Objective: The purpose ofthis study was to investigate the safety and efficacy of risperidone in the treatment ofschizophrenic patients and determine its optimal dose Method: This double-blind study included 388 schizophrenic patients drawn from 20 sites in the United States Patients were randomly assigned to 8 weeks’ treatment with placebo, one of four doses of risperidone (2, 6, 1 0, or 1 6 mg), or 20 mg ofhaloperidol daily Results: Clinical improvement (20% reduction in totalscores on the Positive and Negative Syndrome Scale for Schizophrenia) at the study end point was shown by 35% ofthe patients receiving 2 mg ofrisperidone, 57% receiving 6 mg, 40% receiving 1 0 mg, and 51 % receiving 1 6 mg; and by 30% receiving haloperidoland 22% receiving placebo Statistically significant differences in clinical improvement were found between 6 and 1 6 mg of risperidone versus placebo and versus haloperidol Positive symptom scores were significantly lower after 6, 10, and 1 6 mg of risperidone and 20 mg ofhaloperidol than placebo; negative symptom scores, however, were reduced significantly, compared with placebo, only after 6 and 1 6 mg ofrisperidone The incidence of extrapyramidal side effects (measured by the Extrapyramidal Symptom Rating Scale) was significantly higher in patients treated with 1 6 mg of risperidone or 20 mg of haloperidol than placebo The results indicate that the optimal daily dose ofrisperidone for most schizophrenic patients in this study was 6 mg; this dose was as effective as 1 6 mg, and the incidence of extrapyramidal symptoms in patients receiving 6 mg of risperidone was no higher than that in patients receiving placebo Conclusions: Risperidone is a safe antipsychotic that is effective against both the positive and negative symptoms of schizophrenia (AmJ Psychiatry 1994; 151:825-835)

Risperidone in the treatment of schizophrenia.

Radioreceptor binding profile of the atypical antipsychotic olanzapine

Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules

Fluorine in health care: Organofluorine containing blockbuster drugs

Objective: To compare effects of risperidone with placebo (efficacy and tolerability) and haloperidol (tolerability) for treating demented patients with aggression and other behavioral symptoms. Methods: A 13-week double-blind study involving 344 patients with dementia randomly assigned to receive placebo or flexible doses (0.5 to 4 mg/d) of risperidone or haloperidol. Behavioral symptoms were assessed by the Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD), the Cohen-Mansfield Agitation Inventory (CMAI), and the Clinical Global Impression (CGI) scale. Tolerability assessments included the Extrapyramidal Symptom Rating Scale, sedation levels, Functional Assessment Staging, Mini-Mental State Examination, and incidence of adverse events. Results: The mean dose at endpoint was 1.1 mg/d of risperidone and 1.2 mg/d of haloperidol. Although not significant, a higher percentage of patients receiving risperidone than those receiving placebo showed clinical improvement (≥30% reduction from baseline to endpoint in BEHAVE-AD total score) at endpoint and week 12. Reductions in the BEHAVE-AD total score were significantly greater with risperidone than with placebo at week 12. In a further analysis of aggression, the most dominant symptom in these patients, BEHAVE-AD and CMAI aggression cluster scores were significantly reduced compared with placebo at endpoint and week 12. CGI scores were also significantly reduced at endpoint and week 12. Severity of extrapyramidal symptoms with risperidone did not differ significantly from that of placebo and was less than that of haloperidol. A post hoc analysis showed significantly greater reductions in the BEHAVE-AD aggressiveness score with risperidone than haloperidol at week 12. Conclusion: Low-dose risperidone (mean 1.1 mg/d) was well tolerated and associated with reductions in the severity and frequency of behavioral symptoms, particularly aggression, in elderly patients with dementia.

A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia

Risperidone was compared to the 5-hydroxytryptamine2 antagonist ritanserin and to the dopamine-D2 antagonist haloperidol. The in vitro receptor binding (neurotransmitter-, peptide- and ion channel binding sites) and neurotransmitter uptake profile were investigated. Risperidone revealed, like ritanserin, a very high binding affinity for 5-hydroxytryptamine2 receptors (Ki = 0.16 and 0.30 nM, respectively) and a slow dissociation (half-time, 31 and 160 min). In accordance, risperidone (IC50 = 0.5 nM) and ritanserin (IC50 = 1.8 nM) potently blocked serotonin-induced 32P-phosphatidic acid formation in human blood platelets. Risperidone showed, like haloperidol, high binding affinity for dopamine-D2 receptors (Ki = 3.13 and 1.55 nM, respectively) and rapid dissociation (half-time, 2.7 and 5.8 min). Risperidone displayed higher binding affinity than ritanserin and haloperidol for alpha-1 adrenergic (Ki = 0.8 nM), histamine-H1 (Ki = 2.23 nM) and alpha-2 adrenergic receptors (Ki = 7.54 nM). In in vitro superfusion experiments, risperidone and haloperidol reversed at nanomolar concentrations the inhibition by LY 171555 (a dopamine-D2 agonist) and by amphetamine of potassium and electrically evoked release of [3H]acetylcholine from striatal slices (postsynaptic dopamine-D2 effects). Both drugs reversed with similar potency the inhibition by LY 171555 of electrically evoked release of [3H]dopamine (a presynaptic dopamine-D2 effect). Risperidone did not affect the activation by amphetamine of [3H]dopamine efflux from rat striatal slices. Risperidone enhanced at nanomolar concentrations the stimulated [3H]norepinephrine efflux from cortical slices and it similarly reversed the inhibition by clonidine, at concentrations corresponding to its binding affinity for alpha-2 adrenergic receptors. The in vitro biochemical properties of risperidone are in agreement with the reported in vivo pharmacological profile, the relation to clinical findings is discussed.

Biochemical profile of risperidone, a new antipsychotic.

In mammalian striatal tissue and cat platelets, [3H]ketanserin labels besides serotonin-S2 receptors nonserotonergic saturable binding sites. The sites have been distinguished and characterized in [3H]ketanserin binding assays by selective inhibition with tetrabenazine (Ki = 4 nM), a monoamine depleting agent. In rats, the nonserotonergic ketanserin sites were enriched in the striatum (KD = 12.4 +/- 0.3 nM, maximal number of binding sites = 53.2 +/- 11.8 fmol/mg of tissue at pH 7.7, 37 degrees C) and nucleus accumbens. The sites were decreased by 65 to 78% after 6-hydroxydopamine lesions, suggesting an association with dopaminergic nerve terminals. In in vitro superfusion experiments using [3H]dopamine, [3H]norepinephrine and [3H]serotonin loaded rat brain tissue and [3H]serotonin loaded human platelets, 5 min superfusion with 10(-6) M ketanserin, tetrabenazine and reserpine caused instantaneously a marked increase in tritium efflux. The effect was attenuated by the monoamine oxidase inhibitor, pargyline, in brain slices but not in platelets. High-performance liquid chromatography analysis of endogenous catecholamines, serotonin and metabolites in superfusates from striatal slices revealed that stimulation with these drugs provoked mainly release of 3,4-dihydroxybenzeneacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid. Potencies of a series of ketanserin derivatives, benzoquinolizine derivatives and a variety of drugs affecting neurotransmission were assessed in the in vitro release test using [3H]dopamine loaded striatal slices, and in [3H]ketanserin binding assays to nonserotonergic sites in the striatum and to serotonin-S2 receptors in brain tissue. Activities of drugs in the release test correlated strongly with their binding affinities for nonserotonergic ketanserin sites (rs = 0.83, n = 30, P less than .001). High potency in the latter two tests was confined to few close structural congeners of ketanserin and tetrabenazine. Distinct structural activity relationships for interaction with nonserotonergic ketanserin sites and serotonin-S2 receptors were found. It was concluded that nonserotonergic ketanserin sites mediate release of oxidated metabolites of biogenic amines from nerve endings and of serotonin from platelets. Hence release of biogenic amine metabolites or of cytoplasmic amines is probably not a mere diffusion process but involves specific membranous molecules. Unlike tetrabenazine, ketanserin caused no obvious depletion of central catecholamine and indoleamine stores. Implications of these findings for the mechanism of action of the drugs are discussed.

Identification of nonserotonergic [3H]ketanserin binding sites associated with nerve terminals in rat brain and with platelets; relation with release of biogenic amine metabolites induced by ketanserin- and tetrabenazine-like drugs

Non-serotonergic [3H]ketanserin binding sites in striatal membranes are associated with a dopac release system on dopaminergic nerve endings.

The effect of ketanserin and tetrabenazine treatment on monoamine and metabolite levels in central and peripheral tissues was investigated in young and senescent male Wistar and spontaneously hypertensive Okamota rats. Control animals showed significantly higher brain monoamine levels and 3 and 5.5 times higher dopamine levels in the vas deferens of the senescent and hypertensive rats, as compared with young normotensive rats. Ketanserin (20 mg/kg) produced an average of 20% reduction of brain monoamines without changing metabolite levels. In the vas deferens, dopamine was reduced by 85% and norepinephrine by 30%. In cardiovascular tissues, norepinephrine was 40% to 50% decreased and in the spleen norepinephrine was 60% and 5-hydroxytryptamine 30% reduced. Ketanserin (5 mg/kg) had only a marked effect on dopamine in the vas deferens and on norepinephrine in the portal vein. Tetrabenazine at 20 mg/kg produced complete depletion of the monoamine and 3-methoxytyramine levels in the brain with a concomitant rise in acid metabolites. In peripheral tissues, amine levels were reduced by 55% to 80%; dopamine in the vas deferens was 93% decreased. Tetrabenazine (5 mg/kg) still had marked effects in all tissues. The drug effects were the same in the three types of rats and the effects did not markedly change with chronic treatment up to 20 days. It is hypothesized that at least two different mechanisms are involved in monoamine depletion, 1) the classically proposed inhibition of uptake of monoamines in the storage vesicles, a property of tetrabenazine not shared by ketanserin in vivo and 2) triggering of the release of monoamines from a ketanserin-sensitive pool, which is relatively more important in peripheral tissues than in the brain. The latter process is probably mediated by previously identified ketanserin-binding release sites on nerve terminals and platelets. The ketanserin-sensitive monoamine pools in peripheral tissues may have a role in cardiovascular pathologies.

Ketanserin reduces a particular monoamine pool in peripheral tissues.

Ketanserin is a prototype of a 5-HT2 antagonist which also has moderate α1-adrenoceptor blocking properties. These properties are thought to underly its demonstrated antithrombotic and antivasoconstrictive activities (for reviews see [1, 2]).

Reduction of a distinct pool of monoamines by ketanserin in peripheral tissues

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