浅谈抗精神病药物副反应的观察护理

近年来,精神料药物研究进展迅速,药物品种不断增加。随着临床的广泛应用及认识的不断加深,药物的副作用也逐渐地显现出来。因此,医护人员除采取相应措施减少或避免意外事件的发生外,应正确识别原有精神症状和抗精神病药物所致精神症状,以便为医生增减药量提供参考和依据。     

Drug extrapyramidal side effects. CYP2D6 genotypes and phenotypes

Objective: Among Caucasians, a lack of cytochrome P ₄₅₀ enzyme CYP2D6 is observed in 5–10% of individuals, named poor metabolizers (PMs). A consequence may be an impaired metabolism of many drugs such as most of the psychotropic drugs with an increased risk of drug side effects. This enzyme is also involved in the metabolism of endogenous compounds, including neurotransmitters such as dopamine and dopamine-related neurotransmitters which play a role in the mechanism of action of extrapyramidal drug side effects. The present study investigates whether patients who have developed and those who have not developed extrapyramidal drug side effects differ in their CYP2D6 genotypes and phenotypes. Methods: The CP2D6 genotype (method involving restriction length fragment polymorphism and polymerase chain reaction-single strand conformation polymorphism) was determined in 65 drug-treated in-patients, and the CYP2D6 phenotype (with dextromethorphan probe) in 62 of them. Two groups were constituted, one with 22 patients who had developed extrapyramidal drug side effects, and the second with 43 patients without such side effects. Results: In the whole population, there was an over-representation of PM phenotypes – more marked in the first group than the second (45% vs 14%). Concerning the genotypes, we observed that the percentage of functional alleles (with extensive metabolic capacity) was higher in group 2, whereas the percentage of non-functional alleles (without metabolic activity) was higher in group 1; this frequency difference was only marginally significant (χ² 5.95; P < 0.0509; degrees of freedom=2). Consequently, there was a higher percentage of genotypes with no (extensive) functional alleles in the group of patients suffering from extrapyramidal side effects than in the other group (P < 0.00001). Conclusion: CYP2D6-impaired metabolic capacity may be a contributory factor in extrapyramidal drug side effects. Received: 25 May 1999 / Accepted in revised form: 18 August 1999     

Is there a relationship between the involvement of extrapyramidal and mesolimbic brain areas with the cataleptic action of neuroleptic agents and their clinical antipsychotic effect?

The electrolytic brain lesion technique was used in the rat to disrupt the ascending dopaminergic pathways to the extrapyramidal (striatal) and mesolimbic brain areas in the lateral hypothalamus and the pathways to the mesolimbic areas only in the rostral hypothalamus. The cataleptic effects of the neuroleptic agents spiroperidol and perphenazine were enhanced in the acute stage following the lateral hypothalamic lesions but were unmodifield or reduced by the rostral hypothalamic lesions. The cataleptic effects of the neuroleptic agents AHR 2277 and thioridazine were not significantly modified in the acute stage by either lesions. Both lateral and rostral hypothalamic lesions markedly reduced or abolished the cataleptic ability of all neuroleptics tested in the chronic stage. The cataleptic activities of the non-neuroleptic agents metoclopramide and bulbocapnine were unmodified or potentiated by lesions in the lateral hypothalamus and potentiated or unmodified by lesions in the rostral hypothalamus respectively during the acute stage. In the chronic stage the cataleptic effects of both agents were markedly reduced or abolished in animals with lateral or rostral hypothalamic lesions.     

Clozapine versus typical antipsychotics a retro- and prospective study of extrapyramidal side effects

Schizophrenic patients in long-term neuroleptic monotherapy with clozapine (n=100) and perphenazine, flupenthixol or zuclopentixol (controls,n=100) were evaluated for extrapyramidal side effects (EPS) (blind) as well as other side effects and mental condition (non-blind). In both groups the patients had received neuroleptic treatment for a total of 14 years (median) and the present antipsychotic (clozapine or control drug) for 5 years. Thus the clozapine-treated patients had previously received traditional neuroleptics for 9 years (median). The study was both retrospective (0.3–19 years for clozapine, 0.3–24 years for control drug, by means of chart information) and prospective (1 year, with video-controlled evaluation of EPS). There was a significantly lower prevalence of tardive dyskinesia (TD) in clozapine treated patients than control patients, although prior to this treatment there were more TD patients in the clozapine group (P<0.05). This lower level of TD in the clozapine group was related to a lower induction of new cases (P<0.001) and a tendency towards greater disappearance of TD in the clozapine than in the control group (P=0.07). Clozapine treated patients without TD had started clozapine and ceased traditional neuroleptics at an earlier age than those with TD. Parkinsonian signs were seen in 33% of the clozapine patients versus 61% of the control patients, mainly as hypokinesia; tremor in 3% versus 11% and rigidity in 0 versus 19%. Psychic akathisia was found in 14% versus 40% and motor akathisia in 7% versus 29% of the patients, all differences significantly in favor of clozapine. Clozapine treated patients also had less neuroleptic-induced emotional indifference and depression, but more autonomic side effects than controls.     

The attenuating effect of carteolol hydrochloride, a β-adrenoceptor antagonist, on neuroleptic-induced catalepsy in rats

It is known that β-adrenoceptor antagonists are effective in the treatment of akathisia, one of the extrapyramidal side effects that occur during neuroleptic treatment. Neuroleptic-induced catalepsy, a model of neuroleptic-induced extrapyramidal side effects, was considered suitable as a model for predicting neuroleptic-induced akathisia in humans, although neuroleptic-induced catalepsy was not considered a specific test for neuroleptic-induced akathisia. Therefore, the effects of carteolol, a β-adrenoceptor antagonist, on haloperidol-induced catalepsy in rats were behaviorally studied and compared with those of propranolol and biperiden, a muscarinic receptor antagonist. Carteolol, as well as propranolol and biperiden, inhibited the haloperidol-induced catalepsy. The inhibitory effect of carteolol was almost comparable to that of propranolol, but was weaker than that of biperiden. Carteolol did not evoke postsynaptic dopamine receptor-stimulating behavioral signs such as stereotypy and hyperlocomotion in rats. Carteolol did not antagonize the inhibitory effects of haloperidol on apomorphine-induced stereotypy and locomotor activity in rats. In addition, carteolol did not evoke 5-HT_1A receptor-stimulating behavioral signs such as flat body posture and forepaw treading and did not inhibit 5-hydroxytryptophan-induced head twitch in rats. Finally, carteolol did not inhibit physostigmine-induced lethality in rats. These results strongly suggest that carteolol improves haloperidol-induced catalepsy via its β-adrenoceptor antagonistic activity and is expected to be effective in the treatment of akathisia without attenuating neuroleptic-induced antipsychotic effects due to its postsynaptic dopamine receptor antagonistic activity. Received: 7 March 1996/ Final version: 27 November 1996     

Electrophysiologic interactions of antipsychotic drugs with central noradrenergic pathways

The pathway from the nucleus coeruleus to Purkinje neurons in rat cerebellar cortex was used to analyze effects of antipsychotic neuroleptic drugs on a central noradrenergic pathway. Fluphenazine and haloperidol produced a dose-dependent increase in Purkinje neuron spontaneous discharge. This effect was not seen in animals in which the noradrenergic input had been removed by the neurotoxin 6-hydroxydopamine. In contrast, the effects of neuroleptics were still present in animals which had received neonatal X-ray irradiation, which destroys intrinsic inhibitory and excitatory pathways in cerebellar cortex. Chlorpromazine produced the same increase in discharge rate, but was significantly less potent. -Flupenthixol was equipotent with fluphenazine, but -flupenthixol, a behaviorally inactive steroisomer, was without effect. The dose-response curves showed potencies similar to those in several animal behavioral paradigms. In addition, the rank order of potency was identical to that in clinical tests of antipsychotic activity. Three-week chronic administration of fluphenazine resulted in complete blockade of noradrenergic activity, with no further increase in Purkinje neurons spontaneous discharge rate by additional doses of drug. Thus, tolerance does not develop to the noradrenergic blocking effect of the neuroleptic. Taken together, this evidence suggests that antipsychotic neuroleptic drugs block noradrenergic neurotransmission in the CNS.     

Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients

RATIONALE: Perphenazine, a classical antipsychotic drug, has the potential to induce extrapyramidal side effects (EPS). Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug. OBJECTIVES: To evaluate the impact of polymorphisms in the dopamine D(2) and D(3) and serotonin 2A and 2C receptor genes (DRD2, DRD3, HTR2A, and HTR2C) on short-term effects of perphenazine monotherapy in schizophrenic patients. MATERIALS AND METHODS: Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale, Barnes scale, and Positive and Negative Symptom Scale. Genotyping was performed for common DRD2, DRD3, HTR2A, and HTR2C gene polymorphisms, previously reported to influence receptor expression and/or function. RESULTS: Most of the patients (n = 37) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response. The 102C allele of HTR2A and the -697C and 23Ser alleles of HTR2C were more frequent among patients with EPS (n = 25) compared to patients without EPS (n = 22) (p = 0.02, 0.01, and 0.02, respectively). The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age, gender, and duration of antipsychotic treatment as covariants. There was no significant association between EPS occurrence and polymorphisms in the DRD2 and DRD3 genes. CONCLUSIONS: An association was observed between polymorphisms in HTR2A and HTR2C genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy. Larger study populations are needed to confirm our findings.     

Acute extrapyramidal side effects: Serum levels of neuroleptics and anticholinergics

An assay technique for measuring anticholinergic drugs in human serum based upon their inhibition of the specific binding of [³H]-quinuclidinyl benzilate to rat brain muscarinic receptors is described. The assay was validated by demonstrating a close correlation (r=0.99) between serum levels of nortriptyline measured by the radioenzymatic assay and a GLC technique. The assay measures free anticholinergics, and under standard assay conditions, approximately 95% of benztropine is bound to serum protein. Marked variation in serum anticholinergic levels in patients receiving the same oral dose was observed, and in individual patients there was a non-linear relationship between increasing oral dose and serum anticholinergic levels.In a cross-sectional study of 109 patients receiving concurrently neuroleptics and antichlinergics, there was no correlation (r=0.029) between serum neuroleptic levels measured by a radioreceptor assay and extrapyramidal side effects (EPS). In the patients whose serum anticholinergic levels were also determined, there was a significant inverse correlation (r=0.44) between anticholinergic levels and EPS. In this cohort of patients, there was no significant correlation between serum anticholinergic and serum neuroleptic levels (r=0.16) and the ratio of serum anticholinergic to serum neuroleptic was a poor predictor of EPS (r=0.26).The results suggest a marked variation in sensitivity of patients to the EPS-inducing of neuroleptics; nevertheless, the incidence of EPS decreases with increasing serum levels of anticholinergics. An optimal serum anticholinergic level of 10 pmole atropine equivalent per ml was associated with a low incidence of EPS and is relevant to drug action at the striatal muscarinic receptor.     

Interactions between neuroleptics and 5-HT1A ligands in preclinical behavioral models for antipsychotic and extrapyramidal effects

Rationale: Combining neuroleptics with 5-HT_1A ligands is thought to improve the preclinical profile of neuroleptics and may be of interest in the development of new compounds that have greater therapeutic potential and/or are better tolerated. Objective: To examine 1) the ability of 5-HT_1A ligands to alter the effects of neuroleptics in preclinical models for antipsychotic potential (hindlimb retraction time in the paw test) and extrapyramidal side-effects (forelimb retraction time in the paw test; catalepsy tests), 2) the role of intrinsic activity at 5-HT_1A receptors in the modulatory effects of 5-HT_1A ligands, and 3) the generality of the interactions across neuroleptics. Methods: The effects of different doses of 5-HT_1A ligands with intrinsic activity ranging from high (e.g., 8-OH-DPAT) to low (e.g., WAY 100135) administered together with a fixed, high dose of the neuroleptics haloperidol, risperidone, and tropapride were examined in the paw test and on catalepsy. Results: Firstly, the 5-HT_1A agonists 8-OH-DPAT and ipsapirone attenuated the extrapyramidal-like effects of haloperidol and risperidone more than their therapeutic-like effects; this was not observed for tropapride, where all of its effects were markedly attenuated. Secondly, neither the weak 5-HT_1A agonist WAY 100135 nor the silent antagonist WAY 100635 attenuated the effects of neuroleptics. Thirdly, neuroleptics apparently differed in their sensitivity to interactions with 5-HT_1A agonists inasmuch as 8-OH-DPAT and ipsapirone attenuated the effects of tropapride on hindlimb retraction times more than those of haloperidol or risperidone. Conclusions: The present data suggest that 5-HT_1A agonists with intermediate or high, but not low, intrinsic activity may abolish the extrapyramidal effects of neuroleptics. Together with results of previous studies, it appears that 5-HT_1A agonists alter the antipsychotic-like effects of neuroleptics, although this may depend on the neuroleptic studied. Received: 29 June 1998/Final version: 6 November 1998     

Distention ulcer as a model for testing of drugs for ulcerogenic side effects

A modification of the distention ulcer was studied in albino rats and a new possibility of testing ulcerogenic side effects of drugs was described. The distention alone was not sufficient to produce lesions. The severity of ulcer lesions was highly dependent on the volume of the acid solution. Large volumes of 0.1 N HCl evoked severe ulcers within 1 h. Small amounts of weak acid solution did not cause any ulceration. Anti-inflammatory drugs administered in therapeutic doses, which did not yet produce any ulcers in animals, increased the sensitivity of the gastric mucosa against the aggresive factor, the acid. In animals pretreated by anti-inflammatory drugs in toxic doses an earlier development of ulceration was observed by distention with acid. Stress also accelerated and aggravated the formation of distention ulcers.Some of the results have been communicated at the International Workshop on Pharmacological Methods in Precinical Safety-Evaluation of New Drugs, October 10–13, 1977, Zurich     

1例抗结核药致胃肠道不良反应的药学监护

目的探讨临床药师参与结核患者胃肠道不良反应处理的方法与思路。方法临床药师查阅相关指南及文献,协助医生制定抗结核药致胃肠道不良反应的处理方案。结果药学服务取得了明显临床疗效,患者胃肠道不良反应明显改善,且未对抗结核治疗的疗效产生不利影响。结论临床药师应积极发挥专业优势,在药物治疗过程中早期发现并鉴别药物不良反应,积极寻找不良反应解决方案。     

The risk of cardiovascular side effects with anti-anginal drugs

ABSTRACT

Introduction: Angina pectoris is a common presenting symptom of underlying coronary artery disease or reduced coronary flow reserve. Patients with angina have impaired quality of life; and need to be treated optimally with antianginal drugs to control symptoms and improve exercise performance. A wide range of antianginal medications are approved for the treatment of angina, and often more than one class of antianginal drugs are used to adequately control the symptoms. This expert opinion highlights the likely cardiac adverse effects of available antianginal drugs, and how to minimize these in individual patients and especially during combination treatment.

Areas covered: All approved antianginal drugs, including the older and newly approved medications with different mechanism of action to the older drugs as well as some of the unapproved herbal medications. The safety profiles and potential cardiac side effects of these medications when used as monotherapy or as combination therapy are discussed and highlighted.

Expert opinion: Because of the different cardiac safety profiles and possible side effects, we recommend selection of initial drug or adjustment of therapy based on the resting heart rate; blood pressure, hemodynamic status; and resting left ventricular function, concomitant medications and any associated comorbidities.     

The effect of vitamin E addition to acute neuroleptic treatment on the emergence of extrapyramidal side effects in schizophrenic patients: An open label study

The anti-oxidant vitamin E has been reported to be effective in the treatment of tardive dyskinesia. The present open label study examined the effect of supplemental therapy with vitamin E on acute extrapyramidal symptoms and cell enzymes in patients receiving neuroleptic drugs. Thirty-nine hospitalized schizophrenic patients were randomly assigned to two groups: group 1 (n=20) was treated with neuroleptics, and group 2 (n=19) with neuroleptics combined with a fixed dose of vitamin E (600 IU/day), administered for two weeks. All patients were assessed with the Simpson-Angus Rating Scale (Simpson and Angus, 1970) for neuroleptic induced Parkinsonism (NIP), Barnes’ Akathisia Scale ( Barnes, 1989), and Brief Psychiatric Rating Scale: laboratory parameters included serum creatine kinase (CK) activity, serum glutamate oxaloacetic transaminase (SGOT) and white blood cell count (WBC). The addition of vitamin E to neuroleptic agents was associated with a trend (p=0.08) towards prevention of the emergence of NIP compared to neuroleptic treatment alone. Addition of vitamin E to neuroleptics may reduce the severity of acute NIP in schizophrenic patients.     

Combined treatment of quetiapine with haloperidol in animal models of antipsychotic effect and extrapyramidal side effects: comparison with risperidone and chlorpromazine

Rationale Quetiapine, an atypical neuroleptic, has beneficial antipsychotic effects in schizophrenic patients, but with a lower incidence of extrapyramidal symptoms (EPS) compared with typical antipsychotics. While typical antipsychotics are often switched to atypical agents when adverse effects become limiting, there is little preclinical information to support this strategy, both in terms of efficacy and side effects.Objectives The antipsychotic effects and EPS during concomitant administration of quetiapine with haloperidol, a typical antipsychotic agent, were evaluated in mice and compared with chlorpromazine and risperidone.Methods We first investigated the antipsychotic effects and EPS liability of quetiapine, risperidone, chlorpromazine, and haloperidol when administered alone to select optimal doses for subsequent combination studies. The second study was designed to evaluate the antipsychotic efficacy and EPS profile of concomitant administration of quetiapine, risperidone, or chlorpromazine with haloperidol. Antipsychotic effects were evaluated with the methamphetamine-induced hyperlocomotion test, and EPS liability was evaluated in a catalepsy-induction model.Results Quetiapine, risperidone, chlorpromazine, and haloperidol dose-dependently reduced methamphetamine-induced hyperlocomotion, with ED₅₀ values of 5.6, 0.020, 1.8, 0.035 mg/kg, respectively. In the catalepsy test, quetiapine only weakly induced catalepsy at the highest dose of 100 mg/kg, whereas risperidone, chlorpromazine, and haloperidol dose-dependently induced catalepsy with ED₅₀ values of 0.25, 4.6, and 0.10 mg/kg, respectively. While the combination of quetiapine (6 mg/kg) and haloperidol (0.04 mg/kg) significantly reduced methamphetamine-induced hyperlocomotion in comparison with haloperidol alone, quetiapine (10, 32 mg/kg) plus haloperidol did not potentiate the cataleptogenic activity of haloperidol. In contrast, risperidone (0.1, 0.32 mg/kg) or chlorpromazine (3.2 mg/kg) significantly augmented catalepsy induced by haloperidol. Catalepsy induced by co-administration of quetiapine (10 mg/kg) and haloperidol (0.1 mg/kg) was significantly potentiated by WAY100635, a 5-HT_1A antagonist, and catalepsy induced by co-administration of risperidone (0.1 mg/kg) and haloperidol (0.1 mg/kg) was significantly antagonized by 8-OH-DPAT, a 5-HT_1A agonist.Conclusion The present study demonstrated that the combined administration of quetiapine with haloperidol did not aggravate EPS, possibly because of its affinity for 5-HT_1A receptors. This finding may have the clinical implication that quetiapine could provide a successful regimen in switching from typical antipsychotic agents in the symptom management of schizophrenia, or even in adjunctive therapy with other antipsychotic agents.     

Further evidence for the association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients

Rationale Antipsychotic-induced extrapyramidal side effects (EPS) are still a major problem in the treatment of schizophrenia. Serotonin 2C receptors (5-HT_2C) have regulatory effects on dopaminergic pathways in brain regions involved with EPS. Polymorphisms in the 5-HT_2C gene (HTR2C) have been suggested to be associated with the risk of developing EPS. Objective Our purpose was to evaluate the impact of polymorphisms in the HTR2C gene on the occurrence of EPS in male schizophrenic patients. Methods Ninety-nine male Caucasian chronic schizophrenic patients on long-term treatment with classical antipsychotics were genotyped for the −997 G/A, −759 C/T, −697 G/C and Cys23Ser polymorphisms of HTR2C. EPS (dystonia, parkinsonism, tardive dyskinesia) were assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Fifty-one patients had current or previous history of EPS, whereas 48 patients had no symptoms or history of EPS. To rule out a possible association between HTR2C polymorphisms and schizophrenia, 112 healthy male volunteers were also genotyped. Results Allele frequencies of −997A, −759T and −697C did not differ between the groups, whereas patients with EPS had a significantly (p = 0.025) higher frequency of the 23Ser allele (0.29) than did patients without EPS (0.15) or healthy volunteers (0.13). A similar trend was observed for a haplotype including the −997G, −759C, −697C and 23Ser alleles (p = 0.04). Conclusions Results confirm previously reported associations between the HTR2C 23Ser allele and EPS occurrence and suggest the novel finding of an HTR2C haplotype association with EPS in male chronic schizophrenic patients.     

住院老年精神病患者用药调查与分析

目的了解本院住院老年精神病患者的药物使用情况及药物不良反应。方法采用一日调查法对本院住院老年精神病患者的用药进行调查。结果在参与调查的198例患者中,其中单一用药103例,两药联用68例。在老年精神病患者用药后监测的不良反应中,有110例（55．56％）患者发生不良反应。结论老年精神病患者抗精神病治疗以单一用药为主。     

Mechanisms of action of atypical antipsychotic drugs: a critical analysis

Various criteria used to define atypical antipsychotic drugs include: 1) decrease, or absence, of the capacity to cause acute extrapyramidal motor side effects (acute EPSE) and tardive dyskinesia (TD); 2) increased therapeutic efficacy reflected by improvement in positive, negative, or cognitive symptoms; 3) and a decrease, or absence, of the capacity to increase prolactin levels. The pharmacologic basis of atypical antipsychotic drug activity has been the target of intensive study since the significance of clozapine was first appreciated. Three notions have been utilized conceptually to explain the distinction between atypical versus typical antipsychotic drugs: 1) dose-response separation between particular pharmacologic functions; 2) anatomic specificity of particular pharmacologic activities; 3) neurotransmitter receptor interactions and pharmacodynamics. These conceptual bases are not mutually exclusive, and the demonstration of limbic versus extrapyramidal motor functional selectivity is apparent within each arbitrary theoretical base. This review discusses salient distinctions predominantly between prototypic atypical and typical antipsychotic drugs such as clozapine and haloperidol, respectively. In addition, areas of common function between atypical and typical antipsychotic drug action may also be crucial to our identification of pathophysiological foci of the different dimensions of schizophrenia, including positive symptoms, negative symptoms, and neurocognitive deficits.This study was supported by the Mental Health Clinical Research Center for the Study of Schizophrenia (USPHS MH-41960)     

Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT_2A receptors and D₂-type receptors. Predominant 5HT_2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D₂ antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D₃ and in particular D₄ receptors has been proposed.In vitro, all compounds, except the typical antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT_2A than for D₂ receptors. Subnanomolar affinity for human 5HT_2A receptors was observed for ORG-5222, sertindole, resperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D₂ receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D₂ affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D₄ than for D₂ receptors. For most other compounds, D₄ affinity was only slightly lower than their D₂ affinity. Seroquel was totally devoid of D₄ affinity. None of the compounds had nanomolar affinity for D₁ receptors; their affinity for D₃ receptors was usually slightly lower than for D₂ receptors.In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT_2A than D₂ receptors. Risperidone and ORG-5222 had 5HT_2A versus D₂ potency ratio of about 20. Highest potency for 5HT_2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT_2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D₂ receptors. No regional selectivity for D₂ receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D₂ receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic ₁ receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more ₁ than D₂ receptors. Clozapine showed predominant occupancy of H₁ receptors and occupied cholinergic receptors with equivalent potency to D₂ receptors. A stronger predominance of 5HT_2A versus D₂ receptor occupancy combined with a more gradual occupancy of D₂ receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT_2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D₂ receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT_2A and D₂ occupancy and the avoidance of D₂ receptor overblockade are believed to reduce the risk for extrapyramidal symptoms.     

Brain homovanillic acid: regional changes over time with antipsychotic drugs.

Acute administration of equivalent doses of either chlorpromazine, thioridazine, or clozapine, respectively, produced progressively smaller increases in brain homovanillic acid (HVA) in the rabbit; however, changes in HVA in three brain regions were of equal magnitude for a single dose of a given drug. Chronic administration of fluphenazine enanthate resulted in a decrease in HVA relative to acute treatment in caudate more than limbic regions. No differences between caudate and limbic regions were observed during daily chlorpromazine administration for 3 ro 8 days. Tolerance appeared to develop in approximately 1 week. Chronic treatment with clozapine produced no tolerance at one week but suggestive evidence of tolerance in caudate and limbic regions at two weeks. No tolerance was observed in the hypothalamus during chronic treatment with any drug used. Cisternal CSF HVA paralleled caudate HVA during acute and chronic treatments.     

A monitoring test for the liability of neuroleptic drugs to induce tardive dyskinesia

Two Cebus apella monkeys with haloperidol-induced tardive dyskinesia have been studied. Substitution of chlorpromazine, thioridazine, clozapine, melperone, or fluphenazine for the daily haloperidol administration temporarily reduced the signs of tardive dyskinesia. In a monkey with low-grade symptoms, persisting for more than 100 days after with-drawal of haloperidol, neuroleptic drugs induced a typical sequence of events: first the dyskinetic movements were abolished, but 1–3 days after administration of a single dose of a neuroleptic drug there was a rebound worsening of symptoms. It was noticed that this aggravation of symptoms corresponded in magnitude and duration to the approximate liability of each compound to induce tardive dyskinesia in man. It is therefore suggested that this animal model could be used to monitor neurological side effects in neuroleptic drugs.