S-16924, a novel, potential antipsychotic with marked serotonin1A agonist properties. IV. A drug discrimination comparison with clozapine. (9/3659)

The novel benzodioxopyrrolidine (S-16924) displays a clozapine-like profile of interaction with multiple monoaminergic receptors, in addition to potent agonist activity at serotonin (5-HT)1A receptors. S-16924 (2.5 mg/kg i.p.) and clozapine (5.0 mg/kg i.p.) generated robust discriminative stimuli (DS) and displayed full mutual generalization. The D4 antagonists L-745,870 and S-18126, the D1/D5 antagonist SCH-39166, and the D3 antagonist S-14297 showed at most partial generalization to S-16924 and clozapine. The D2/D3 antagonist raclopride fully generalized to S-16924, but only partially generalized to clozapine. The 5-HT2A antagonist MDL-100, 907 fully generalized to S-16924 and two further 5-HT2A antagonists, fananserin and SR-46349, showed partial generalization. However, MDL-100,907, fananserin, and SR-46349 showed less pronounced generalization to clozapine. Similarly, the 5-HT2C antagonists SB-200,646 and SB-206,553 more markedly generalized to S-16924 than to clozapine. The 5-HT1A receptor agonist (+/-)-8-dihydroxy-2-(di-n-propylamino) tetralin generalized fully to S-16924 but not to clozapine. Full generalization was obtained to both S-16924 and clozapine for the clozapine congeners, olanzapine and quetiapine. In distinction, the benzisoxazole, risperidone, and the phenylindole, sertindole, weakly generalized to S-16924 and clozapine. However, the benzisoxazole ziprasidone, which possesses 5-HT1A agonist properties, generalized fully to S-16924 but not to clozapine. Finally, the muscarinic antagonist scopolamine generalized fully to clozapine and partially to S-16924. In conclusion, S-16924 and clozapine display both communalities and differences in their "compound" DS; this likely reflects their respective complex patterns of interaction with multiple monoaminergic receptors. Although no specific receptor was identified as underlying the clozapine DS, 5-HT1A agonist as well as D2 and 5-HT2A/2C antagonist properties contribute to the S-16924 DS.  (+info)

Chlorpromazine inhibits miniature GABAergic currents by reducing the binding and by increasing the unbinding rate of GABAA receptors. (10/3659)

Recent studies have emphasized that nonequilibrium conditions of postsynaptic GABAA receptor (GABAAR) activation is a key factor in shaping the time course of IPSCs (Puia et al., 1994; Jones and Westbrook, 1995). Such nonequilibrium, resulting from extremely fast agonist time course, may affect the interaction between pharmacological agents and postsynaptic GABAARs. In the present study we found that chlorpromazine (CPZ), a widely used antipsychotic drug known to interfere with several ligand and voltage-gated channels, reduces the amplitude and accelerates the decay of miniature IPSCs (mIPSCs). A good qualitative reproduction of the effects of CPZ on mIPSCs was obtained when mIPSCs were mimicked by responses to ultrafast GABA applications to excised patches. Our experimental data and model simulations indicate that CPZ affects mIPSCs by decreasing the binding (kon) and by increasing the unbinding (koff) rates of GABAARs. Because of reduction of kon by CPZ, the binding reaction becomes rate-limiting, and agonist exposure of GABAARs during mIPSC is too short to activate the receptors to the same extent as in control conditions. The increase in unbinding rate is implicated as the mechanism underlying the acceleration of mIPSC decaying phase. The effect of CPZ on GABAAR binding rate, resulting in slower onset of GABA-evoked currents, provides a tool to estimate the speed of synaptic clearance of GABA. Moreover, the onset kinetics of recorded responses allowed the estimate the peak synaptic GABA concentration.  (+info)

M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats. (11/3659)

In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague-Dawley rats found no effect with 5-HT2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of dizocilpine in Wistar and Sprague-Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the alpha 1 adrenergic receptor antagonist prazosin. Furthermore, the alpha 1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the alpha 1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of dizocilpine in Sprague-Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains.  (+info)

Effects of atypical antipsychotic drug treatment on amphetamine-induced striatal dopamine release in patients with psychotic disorders. (12/3659)

Clozapine, risperidone, and other new "atypical" antipsychotic agents are distinguished from traditional neuroleptic drugs by having clinical efficacy with either no or low levels of extrapyramidal symptoms (EPS). Preclinical models have focused on striatal dopamine systems to account for their atypical profile. In this study, we examined the effects of clozapine and risperidone on amphetamine-induced striatal dopamine release in patients with psychotic disorders. A novel 11C-raclopride/PET paradigm was used to derive estimates of amphetamine-induced changes in striatal synaptic dopamine concentrations and patients were scanned while antipsychotic drug-free and during chronic treatment with either clozapine or risperidone. We found that amphetamine produced significant reductions in striatal 11C-raclopride binding during the drug-free and antipsychotic drug treatment phases of the study which reflects enhanced dopamine release in both conditions. There were no significant differences in % 11C-raclopride changes between the two conditions indicating that these atypical agents do not effect amphetamine-related striatal dopamine release. The implications for these data for antipsychotic drug action are discussed.  (+info)

Functional neuropsychophysiological asymmetry in schizophrenia: a review and reorientation. (13/3659)

In reviewing the neuropsychophysiological evidence of functional asymmetry it is proposed that schizophrenia is characterized by a greater dispersion of leftward and rightward asymmetries. The two extremes are represented by active (left greater than right) and withdrawn (right greater than left) syndromes, as is the case with psychometric schizotypy. Syndrome-asymmetry relations extended beyond fronto-temporal systems to include posterior activity, infracortical motoneuron excitability, and individual differences in interhemispheric connectivity and directional biases. Central to these are lateral imbalances in thalamo-cortical and callosal arousal systems, while centrality to schizophrenia follows evidence of reversals in asymmetry with changes in symptom profile, clinical recovery, and neuroleptic treatment. Affinities are found in intact animals from challenge-induced turning tendencies representing coordinated activity of attentional, motor, and reinforcement systems. In both patients and animals, neuroleptics have reciprocal interhemispheric effects, with a bidirectionality that depends on syndrome or endogenous turning preference. Bidirectionality implicates nonspecific thalamic system (NSTS) and not limbic projections. It is proposed that the asymmetries arise from endogenous influences of genes, hormones, and early experience including stressors on NSTS asymmetry, and these underpin approach/withdrawal behavior that is manifested in temperament, personality, and clinical syndrome, and which precedes language development.  (+info)

A cost-effectiveness clinical decision analysis model for schizophrenia. (14/3659)

A model was developed to estimate the medical costs and effectiveness outcomes of three antipsychotic treatments (olanzapine, haloperidol, and risperidone) for patients with schizophrenia. A decision analytic Markov model was used to determine the cost-effectiveness of treatments and outcomes that patients treated for schizophrenia may experience over a 5-year period. Model parameter estimates were based on clinical trial data, published medical literature, and, when needed, clinician judgment. Direct medical costs were incorporated into the model, and outcomes were expressed by using three effectiveness indicators: the Brief Psychiatric Rating Scale, quality-adjusted life years, and lack of relapse. Over a 5-year period, patients on olanzapine had an additional 6.8 months in a disability-free health state based on Brief Psychiatric Rating Scale scores and more than 2 additional months in a disability-free health state based on quality-adjusted life years, and they experienced 13% fewer relapses compared with patients on haloperidol. The estimated 5-year medical cost associated with olanzapine therapy was $1,539 less than that for haloperidol therapy. Compared with risperidone therapy, olanzapine therapy cost $1,875 less over a 5-year period. Patients on olanzapine had approximately 1.6 weeks more time in a disability-free health state (based on Brief Psychiatric Rating Scale scores) and 2% fewer relapses compared with patients on risperidone. Sensitivity analyses indicated the model was sensitive to changes in drug costs and shortened hospital stay. Compared with both haloperidol and risperidone therapy, olanzapine therapy was less expensive and provided superior effectiveness outcomes even with conservative values for key parameters such as relapse and discontinuation rates.  (+info)

Economic outcomes associated with the use of risperidone in a naturalistic group practice setting. (15/3659)

The purpose of this cohort pilot study was to compare the resource utilization and economic outcomes associated with the use of risperidone versus haloperidol in a naturalistic setting. Patient charts from a large psychiatric group practice were reviewed, and hospital billing data were obtained. Patients meeting the inclusion criteria were placed into one of two cohorts depending on their medication history. Thirty patients treated with risperidone met the selection criteria, and a random quota sampling technique was used to allow for a matched control cohort of 30 patients treated with haloperidol. In the haloperidol and risperidone cohorts, 24 and 28 patients, respectively, were evaluated statistically. Mean utilization rates and costs per patient per month for each service were estimated by using regression analysis. Patients in the risperidone cohort had significantly fewer hospitalizations than did those in the haloperidol cohort (P = 0.004). Likewise, risperidone patients had significantly lower hospitalization costs than haloperidol patients (P = 0.005). Conversely, patients treated with risperidone visited the physician more frequently than did those treated with haloperidol (P = 0.0005). Estimated mean total monthly costs were $123.34 lower (95% confidence interval = $464, $217) per patient in the risperidone cohort than in the haloperidol cohort ($1,636.11 vs $1759.45; P = 0.4693). Significant reductions in hospital costs in the risperidone cohort offset higher medication and physician costs. Overall, total monthly costs were similar for the two cohorts.  (+info)

Treatment of schizophrenia: let's talk dollars and sense. (16/3659)

Schizophrenia is a major neurologic illness with an impact on public health that has been unappreciated. Newer and arguably more effective medication treatments are now available and hold considerable promise. The higher up-front cost of these drugs is, on current evidence, offset by other economic advantages and, from a humanitarian perspective, by the expectation of improved patient outcome with less drug toxicity. The extent to which these drugs replace older drug treatments will be determined by the relative influences of clinical, pharmacoeconomic, mental health administrative, and advocacy factors over the coming years.  (+info)