Markianos M, Hatzimanolis J, Lykouras L
Athens University Medical School, Psychiatric Clinic, Eginition Hospital, Vass. Sophias 74, 11528 Athens, Greece.
Psychopharmacology (Berl). 2001 Aug;157(1):55-9. doi: 10.1007/s002130100768.
The pharmacological profile of risperidone is that of an atypical neuroleptic regarding its serotonin 5-HT2A and dopamine D2 receptor blocking properties. Treatment with risperidone, though, results in considerably elevated plasma prolactin (PRL) levels which are not observed with other atypical neuroleptics, such as clozapine, indicating a differentiated action on receptors that are involved in PRL release, mainly dopaminergic and serotonergic.
To assess the responsivity of serotonergic and dopaminergic receptors during treatment with neuroleptics and after switch to risperidone, using neuroendocrine paradigms.
Two neuroendocrine challenge tests, measuring the PRL increases induced by acute administration of serotonergic (clomipramine, 25 mg i.v.) and dopaminergic (haloperidol, 5 mg i.m.) drugs were performed in 13 male schizophrenic patients during treatment with typical neuroleptics and, later, after 6 weeks of treatment with risperidone. The tests were also performed in a group of nine healthy male volunteers. PRL was estimated in blood samples taken every 15 min for 1 h for clomipramine and every 30 min for 2 h for haloperidol. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS).
During treatment with neuroleptics (mean dose 1354 mg chlorpromazine equivalents, range 300-2400 mg), i.m. haloperidol caused significant elevations in plasma PRL, which were totally abolished after 6 weeks treatment with risperidone (mean dose 12.1 mg/day, range 8-16 mg/day), indicating complete D2 receptor blockade. In contrast, the PRL increases obtained after clomipramine administration during neuroleptic treatment were preserved after treatment with risperidone. Both PRL response patterns to clomipramine were similar to that of healthy controls. BPRS score was 50.2+/-9.3 points during neuroleptic treatment and was reduced after risperidone to 30.1+/-6.6 points, i.e., 40% in the mean.
During treatment with typical neuroleptics, the PRL responses to clomipramine are normal, and they are preserved after switch to risperidone in doses that cause complete dopamine receptor blockade. Risperidone, a dopamine and 5-HT receptor blocker, does not affect 5-HT receptors that are involved in the PRL release by the 5-HT uptake blocker clomipramine, indicating a different behavior than other atypical neuroleptics such as clozapine or olanzapine, for which a reduction of the PRL release induced by serotonergic agents like fenfluramine or mCPP has been reported. A conclusive identification of the 5-HT receptor subtypes that are involved in this different action cannot be identified at present, but it should be taken into account that risperidone differs from clozapine, showing higher affinity for 5-HT2A than 5-HT2C receptors and lacking the marked affinity of clozapine to 5-HT1A receptors.
利培酮的药理学特征在于其作为非典型抗精神病药物，具有5-羟色胺5-HT2A和多巴胺D2受体阻断特性。然而，与其他非典型抗精神病药物（如氯氮平）不同，使用利培酮治疗会导致血浆催乳素（PRL）水平显著升高，这表明其对参与PRL释放的受体（主要是多巴胺能和5-羟色胺能受体）具有不同的作用。
采用神经内分泌范式评估使用抗精神病药物治疗期间及换用利培酮后血清素能和多巴胺能受体的反应性。
对13名男性精神分裂症患者在使用典型抗精神病药物治疗期间以及之后使用利培酮治疗6周后，进行了两项神经内分泌激发试验，分别测量静脉注射血清素能药物（氯米帕明，25mg）和肌肉注射多巴胺能药物（氟哌啶醇，5mg）后PRL的升高情况。还对一组9名健康男性志愿者进行了同样的试验。静脉注射氯米帕明后，每15分钟采集一次血样，共采集1小时；肌肉注射氟哌啶醇后，每30分钟采集一次血样，共采集2小时，以测定PRL水平。使用简明精神病评定量表（BPRS）评估精神病理学情况。
在使用抗精神病药物治疗期间（平均剂量为1354mg氯丙嗪等效物，范围为300 - 2400mg），肌肉注射氟哌啶醇可使血浆PRL显著升高，而使用利培酮治疗6周后（平均剂量为12.1mg/天，范围为8 - 16mg/天），这种升高完全消失，表明D2受体被完全阻断。相比之下，在抗精神病药物治疗期间静脉注射氯米帕明后引起的PRL升高在使用利培酮治疗后仍然存在。两种药物对氯米帕明的PRL反应模式均与健康对照组相似。在抗精神病药物治疗期间，BPRS评分为50.2±9.3分，使用利培酮后降至30.1±6.6分，平均降低了40%。
在使用典型抗精神病药物治疗期间，对氯米帕明的PRL反应正常，在换用导致多巴胺受体完全阻断的剂量的利培酮后，这种反应仍然保留。利培酮作为多巴胺和5-HT受体阻断剂，不影响5-HT摄取阻断剂氯米帕明所涉及的PRL释放中的5-HT受体，这表明其行为与其他非典型抗精神病药物（如氯氮平或奥氮平）不同，据报道，对于氯氮平或奥氮平，血清素能药物（如芬氟拉明或mCPP）诱导的PRL释放会减少。目前尚无法确定参与这种不同作用的5-HT受体亚型，但应考虑到利培酮与氯氮平不同，它对5-HT2A受体的亲和力高于5-HT2C受体，且缺乏氯氮平对5-HT1A受体的显著亲和力。
