Atypical antipsychotic properties of blonanserin, a novel dopamine D2 and 5-HT2A antagonist

Blonanserin is a novel antipsychotic agent that preferentially interacts with dopamine D₂ and 5-HT_2A receptors. To assess the atypical properties of blonanserin, we evaluated its propensity to induce extrapyramidal side effects (EPS) and to enhance forebrain Fos expression in mice. The actions of AD-6048, a primary metabolite of blonanserin, in modulating haloperidol-induced EPS were also examined. Blonanserin (0.3-10 mg/kg, p.o.) did not significantly alter the pole-descending behavior of mice in the pole test or increase the catalepsy time, while haloperidol (0.3-3 mg/kg, p.o.) caused pronounced bradykinesia and catalepsy. Blonanserin and haloperidol at the above doses significantly enhanced Fos expression in the shell (AcS) region of the nucleus accumbens and dorsolateral striatum (dlST). The extent of blonanserin-induced Fos expression in the AcS was comparable to that induced by haloperidol. However, the striatal Fos expression by blonanserin was less prominent as compared to haloperidol. Furthermore, combined treatment of AD-6048 (0.1-3 mg/kg, s.c.) with haloperidol (0.5 mg/kg, i.p.) significantly attenuated haloperidol-induced bradykinesia and catalepsy. The present results show that blonanserin behaves as an atypical antipsychotic both in inducing EPS and enhancing forebrain Fos expression. In addition, AD-6048 seems to contribute at least partly to the atypical properties of blonanserin.     

Mirtazapine enhances the effect of haloperidol on apomorphine-induced climbing behaviour in mice and attenuates haloperidol-induced catalepsy in rats

 Activation of 5-HT_1A receptors has been shown to attenuate catalepsy induced by typical antipsychotic compounds. Since mirtazapine (Remeron; Org 3770) has indirect 5-HT_1A receptor stimulating properties as well as antagonist properties at α₂-adrenoceptors and 5-HT₂ receptors, it was of interest to investigate how the compound could modulate the effect of haloperidol on apomorphine-induced climbing behaviour in mice and haloperidol-induced catalepsy in rats. In the apomorphine climbing test, it was found that mirtazapine (2.2–22 mg/kg) did not change the climbing behaviour of mice induced by 1 mg/kg of apomorphine. However, when given as a co-treatment with haloperidol, mirtazapine (1 and 10 mg/kg) dose-dependently augmented the inhibiting effect of haloperidol on this climbing behaviour. Co-treatment with the 5-HT_1A receptor agonist 8-OH-DPAT (0.1 mg/kg) also augmented the effect of haloperidol. Catalepsy induced by haloperidol (4.6 mg/ kg) was attenuated by mirtazapine (2.2–22 mg/kg). The strongest effect was seen at 90 min after haloperidol treament. The results obtained in these experiments suggest that co-treatment with mirtazapine may enhance the antipsychotic effect of haloperidol and reduce its extrapyramidal side effects, thereby widening its therapeutic window. Received: 6 May 1997/Final version: 10 August 1997     

Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics

The effect of the selective dopamine D2 receptor agonist quinpirole, the selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT2A receptor antagonist ketanserin on catalepsy induced by atypical antipsychotics clozapine, risperidone, olanzapine and sertindole at higher doses was studied in rats. Haloperidol (0.5, 1 and 2 mg/kg), clozapine (50 and 75 mg/kg) and olanzapine (15 and 30 mg/kg) produced catalepsy dose-dependently while sertindole at doses up to 40 mg/kg failed to produce catalepsy in rats. However, sertindole (15, 30 and 45 mg/kg) produced a cataleptic effect in mice in a dose-dependent manner. At a high dose (5 mg/kg), risperidone produced catalepsy in rats. Quinpirole (0.05 and 0.1 mg/kg) reversed the cataleptic effect of haloperidol (2 mg/kg), risperidone (5 mg/kg), olanzapine (30 mg/kg) and sertindole (45 mg/kg). Quinpirole (0.05 and 0.1 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15 and 0.3 mg/kg) dose-dependently reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg) without affecting the cataleptic effect of olanzapine. However, the higher dose (0.45 mg/kg) of 8-OH-DPAT reversed it significantly. 8-OH-DPAT (0.3 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15, 0.3 and 0.45 mg/kg) failed to reverse sertindole-induced catalepsy. Ketanserin (0.75 and 1.5 mg/kg) completely reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg). Ketanserin (0.75 and 1.5 mg/kg) dose-dependently reversed olanzapine (30 mg/kg) and sertindole (45 mg/kg)-induced catalepsy without any effect on clozapine (75 mg/kg)-induced catalepsy. A higher dose (3 mg/kg) of ketanserin reversed clozapine-induced catalepsy. The present study suggests that atypical antipsychotics show fewer extrapyramidal symptoms (EPS) due to greater modulation of the serotonergic system. Therefore, an antipsychotic with dopamine D2/5-HT2A antagonistic action and 5-HT1A agonistic action may prove to be superior to the existing antipsychotics.     

Behavioral effects of sertindole,risperidone, clozapine and haloperidol inCebus monkeys

Extrapyramidal side effects (EPS) are major limitations to neuroleptic treatment of psychoses. To evaluate further the behavioral characteristics of the novel antipsychotic agents, a wide range of single intramuscular doses of sertindole (0.1–2.5 mg/kg IM), risperidone (0.01–0.25 mg/kg IM), clozapine (1.0–25.0 mg/kg IM), and haloperidol (0.01–0.25 mg/kg IM) were blindly evaluated at weekly intervals inCebus monkeys previously sensitized to neuroleptics. All drugs except clozapine produced dystonia and parkinsonian symptoms, but haloperidol and risperidone were 50–100 times more potent than sertindole in producing EPS. Sertindole, risperidone and haloperidol had no significant sedative effects, whereas clozapine produced dose related sedation. Risperidone, clozapine and haloperidol but not sertindole decreased locomotor activity. Sertindole, risperidone and clozapine had a calming effect at doses below the EPS threshold, unlike haloperidol. Sertindole has many behavioral effects in nonhuman primates that are similar to those seen with the new antipsychotics, risperidone and clozapine, which suggests a favorable antipsychotic benefit/risk ratio in the clinic, especially regarding EPS.     

Efficacy and tolerability of quetiapine in patients with schizophrenia who switched from haloperidol, olanzapine or risperidone

A post hoc analysis of the SPECTRUM trial was carried out to evaluate whether the improvements in efficacy and tolerability gained on switching to quetiapine occurred consistently for patients previously treated with either: haloperidol (n = 43); olanzapine (n = 66); or risperidone (n = 55) monotherapy. Patients were initiated with quetiapine to 400 mg/day over 7 days, and then flexibly dosed (300-750 mg/day) for 11 weeks. The mean (SD) modal dose of quetiapine was 501 (138) mg/day in the haloperidol subgroup, 472 (147) mg/day in the olanzapine subgroup and 485 (141) mg/day in the risperidone subgroup at the study endpoint. Switching to quetiapine induced significant improvements from baseline in PANSS scores, with least square mean changes in total scores of -32.5, -15.4, and -18.5 for patients previously treated with haloperidol, olanzapine and risperidone, respectively, (all p < 0.001 vs baseline). Significant improvements were also noted in CDSS scores, particularly for patients clinically depressed at baseline (all p < 0.001 vs baseline). There were significant reductions in EPS on the SAS and BAS for all subgroups (all p < 0.001 vs baseline). Switching to quetiapine produced efficacy and tolerability benefits regardless of whether their previous antipsychotic was haloperidol, olanzapine or risperidone.     

Quetiapine. A review of its use in the management of schizophrenia

Quetiapine (Seroquel), a dibenzothiazepine derivative, is an atypical antipsychotic with demonstrated efficacy in acute schizophrenia. In short-term, randomised, double-blind trials, it was usually more effective than placebo, and was generally effective against both positive and negative symptoms. Overall, quetiapine (up to 750 mg/day) was at least as effective as chlorpromazine (up to 750 mg/day) and had similar efficacy to haloperidol (up to 16 mg/day) in patients with acute schizophrenia in randomised, double-blind trials; it was at least as effective as haloperidol 20 mg/day in patients with schizophrenia unresponsive or partially responsive to previous antipsychotic treatment. Improvements in overall psychopathology and positive and negative symptoms with quetiapine (up to 800 mg/day) were similar to those with risperidone (up to 8 mg/day) or olanzapine (15 mg/day) [interim analysis]. Efficacy was maintained for at least 52 weeks in open-label follow-up studies in adult and elderly patients. Quetiapine improved cognitive function versus haloperidol, and depressive symptoms and hostility/aggression versus placebo. Quetiapine is well tolerated. It is associated with placebo-level incidence of extrapyramidal symptoms (EPS) across its entire dose range, appears to have a low risk for EPS in vulnerable patient groups (e.g. the elderly, adolescents or patients with organic brain disorders) and has a more favourable EPS profile than risperidone. Irrespective of dose, quetiapine, unlike risperidone and amisulpride, does not elevate plasma prolactin levels compared with placebo, and previously elevated levels may even normalise. Quetiapine appears to have minimal short-term effects on bodyweight and a favourable long-term bodyweight profile. Preliminary studies indicate that there is a high level of patient acceptability and satisfaction with quetiapine. In conclusion, quetiapine has shown efficacy against both positive and negative symptoms of schizophrenia, and has benefits in improving cognitive deficits, affective symptoms and aggression/hostility. The beneficial effects of quetiapine have been maintained for at least 52 weeks. Quetiapine was effective and well tolerated in hard-to-treat patients, and may be of particular use in these individuals. It is at least as effective as standard antipsychotics and appears to have similar efficacy to risperidone and olanzapine. The relative risk/benefit profile of quetiapine compared with other atypical antipsychotics requires further research in head-to-head trials, although quetiapine's relatively benign tolerability profile distinguishes it from other commonly used atypical agents, particularly with respect to bodyweight, EPS and plasma prolactin levels. Overall, quetiapine has an excellent risk/benefit profile and is a suitable first-line option for the treatment of schizophrenia.     

Clozapine-Induced Locomotor Suppression is Mediated by 5-HT2A Receptors in the Forebrain

The need for safer, more effective therapeutics for the treatment of schizophrenia is widely acknowledged. To optimally target novel pharmacotherapies, in addition to establishing the mechanisms responsible for the beneficial effects of antipsychotics, the pathways underlying the most severe side effects must also be elucidated. Here we investigate the role of serotonin 2A (5-HT_2A), serotonin 2C (5-HT_2C), and dopamine 2 receptors (D₂) in mediating adverse effects associated with canonical first- and second-generation antipsychotic drugs in mice. Wild-type (WT) and 5-HT_2A knockout (KO) mice treated with haloperidol, clozapine, and risperidone were assessed for locomotor activity and catalepsy. WT mice showed a marked reduction in locomotor activity following acute administration of haloperidol and high-dose risperidone, which was most likely secondary to the severe catalepsy caused by these compounds. Clozapine also dramatically reduced locomotor activity, but in the absence of catalepsy. Interestingly, 5-HT_2A KO mice were cataleptic following haloperidol and risperidone, but did not respond to clozapine''s locomotor-suppressing effects. Restoration of 5-HT_2A expression to cortical glutamatergic neurons re-instated the locomotor-suppressing effects of clozapine in the open field. In sum, we confirm that haloperidol and risperidone caused catalepsy in rodents, driven by strong antagonism of D₂. We also demonstrate that clozapine decreases locomotor activity in a 5-HT_2A-dependent manner, in the absence of catalepsy. Moreover, we show that it is the cortical population of 5-HT_2A that mediate the locomotor-suppressing effects of clozapine.     

Low dose quetiapine reverses deficits in contextual and cued fear conditioning in rats with excitotoxin-induced hippocampal neuropathy

Previous studies have demonstrated that adult rats with excitotoxic lesions of the hippocampus display deficits in memory-related behaviors similar to the memory deficits associated with schizophrenia. In this study, we assessed the sub-chronic effects of quetiapine, risperidone and haloperidol on performance deficits after intracerebroventricular administration of the excitotoxin, kainic acid, using paradigms for contextual and cued fear conditioning and spatial reversal learning in rats. The effects of three doses of quetiapine (5, 10 and 20 mg/kg) and single doses of risperidone (0.5 mg/kg) and haloperidol (0.15 mg/kg) were compared. Quetiapine administration at the lowest dose (5 mg/kg) reversed deficits in contextual and cued fear conditioning, but not deficits in spatial reversal learning, in kainic acid-treated animals. However, the two higher doses of quetiapine, and the single doses of risperidone and haloperidol, did not reverse any of the kainic acid-induced behavioral deficits. These results may be relevant to the effects of quetiapine and other antipsychotic drugs on memory deficits in patients with schizophrenia.     

Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice

Cannabidiol is a non-psychotomimetic compound from Cannabis sativa. It is proposed as a possible antipsychotic drug, since it can prevent some psychotomimetic-like effects of Delta9-tetrahydrocannabinol or apomorphine. Therefore, the aim of this work was to test the hypothesis that cannabidiol would inhibit the hyperlocomotion induced by two psychotomimetic drugs, D-amphetamine or ketamine. Male Swiss mice received i.p. injections of haloperidol (0.15-0.6 mg/kg), clozapine (1.25-5 mg/kg) or cannabidiol (15-60 mg/kg) followed by D-amphetamine (5 mg/kg) or ketamine (60 mg/kg). Thirty minutes after the first injection, the distance moved in circular arena was measured during 10 min. In another group of experiments, catalepsy was measured 30 min after haloperidol, clozapine or cannabidiol injections. Cannabidiol, like clozapine but unlike haloperidol, inhibited hyperlocomotion without inducing catalepsy. Moreover, cannabidiol itself, unlike haloperidol and clozapine, did not decrease locomotion. In conclusion, cannabidiol exhibits an antipsychotic-like profile without inducing extrapyramidal-like effects.     

Serotonergic modulation of extrapyramidal motor disorders in mice and rats: Role of striatal 5-HT3 and 5-HT6 receptors

Previous studies showed that 5-HT_1A and 5-HT₂ receptors play an important role in controlling the extrapyramidal motor disorders. However, the functions of other 5-HT receptor subtypes remain elusive. To elucidate the role of 5-HT receptors, specifically of 5-HT₃～5-HT₇ subtypes, in modifying antipsychotic- induced extrapyramidal side effects (EPS), we studied the effects of the 5-HT stimulant 5-hydroxytryptophan (5-HTP) and various 5-HT receptor antagonists on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. Pretreatment of mice with 5-HTP (25–100 mg/kg, i.p.) dose-dependently enhanced HAL (0.3 mg/kg, i.p.)-induced bradykinesia and catalepsy. The potentiation of HAL-induced EPS by 5-HTP (50 mg/kg, i.p.) was significantly inhibited by ritanserin (5-HT₂ antagonist, 0.3-3 mg/kg, i.p.), ondansetron (5-HT₃ antagonist, 0.1–1 mg/kg, i.p.), or SB-258585 (5-HT₆ antagonist, 1–10 mg/kg, i.p.) in a dose-dependent manner. However, neither WAY-100135 (5-HT_1A antagonist, 1–10 mg/kg, i.p.), GR-125487 (5-HT₄ antagonist, 1–10 mg/kg, i.p.), SB-699551 (5-HT_5A antagonist, 1–10 mg/kg, i.p.) nor SB-269970 (5-HT₇ antagonist, 1–10 mg/kg, i.p.) reduced the 5-HTP and HAL-induced bradykinesia or catalepsy. In addition, both ondansetron (0.1–1 mg/kg, i.p.) and SB-258585 (3 and 10 mg/kg, i.p.) also alleviated bradykinesia and catalepsy induced by HAL (0.5 mg/kg, i.p.) alone in mice. Furthermore, bilateral microinjection of ondansetron (5 μg (13.7 nmol) per side) or SB-258585 (5 μg (8.92 nmol) per side) into the dorsolateral striatum (dlST) attenuated haloperidol-induced catalepsy in rats. These results suggest that serotonergic stimulation augments extrapyramidal motor disorders by activating the striatal 5-HT₃ and 5-HT₆ receptors and the antagonism of these receptors effectively alleviates antipsychotic-induced EPS.     

Effects of NRA0045, a novel potent antagonist at dopamine D4, 5-HT2A,and alpha1 adrenaline receptors,and NRA0160, a selective D4 receptor antagonist,on phencyclidine-induced behavior and glutamate release in rats

Rationale Administration of phencyclidine (PCP) to animals produces abnormal behavior such as hyperlocomotion, stereotyped behavior, and ataxia; this abnormal behavior is only weakly blocked by dopamine D₂ receptor antagonists. This study examined the effects of a novel thiazole derivative, NRA0045 which potently antagonizes not only dopamine D₄ receptors but also 5-HT_2A and ₁ adrenaline receptors, and NRA0160, a selective dopamine D₄ receptor antagonist, on PCP-induced abnormal behavior, and accompanying increases in extracellular levels of glutamate in the medial prefrontal cortex. Furthermore, this study compared the effects of these drugs with those of clozapine and haloperidol.Methods To study the effects of NRA-drugs, atypical and typical antipsychotics, we measured locomotor activity with an infra-red sensor, and stereotypy and ataxia on a rating scale. Extracellular glutamate levels were measured by in vivo microdialysis.Results NRA0045 (1 or 3 mg/kg) or clozapine (1 mg/kg) attenuated hyperlocomotion, stereotypy, and ataxia induced by PCP (7.5 mg/kg) without affecting behavior after saline injection. Although haloperidol (0.1 or 1 mg/kg) attenuated or inhibited PCP-induced behavior, this drug also affected behavior after saline injection. NRA0160 (0.1, 1, or 3 mg/kg) had no effect on behavior induced by PCP or saline. NRA0045 (3 mg/kg), but not NRA0160, inhibited PCP-induced increases in glutamate levels in the medial prefrontal cortex. PCP-induced hyperlocomotion correlated with the PCP-induced increases in glutamate levels in this brain region.Conclusions These results suggest that the effects of NRA0045 on PCP-induced abnormal behavior are similar to those of the atypical antipsychotic clozapine. NRA0045 probably attenuates PCP-induced abnormal behavior by inhibiting the PCP-induced increase in glutamate levels in the medial prefrontal cortex; this inhibition may be mediated via the blockade of 5-HT_2A receptors.     

ACP-103, a 5-HT<Subscript>2A/2C</Subscript> inverse agonist,potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens

Rational Atypical antipsychotic drugs (APDs) such as clozapine, olanzapine, quetiapine, risperidone, and ziprasidone are serotonin (5-HT)_2A antagonists and relatively weaker dopamine (DA) D₂ antagonists, with variable 5-HT_2C antagonist properties. The ability of atypical APDs to preferentially increase DA release in the cortex compared to the limbic system is believed to be due in part to their antagonism of 5-HT_2A and D₂ receptors and believed to contribute to their beneficial effects on cognition, negative, and psychotic symptoms. Previous studies from this laboratory using microdialysis have shown that pretreatment of the 5-HT_2A antagonist M100907 with the typical APD and D₂ antagonist haloperidol produced an increase in the medial prefrontal cortex (mPFC), but not in the nucleus accumbens (NAC), DA release. However, pretreatment with the 5-HT_2A/2C receptor antagonist SR46349-B with haloperidol increased both mPFC and NAC DA release, suggesting that both 5-HT_2A and 5-HT_2C properties may be important for atypical APD effects.Objective The purpose of this study was to examine the effects of a novel putative atypical APD ACP-103 on mPFC and NAC DA release using in vivo microdialysis in freely moving rats that are awake. ACP-103 is an inverse agonist at both 5-HT_2A and 5-HT_2C receptors and has intermediate affinities for 5-HT_2C receptors relative to their affinities for 5-HT_2A receptors compared to M100907 and SR46349-B. In addition, the effects of ACP-103 were compared to M100907 and SR46349-B, and ACP-103 was also coadministered with haloperidol.Results ACP-103 10.0 mg/kg, but not 3.0 mg/kg, increased DA release in the mPFC, while neither dose increased DA release in the NAC. Like M100907, ACP-103 (3.0 mg/kg) potentiated 0.1 mg/kg haloperidol-induced DA release in the mPFC while inhibiting that in the NAC. However, ACP-103 (3.0 mg/kg), similar to SR46349-B, potentiated a high dose of haloperidol (1.0 mg/kg)-induced DA release in both regions. The potent 5-HT_2C antagonist SB242084 1.0 mg/kg significantly potentiated 0.1 mg/kg haloperidol-induced DA release in both the mPFC and NAC. However, SB242084, at 0.2 mg/kg, significantly potentiated DA release only in the NAC. Moreover, SB242084 0.2 mg/kg potentiated DA release in the NAC produced by the combination treatment of 3 mg/kg ACP-103 and 0.1 mg/kg haloperidol.Conclusion These data suggest that the relative extent of 5-HT_2A and 5-HT_2C antagonism, as well as the extent of D₂ receptor blockade, has a critical influence on DA release in the mPFC and NAC and may be a determining factor in the action of this class of atypical APDs on these two potentially clinically relevant parameters.     

Effects of dopamine- and serotonin-related compounds on methamphetamine-induced self-injurious behavior in mice

Methamphetamine induces hyperlocomotion, and high doses of methamphetamine induce self-injurious behavior (SIB) in rodents. It is well known that the monoaminergic system is involved in methamphetamine-induced behavior. However, the effects of dopamine- and serotonin (5-HT)-related compounds on high-dose methamphetamine-induced behavior have not been sufficiently clarified. Therefore, the present study was designed to investigate the effects of dopamine receptor antagonists and indirect 5-HT receptor agonists on high-dose methamphetamine-induced behavior in mice. Methamphetamine (20 mg/kg) initially increased locomotor activity. As the dosage increased, continuous SIB accompanied by a reduction in locomotor activity was observed. The hyperlocomotion and SIB induced by 20 mg/kg of methamphetamine was abolished by high doses of SCH23390 and haloperidol, indicating that the hyperlocomotion and SIB induced by high doses of methamphetamine are mediated by the activation of D1- and D2-receptors. Furthermore, haloperidol (0.1 mg/kg) potently increased locomotor activity in combination with 20 mg/kg methamphetamine. These results suggest that excess dopaminergic activation, especially activation of dopamine D2-receptors, may be involved in the decrease in locomotor activity induced by a high dose of methamphetamine. On the other hand, indirect 5-HT receptor agonists attenuated methamphetamine-induced SIB, suggesting that the stimulation of 5-HT receptors plays an important role in high-dose methamphetamine-induced SIB in mice.     

Evaluation of amphetamine-induced hyperlocomotion and catalepsy following long-acting risperidone administration in rats

It has been proposed that long-acting risperidone could provide a constant antipsychotic efficacy associated with a reduced liability to induce extra-pyramidal symptoms. To ascertain this hypothesis, antagonism of amphetamine-induced hyperlocomotion and catalepsy were analyzed in rats for a period of 1–6 weeks following long-acting risperidone (20–60 mg/kg) injection. Long-acting risperidone reduced amphetamine-induced hyperlocomotion after 2–5 weeks from drug injection, without producing significant extra-pyramidal symptoms. Following the administration of long-acting risperidone a constant ability to antagonize amphetamine-induced hyperlocomotion was observed during the day, but not when the antipsychotic was chronically administered using a short-acting formulation. The pre-clinical results confirmed that long-acting risperidone may represent an advance in antipsychotic therapy.     

An analysis of safety and tolerability data from controlled, comparative studies of quetiapine in patients with schizophrenia, focusing on extrapyramidal symptoms

AIM: This analysis evaluated the tolerability profile of quetiapine using data from all comparative controlled studies in patients with schizophrenia or related disorders in the AstraZeneca clinical trials database, focusing on extrapyramidal symptoms (EPS). METHODS: Adverse event (AE) data from randomised, double-blind, controlled studies in the AstraZeneca clinical trials database were pooled, allowing comparison of quetiapine (mean daily doses 357-496 mg/day) with placebo, haloperidol (10.4 mg/day), risperidone (5.5 mg/day) or chlorpromazine (552 mg/day). Incidence of EPS-related AEs in relation to quetiapine dose was also analysed using a subset of data from fixed-dose studies. RESULTS: Data from 4956 patients were analysed. Quetiapine was well tolerated, and did not increase EPS-related AEs when compared with placebo (9.6 vs. 10.6%, respectively). The incidence of EPS-related AEs with quetiapine was consistent across the dose range (4.2-13.2% vs. 11.1% with placebo). Patients receiving haloperidol, risperidone and chlorpromazine experienced significantly higher levels of EPS-related AEs than those on quetiapine. The most common quetiapine- associated AEs, with significantly higher incidence than placebo, were sedation, somnolence and orthostatic hypotension. CONCLUSION: Quetiapine is generally well tolerated in patients with schizophrenia or related disorders, with placebo-level EPS-related AEs. Quetiapine has a more favourable EPS profile than haloperidol, chlorpromazine or risperidone.     

Catalepsy as a rodent model for detecting antipsychotic drugs with extrapyramidal side effect liability

The predictive validity of catalepsy as a rodent model for detecting the extrapyramidal side effects (EPS) of antipsychotic drugs was recently questioned when the novel antipsychotic savoxepine produced little catalepsy in rodents while producing significant EPS in schizophrenic patients. Because catalepsy is viewed as an important model for predicting EPS, we decided to re-evaluate the effects of savoxepine. Savoxepine, clozapine, haloperidol, olanzapine, ORG 5222, raclopride, and risperidone were examined in two tests for catalepsy (grid and bar tests) in male Sprague-Dawley rats. The ability to antagonize amphetamine-induced hypermotility was also examined, since this measure is believed to predict clinical efficacy. With the exception of clozapine, all drugs produced dose-dependent catalepsy in both tests. For each drug, the minimum effective dose for producing catalepsy was greater than or equal to the ED₅₀ for antagonizing amphetamine-induced hyperactivity (defined as the dose producing a 50% reduction in hyperactivity). Clozapine resulted in the widest separation of effective doses in the catalepsy and activity models. Raclopride produced the next largest separation while the remaining drugs resulted in only a one-or two-fold dose separation between the two behavioral tests. The results with haloperidol and clozapine are consistent with the clinical effects of these drugs (severe versus mild EPS). The ratios of effective doses in catalepsy and activity for the remaining novel drugs are also consistent with preliminary clinical findings indicating some EPS with each of these compounds. Thus, catalepsy remains a suitable rodent model for detecting compounds with EPS liability in humans.     

Effects of the antidepressant trazodone,a 5-HT<Subscript>2A/2C</Subscript> receptor antagonist,on dopamine-dependent behaviors in rats

Rationale 5-Hydroxytryptamine, via stimulation of 5-HT_2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT_2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT_2A/2C receptor antagonist.Objectives To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system.Methods The effect of pretreatment with trazodone on dexamphetamine- and apomorphine-induced oral stereotypies, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces catalepsy in rats.Results Trazodone at 2.5–20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized haloperidol catalepsy, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies.Conclusions Our results indicate that trazodone at 2.5–20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT_2A and 5-HT_2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT_2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.     

Effect of metergoline,fenfluramine, and 8-OHDPAT on catalepsy induced by haloperidol or morphine

Summary The influences of the indirect serotonin agonist fenfluramine (5; 10 mg/kg s.c.), the serotonin antagonist metergoline (5; 10 mg/kg s.c.) and the 5-HT_1A agonist 8-OHDPAT (0.1; 0.2; 0.46 mg/kg s. c.) on haloperidol-induced catalepsy in rats or mice and on morphine-induced catalepsy in rats were studied. Morphine-induced catalepsy was enhanced by fenfluramine and attenuated by metergoline, whereas neither fenfluramine nor metergoline had any effect on haloperidol-induced catalepsy. 8-OHDPAT strongly antagonised catalepsy induced by morphine or haloperidol. We conclude that serotonergic transmission plays a major role in effectuating morphine catalepsy but not in effectuating haloperidol catalepsy. The antagonistic effect of 8-OHDPAT suggests a secondary, modulating role for 5-HT_1A receptor mediated events in both types of catalepsy. Send offprint requests to C. L. E. Broekkamp at the above address     

The alpha-7 nicotinic receptor partial agonist/5-HT3 antagonist RG3487 enhances cortical and hippocampal dopamine and acetylcholine release

Rationale

Alpha-7 nicotinic acetylcholine receptor (nAChR) agonists may ameliorate cognitive deficits in schizophrenia, in part, because of their ability to enhance dopaminergic and cholinergic neurotransmission.

Objectives

In the current study, the effects of partial nAChR agonist and 5-HT₃ receptor antagonist RG3487 (previously R3487/MEM3454) on dopamine (DA) and acetylcholine (ACh) effluxes in rat prefrontal cortex (mPFC) and hippocampus (HIP) were investigated in awake, freely moving rats.

Results

R3487/MEM3454, at doses of 0.1–10 mg/kg, s.c., enhanced DA and ACh effluxes in rat mPFC and (HIP), with a peak effect at 0.3- to 0.6-mg/kg doses, producing a bell-shaped dose–response curve. Pretreatment with the selective nAChR antagonist, methyllycaconitine (1.0 mg/kg), completely blocked RG3487-induced (0.45 mg/kg) DA but not ACh efflux, while the selective 5-HT₃ receptor agonist 1-(m-chlorophenyl)-biguanide (1.0 mg/kg) partially inhibited cortical ACh but not DA efflux. RG3487 (0.45 mg/kg) combined with atypical antipsychotic drug (APD) risperidone (0.1 mg/kg), but not typical APD haloperidol (0.1 mg/kg), induced a significantly greater increase in HIP ACh efflux. Their combined effect on DA efflux was additive. RG3487, combined with other atypical APDs, namely aripiprazole (0.3 mg/kg), olanzapine (1.0 mg/kg), and quetiapine (30 mg/kg), also produced additive effects on DA efflux.

Conclusions

These results suggest that RG3487 enhances DA efflux by nAChR stimulation, whereas ACh efflux is primarily mediated via 5-HT₃ receptor antagonism, and that RG3487 alone or as augmentation may improve cognitive impairment in schizophrenia.     

Comparative behavioural effects of typical and atypical antipsychotic drugs in rhesus monkey

Behavioural effects of typical and atypical antipsychotic agents were compared in unrestrained rhesus monkey (Macaca mulatta) living in social colonies. The behaviours were categorized as social, solitary and abnormal. They were studied with the help of video cameras fixed in the observation chamber. The behavioural effects were recorded on videotape and analyzed for significant changes. Chlorpromazine (2.5-10 mg/kg, i.m.), haloperidol (0.01-0.04 mg/kg, i.m.), risperidone (0.05-0.2 mg/kg, p.o.) and clozapine (5-20 mg/kg, p.o.) induced significant alterations in parameters of social and solitary behaviour. Chlorpromazine produced a marked decrease in locomotor activity whereas haloperidol showed marked extrapyramidal effects. Risperidone produced minimal extrapyramidal effects and sedation compared to haloperidol and chlorpromazine. Clozapine had intermediate extrapyramidal effects similar to those of chlorpromazine but it produced hypersalivation and dose-related sedation. Thus, risperidone had advantages over the other antipsychotics used in this study because it did not produce salivation, had minimal extrapyramidal effects and caused less sedation. These antipsychotic drugs produced many behavioural effects in the rhesus monkey that were similar to their clinically observed effects. A study of behavioural effects in the monkey can thus be a useful predictive tool in the preclinical development of new antipsychotics.