats

It is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D₂-receptor occupancy by antipsychotics within the striatum must exceed 60?65%. However, at high levels of D₂-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D₂-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak?trough fluctuations and consistent D₂-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.     

Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double-blind comparative study.

Forty-four chronic schizophrenic inpatients participated in this multicentre 12-week parallel-group double-blind trial. After a run-in period of 2 weeks and a single-blind placebo wash-out of 1 week, they were randomly assigned to treatment with either the serotonin2 and dopamine-D2 antagonist risperidone or haloperidol. Two patients were excluded from the efficacy analysis. Five patients dropped out in the haloperidol group and 1 in the risperidone group. At the end of the trial, the mean daily dose was 12 mg for risperidone and 10 mg for haloperidol. The risperidone group showed greater improvement on the Positive and Negative Syndrome Scale for Schizophrenia, the Schedule for Affective Disorders and Schizophrenia-change version, and the Nurses' Observation Scale for Inpatient Evaluation. The improvement of negative symptoms was more pronounced in the risperidone group until week 8 of double-blind treatment. The consumption of antiparkinsonian medication was 10 times lower with risperidone. Both drugs were well tolerated and the laboratory, endocrinological and cardiovascular safety parameters were comparable. This study suggests that risperidone is comparable to haloperidol as an antipsychotic, but that it has a safer EPS profile.     

A qualitative assessment of the neurological safety of antipsychotic drugs; an analysis of a risperidone database.

BACKGROUND: Neurological side effects of antipsychotic agents limit the use of these drugs, and development of newer antipsychotic agents has been focused on a reduced risk of extrapyramidal symptoms (EPS) as well as effective symptom control. METHODS: A qualitative analysis of EPS was performed using Extrapyramidal Symptom Rating Scale (ESRS) data from 11 double-blind risperidone trials. An ESRS factor analysis and maximum changes in ESRS scores were compared for the risperidone, haloperidol, and placebo groups. RESULTS: The factor analysis revealed five factors. Between-group comparisons showed no differences between placebo and 1 to 2 mg/day-risperidone groups. Parkinsonism, tremor, akathisia, and sialorrhea were more likely to occur with haloperidol than with placebo or risperidone at 1 to 6 mg/day. Similar results were noted by maximum changes in ESRS scores. At risperidone doses of more than 8 mg/day, acute EPS severity lay between that of the placebo and haloperidol groups. The severity of tardive dyskinesia was greater in patients receiving placebo than in those receiving either active treatment. CONCLUSIONS: As the results described above were derived from a post hoc analysis of an existing database, conclusions must remain tentative. To provide more definitive answers, EPS assessments in future studies should be refined to more accurately predict the type of EPS expected with a given agent in clinical practice.     

Reduced basal and phencyclidine-induced expression of heat shock protein-70 in rat prefrontal cortex by the atypical antipsychotic abaperidone

The effect of antipsychotic treatment on basal and phencyclidine (PCP)-induced heat shock protein-70 (hsp70) mRNA expression was studied in the rat striatum and in the prefrontal cortex. Abaperidone, a novel drug with an atypical antipsychotic profile, was compared, at pharmacologically equivalent doses, with the atypical antipsychotics clozapine and risperidone and also with haloperidol, a classical antipsychotic. Abaperidone and clozapine reduced basal hsp70 mRNA expression in the rat striatum and in the prefrontal cortex. No change in either region was found after haloperidol, whereas risperidone reduced hsp70 mRNA in the striatum but not in the prefrontal cortex. The N-methyl-D-aspartate (NMDA) receptor antagonist PCP significantly elevated hsp70 mRNA levels in the prefrontal cortex, an elevation that was potentiated by haloperidol and prevented by all of the atypical antipsychotics tested. Since hsp70 has been associated to some schizophrenia symptoms, we suggest that reduced hsp70 in the prefrontal cortex, a cortical area that plays a critical role in the etiology of many schizophrenia symptoms, may be linked to an atypical profile of antipsychotics, such as clozapine, and possibly also abaperidone.     

Differential effects of olanzapine, haloperidol and risperidone on calcitonin gene-related peptide in the rat brain

Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide which acts on central nervous system (CNS) neurons and is involved in activities related to dopamine. These effects of CGRP suggest that the peptide may have a role in pathophysiology and treatment of schizophrenia where dopaminergic system hypoactivity in the frontal cortex and hyperactivity in the subcortical structures have been demonstrated. In this study we measured by radioimmunoassay (RIA) the brain levels of CGRP-like immunoreactivity (CGRP-LI) in rats treated with either classical (haloperidol) or atypical (risperidone and olanzapine) antipsychotic drugs. Both haloperidol and risperidone decreased CGRP-LI in the striatum. Risperidone also decreased CGRP-LI in the occipital cortex. On the other hand, olanzapine increased CGRP-LI in the striatum, the frontal cortex and hypothalamus. The differential effects on CGRP could reflect a different profile of side effects and further suggest that CGRP is involved in CNS functions related to psychiatric disorders.     

Risperidone versus haloperidol in psychotic patients with disturbing neuroleptic-induced extrapyramidal symptoms: a double-blind, multi-center trial

BACKGROUND: A randomized, double-blind, multi-center trial was started to compare the severity of extrapyramidal symptoms (EPS) during risperidone and haloperidol treatment in schizophrenic patients who had disturbing EPS during their previous neuroleptic treatment. Additional objectives of this trial were comparing the antipsychotic effectiveness of the two treatments and the use of antiparkinsonian medication. METHODS: Effects of flexible doses of risperidone and haloperidol were compared in 77 psychotic patients (83% with chronic schizophrenia) with disturbing neuroleptic-induced EPS (risperidone 40 patients, haloperidol 37). The trial was completed by 47 patients: 25 in the risperidone group (12 women, 13 men), and 22 in the haloperidol group (10 women, 12 men). RESULTS: An adequate antipsychotic effect was obtained in most patients by both treatments. The primary aim of this trial was comparing parkinsonism measured with the extrapyramidal syndrome rating scale (ESRS) during treatment with risperidone and haloperidol. Two primary parameters were selected: the change from baseline to the worst score during treatment of ESRS II (parkinsonism) and ESRS VI (clinical global impression of severity of parkinsonism). The CGI of severity of parkinsonism was better with risperidone (P=0.025), while the parkinsonism total score tended to be better with risperidone (P<0. 10). Before the double-blind treatment, 34 (of the 77) had used antiparkinson medication (risperidone 18, haloperidol 16). During the double-blind treatment phase, 21 patients had used antiparkinson medication (risperidone 11, haloperidol 10). The larger reduction of parkinsonism in the risperidone group was not due to a difference in the use of anti-parkinsonian medication. CONCLUSIONS: In this group of schizophrenic patients with disturbing EPS during previous neuroleptic treatment, a stronger reduction of parkinsonism was observed with risperidone than with haloperidol.     

利培酮的血药浓度与临床效应的关系

目的 观察利培酮治疗精神分裂症时的血药浓度及其与疗效及不良反应之间的关系。方法 共纳入31例精神分裂症患者,其中男性17列,女性14列,平均年龄31.00±8.98岁。在治疗前及治疗后1周,2周、4周.6周及8周评定PANSS、CGI、TESS及ESRS。采用HPLC方法测定治疗后4周及8周时利培酮及其代谢产物9—羟利培酮的血药浓度。结果 利培酮治疗精神分裂症疗效肯定,不良反应较少,部分患者出现轻度的EPS。服用固定剂量利培酮(4mg/d)治疗8周时利培酮的血药浓度为41.46±17.36nmol/L,9-羟利培酮的浓度为60.88±42.73nmol/L。利培酮及代谢产物的总浓度与疗效有关,利培酮浓度与EPS有关。结论 利培酮是一种有效的抗精神病药,服用治疗剂量时,利培酮及其代谢产物的总浓度与疗效有关,而利培酮的血药浓度与EPS有关,故检测利培酮及其代谢产物9-羟利培酮的药物浓度对指导临床用药具有重要意义。     

Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection

Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm³/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p=0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model.     

Antipsychotic treatment of psychosis associated with multiple sclerosis

This case report deals with the antipsychotic treatment in multiple sclerosis (MS). Psychiatric symptoms are a frequent event in patients with MS. However, there are only few systematic studies of antipsychotic treatment in MS patients. Most of the studies are related to clozapine due to the lack of neurological, particularly extrapyramidal side effects (EPS). Therefore, experiences with other atypical drugs are requested. This paper discusses the pros and cons of different atypical drugs using the example of one patient, who showed adverse effects after treatment with quetiapine and olanzapine. Risperidone was not administered with respect to possible EPS. However, ziprasidone was tolerated well and appeared to be effective.     

Antipsychotic occupancy of dopamine receptors in schizophrenia

Antipsychotic drugs were introduced in the early 50s on the basis of clinical observations in patients with schizophrenia. Experimental studies later revealed that antagonism at the D(2) dopamine receptor is a common characteristic of all antipsychotic drugs. In the 80s, the advent of brain imaging technologies such as positron emission tomography (PET) allowed for direct noninvasive studies of drug binding in treated patients. The concept receptor occupancy is defined as the fraction (%) of a receptor population that is occupied during treatment with an unlabelled drug. With regard to antipsychotic drugs, the radioligand [(11) C]-raclopride has been the most widely used for binding to the D(2) /D(3) -dopamine receptors. The present review discusses the contribution from molecular imaging to the current understanding of mechanism of action (MoA) of antipsychotic drugs. Consistent initial PET-findings of high D2-receptor occupancy in the striatum of patients responding to different antipsychotic drug treatments provided clinical support for the dopamine hypothesis of antipsychotic drug action. It has subsequently been demonstrated that patients with extrapyramidal syndromes (EPS) have higher occupancy (above 80%) than patients with good response but no EPS (65-80%). The PET-defined interval for optimal antipsychotic drug treatment has been implemented in the evolvement of dose recommendations for classical as well as more recently developed drugs. Another consistent finding is lower D(2) -occupancy during treatment with the prototype atypical antipsychotic clozapine. The MoA of clozapine remains to be fully understood and may include nondopaminergic mechanisms. A general limitation is that currently available PET-radioligands are not selective for any of the five dopamine receptor subtypes. Current attempts at developing such ligands may provide the tools required to refine further the MoA of antipsychotic drugs.     

New antipsychotics: classification, efficacy, and adverse effects.

Compared to traditional neuroleptics, most of the new antipsychotics are characterized by a low extrapyramidal side effect (EPS) liability and varying antipsychotic efficacy. This topic is reviewed for four principal classes of new, established, and potential antipsychotics: (1) Antipsychotics such as sulpiride and remoxipride that block a subgroup of dopamine (DA) D2/D3 receptors produce a relatively low level of side effects, including EPS, and have an antipsychotic effect equal to or slightly weaker than traditional neuroleptics. D1 antagonists demonstrate a low level of EPS in primates and may prove to be a valuable new type of antipsychotic drug. (2) Theoretically, partial D2 agonists have the advantage of producing few or no EPS and a specific beneficial effect in negative symptoms, but as yet the expectations have not been fulfilled. (3) Nondopamine drugs such as serotonin (5HT1) agonists, 5HT2 antagonists, 5HT3 antagonists, and gamma-amino-butyric-acid-A (GABA-A) benzodiazepine agonists have anxiolytic, antidepressant, antiaggressive, and maybe antiparkinsonian effects and may play an adjunctive role in the treatment of schizophrenia. 5HT3 antagonists (e.g., ondansetron), partial benzodiazepine agonists, and partial glutamate agonists may prove to be effective antipsychotics. (4) Antipsychotics such as clozapine and risperidone, which affect D2/D3 receptors as well as 5HT, alpha 1, and/or D1 receptors appear to have the most pronounced antipsychotic effect.     

Risperidone oral solution versus standard tablets for the acute treatment of patients with schizophrenia

The time required to attain the maximum plasma level of risperidone (RIS) is shorter for RIS oral solution (OS) than for RIS standard tablets (ST), although both forms have equal bioavailability. The objective of this study was to clarify whether RIS-OS shows a faster onset of efficacy and lower adverse events than RIS-ST. The two forms of risperidone were compared with respect to effectiveness including a speed of response, efficacy and tolerability. An open-label, 24-week, multicentre, randomized, flexible-dose study comparing the RIS-OS (mean dose, 3.7 mg; N = 44) to the RIS-ST (mean dose, 3.7 mg; N = 37) in acutely ill patients with schizophrenia showed no differences. Outcome measures included psychopathology, tolerability (extrapyramidal symptoms and serum prolactin), and Drug Attitude Inventory. This study was conducted between October 2006 and October 2008. Both RIS-OS- and RIS-ST-treated patients showed statistically significant reductions from the baseline in the mean scores of the Positive and Negative Syndrome Scale (PANSS)-total and PANSS-excite component, with no statistically significant differences between the treatment groups. The accumulated treatment response ratio was similar between the two groups. There was no significant difference in the Drug-Induced Extrapyramidal Symptom Scale score or serum prolactin increase between the treatment groups, but RIS-OS appeared to induce less serum prolactin increase than RIS-ST in drug-naïve female patients. Because there is no theoretical reason why this should be so, these results will require confirmation from a double-blind study in a larger sample. No significant difference was observed in the subjective drug attitude between the two groups. The original hypothesis that RIS-OS shows an earlier onset of efficacy or less adverse events than RIS-ST was not supported in this study. Subsequent studies should carefully establish the differences among various forms of antipsychotic drugs.     

The effect of serotonin(1A) receptor agonism on antipsychotic drug-induced dopamine release in rat striatum and nucleus accumbens

Serotonin (5-HT)(1A) receptor agonism may be of interest in regard to both the antipsychotic action and extrapyramidal symptoms (EPS) of antipsychotic drugs (APD) based, in part, on the effect of 5-HT(1A) receptor stimulation on the release of dopamine (DA) in the nucleus accumbens (NAC) and striatum (STR), respectively. We investigated the effect of R(+)-8-hydroxy-2-(di-n-propylamino)-tetralin (R(+)-8-OH-DPAT) and n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-n-(2-pyridinyl)cyclohe xanecarboxamide trihydrochloride (WAY100635), a selective 5-HT(1A) receptor agonist and antagonist, respectively, on basal and APD-induced DA release. In both STR and NAC, R(+)-8-OH-DPAT (0.2 mg/kg) decreased basal DA release; R(+)-8-OH-DPAT (0.05 mg/kg) inhibited DA release produced by the 5-HT(2A)/D(2) receptor antagonists clozapine (20 mg/kg), low dose risperidone (0.01 and 0. 03 mg/kg) and amperozide (10 mg/kg), but not that produced by high dose risperidone (0.1 and 1.0 mg/kg) or haloperidol (0.01-1.0 mg/kg), potent D(2) receptor antagonists. This R(+)-8-OH-DPAT-induced inhibition of the effects of clozapine, risperidone and amperozide was antagonized by WAY100635 (0.05 mg/kg). WAY100635 (0.1-0.5 mg/kg) alone increased DA release in the STR but not NAC. The selective 5-HT(2A) receptor antagonist M100907 (1 mg/kg) did not alter the effect of R(+)-8-OH-DPAT or WAY100635 alone on basal DA release in either region. These results suggest that 5-HT(1A) receptor stimulation inhibits basal and some APD-induced DA release in the STR and NAC, and that this effect is unlikely to be mediated by an interaction with 5-HT(2A) receptors. The significance of these results for EPS and antipsychotic action is discussed.