Reduced haloperidol plasma concentration and clinical response in acute exacerbations of schizophrenia

Twenty-nine hospitalized patients suffering acute exacerbations of schizophrenia were treated for 2 weeks with fixed daily oral doses of haloperidol prospectively calculated to achieve a haloperidol plasma concentration of either 8–18 ng/ml or 25–35 ng/ml. Reduced haloperidol as well as haloperidol concentrations were assayed to determine if the former enhanced the predictability of response. Week 2 haloperidol plasma concentrations were negatively correlated to clinical response as measured by the percentage change in the BPRS score from baseline (r=–0.43,P<0.05). In contrast, week 2 plasma concentrations of reduced haloperidol, total haloperidol (haloperidol+reduced haloperidol), and reduced haloperidol/haloperidol ratio did not correlate with the change in the BPRS score. Chi-square analysis concluded that patients with ratios greater than one were no less likely to be treatment responders (<25% improvement in BPRS from baseline and week 2 BPRS <55) than those with ratios less than one. Although these data lend additional support to reports of a curvilinear relationship between haloperidol plasma concentration and clinical response, they also suggest that reduced haloperidol plasma concentrations are of no value in predicting treatment response.From the Mental Health Research Center — Major Psychoses, funded in part by NIMH Grant #5 P50 MH43271     

Serum level monitoring and therapeutic effect of haloperidol in schizophrenic patients

Haloperidol serum concentrations were determined after IM or oral treatment in 15 schizophrenic patients. No correlation was found between drug levels and therapeutic effect. However, a good relationship was found between the half-life calculated after the first IM injection and the BPRS decrease after 3 weeks. Therefore a serum level study on the first day may forecast the therapeutic response.     

阿立哌唑与氟哌啶醇治疗精神分裂症对照研究

目的评价阿立哌唑与氟哌啶醇治疗精神分裂症的疗效及安全性。方法阿立哌唑组35例,氟哌啶醇组36例,以阳性与阴性症状量表（PANSS）、临床疗效总评量表疾病严重程度（CGI—SI）、治疗中出现的症状量表（TESS）、锥体外系反应量表（RSESE）评定疗效及不良反应。疗程6周。结果两组疗效相仿。阿立哌唑组PANSS阴性症状因子减分在治疗后4周及6周显著优于氟哌啶醇组。阿立哌唑组不良反应显著较少。结论阿立哌唑是一种有效安全的抗精神病药。     

齐拉西酮与氟哌啶醇治疗精神分裂症对照研究

目的：探讨齐拉西酮治疗精神分裂症的疗效及不良反应。方法：将符合入组标准的100例精神分裂症患者随机分为齐拉西酮组与氟哌啶醇组各50例。进行为期8周的治疗。采用阳性与阴性症状量表（PANSS）评定疗效、副反应量表CRESS）评定副反应。结果：氟哌啶醇组有效率为74％,显效率为38％;齐拉西酮组有效率为84％,显效率为72％。两组药物显效率比较,差异有统计学意义（P〈0．01）;阳性与阴性症状量表评分,两组治疗第4周末起总分及各因子分与治疗前比较,差异有统计学意义（P均〈0．01）。结论：该两种药物对精神分裂症均有确切疗效,且安全性相对较高,齐拉西酮对症状的改善效果更好,不良反应轻微。     

Effects of haloperidol treatment on prolactin response to D-fenfluramine challenge in acute schizophrenia

We have previously described an association between higher serotonin (5-HT) responsivity, indexed by prolactin response to D-fenfluramine challenge, and poorer treatment response to haloperidol in non-medicated schizophrenics. The aim of the present study was to investigate the effects of antidopaminergic treatment on the prolactin response in the repeated challenge test. D-Fenfluramine was administered to 22 young, acutely ill schizophrenics (11 females and 11 males) after 4 weeks of haloperidol treatment. Whereas neuroleptic administration significantly raised basal prolactin levels (P <0.0001), subsequent D-fenfluramine challenge produced an additional significant increase (P <0.001). Moreover, the magnitude of this increase was not different from the pretreatment response. Our results demonstrate that prolactin response to the challenge is mediated through the 5-HT system. An observed negative association between posttreatment prolactin response and therapeutic response to haloperidol did not reach statistical significance. Received: 4 May 1998/Final version: 7 July 1998     

Disposition of haloperidol and reduced haloperidol plasma levels after single dose haloperidol decanoate administration

A single dose of haloperidol decanoate 100 mg was administered to 15 schizophrenic patients. Blood samples were obtained prior to injection, 1 h, 3 h, 6 h, 8 h, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks and four weeks post-injection. Haloperidol and its reduced metabolite, reduced haloperidol, plasma levels were assayed by HPLC with electrochemical detection. The pharmacokinetic parameters of haloperidol were determined. The mean time of maximal (T_max) plasma levels for haloperidol was 5·73 ± 0·80 days. The haloperidol plasma levels showed a biexponential decline with an elimination half-life of 15·78 ± 5·90 days. Reduced haloperidol was rapidly formed from the haloperidol. The T_max of reduced haloperidol was 7·00 ± 2·35 days. The mean ratio reduced haloperidol/haloperidol was 0·155 ± 0·111. Since the T_max occurs at approximately six days, a weekly loading dose of haloperidol decanoate is feasible during the transition from oral to depot therapy.     

The plasma haloperidol and reduced haloperidol concentrations in chinese schizophrenic patients: Relationship between reduced haloperidol/haloperidol ratio and red blood cell haloperidol reductase activity

Fifteen chinese schizophrenic patients were given titrated doses of haloperidol (0.05-0.42 mg/kg) for two weeks. All these 15 patients were in clinical remission on maintenance dose of haloperidol. The mean plasma haloperidol and reduced haloperidol concentrations were 16.8 ± 4.8 ng/ml and 13.6- 5.7 ng/ml respectively. The plasma RHAL/HAL ratio was in the range of 0.13±1.94. These values were similar to that reported for the Japanese population. The frequency distribution appeared to be bimodal. RBC reductase activity were found to be distributed normally and no correlation was found between plasma RHAL/HAL ratio and RBC reductase activity.     

High dosage haloperidol therapy in chronic schizophrenic patients: A double-blind study of clinical response,side effects,serum haloperidol,and serum prolactin

In a 12-weeks double-blind study high dosage versus standard dosage haloperidol therapy was evaluated in 23 male, chronic schizophrenic inpatients. The patients were relatively treatment-resistant and, in spite of traditional neuroleptic medication, were characterized by a moderate to severe degree of illness. At the end of the trial the dose of haloperidol in the standard dosage group was 12–36 mg/day (mean 15), in the high dosage group 10–240 mg/day (mean 103). No significant difference in therapeutic effect was found between the two groups as measured by the Brief Psychiatric Rating Scale and global assessment. About half the patients in both groups improved during the trial. A greater incidence of side effects was noticed in the high dosage group than in the standard group, especially in the form of sedation (5 of 12 patients), aggressive episodes (three patients), muscular weakness and tendency to fall (two patients), and epileptic attacks (one patient). The incidence of extrapyramidal phenomena showed fewer differences between the two groups. In addition, the high dosage group showed a temporary rise in serum alkaline phosphatase and serum aspartate-aminotransferase. There was a positive correlation between the dose of haloperidol and serum haloperidol, and between the haloperidol dose of up to 80 mg/day and serum prolactin. At higher doses prolactin response leveled off. Neither serum haloperidol nor serum prolactin showed any correlation to clinical response. It is concluded (1) that very high doses of haloperidol in only a few cases show any therapeutic advantage over haloperidol in standard doses; (2) that high dosage treatment has a higher incidence of side effects; and (3) that the serum concentrations of a given neuroleptic and of prolactin are of very limited value in the monitoring of neuroleptic treatment.     

齐拉西酮注射液治疗精神分裂症激越症状的研究

目的本研究应用氟哌啶醇注射液作为对照,评价齐拉西酮注射液治疗精神分裂症激越患者的疗效、安全性和耐受性。方法连续入组急性精神分裂症患者,按照1：1的比例随机分配到齐拉西酮注射液治疗组（试验组）和氟哌啶醇注射液治疗组（对照组）,对患者进行筛选访视、基线访视,以及肌注治疗第一剂药后的2、4、24、48h和72h的访视。采用简明精神评定量表（BPRS）评价主要疗效,Simpson-Angus量表评定药物的锥体外系反应。结果两组均纳入受试者30例。药物治疗72h后与基线比较,试验组BPRS总分减分平均为12.55±6.88,对照组BPRS总分减分平均为15.60±5.94。两组主要疗效指标差异无统计学意义（P=0.110）。试验组未见锥体外系不良反应,Simpson-Angus量表评分在治疗前后差异无统计学意义（P=0.16）;对照组出现锥体外系不良反应,治疗前后差异有统计学意义（P=0.02）。结论甲磺酸齐拉西酮注射液能够快速有效控制精神分裂症急性激越症状,疗效与氟哌啶醇注射液相当,不良反应轻微,安全性、耐受性好,值得临床推广应用。     

Determination of haloperidol and reduced haloperidol in the plasma and blood of patients on depot haloperidol

We developed a sensitive HPLC assay to measure haloperidol (HA) and its metabolite, reduced haloperidol (RH), in plasma and whole blood. The conditions under which HA might be converted to RH during collection and analysis of blood were examined. Provided the blood was kept at 0° C, erythrocyte ketone reductase activity was insignificant. The solid phase extraction method did not generate RH. We studied ten patients taking 25–400 mg/month of HA decanoate and one patient for 4 weeks after the daily oral dose of 120 mg HA was ceased. In the patients on depot HA, the plasma and blood concentrations of HA were not significantly different (P>0.1). For the first time, RH was detected in plasma patients on depot drug, but only in three cases. In contrast, RH was present in the blood of eight of these patients. The accumulation of RH in red blood cells was also evident in the patient on oral HA, in whom the mean ratio of RH concentrations in whole blood to plasma was 3.6±1.1. Plasma concentrations of HA correlated highly with total neuroleptic activity measured by a radioreceptor assay. Compared to plasma, analysis of concentrations of HA and RH in blood has the advantages of greater sensitivity, of using smaller volumes of blood and of avoiding the efflux of HA and RH during separation of plasma and red cells.     

Serum and CSF levels of haloperidol by radioimmunoassay and radioreceptor assay during high-dose therapy of resistant schizophrenic patients

Serum and cerebrospinal fluid (CSF) levels of haloperidol were measured in 12 chronic neuroleptic-non-responsive schizophrenic patients after 1 month on 60 mg haloperidol daily and then again after 1 month on 120 mg haloperidol daily. Serum haloperidol and CSF haloperidol rose with increasing dose. Serum and CSF levels were significantly correlated. No clinical improvement was achieved despite the high serum and CSF drug levels.     

Inhibition of monoamine oxidases by haloperidol and its metabolites: pharmacological implications for the chemotherapy of schizophrenia

The effect of haloperidol and its metabolites on human platelet monoamine oxidase B (MAO-B) and human placenta monoamine oxidase A (MAO-A) in vitro has been investigated. We found that 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP⁺), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HTP) and 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP) are potent inhibitors of MAO. HP⁺ appeared to be a reversible, uncompetitive and selective MAO-B inhibitor with a Ki of 0.83 µM. HTP was found to be an irreversible, uncompetitive and selective MAO-B inhibitor (Ki of 1.84 µM). CPTP inhibits both MAO-A and MAO-B. Some other haloperidol metabolites, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine N-oxide (HTPNO) and reduced haloperidol (RHAL), do not inhibit MAO to any appreciable degree at concentrations up to 100 µM. The results suggest that haloperidol metabolites may contribute to the reduction of platelet MAO-B activity in schizophrenic patients undergoing neuroleptic chemotherapy. An examination of the literature reveals that schizophrenic patients with low platelet MAO activity exhibit a strong association with the use of haloperidol. Other possible pharmacological implications of the inhibition of MAO activity are discussed.     

氟哌啶醇联合用药治疗儿童抽动障碍及精神分裂症的研究进展

氟哌啶醇为一种重要的抗精神分裂药,临床上用于治疗精神疾病引起的行为冲动和焦虑等症状,但单独使用该药物治疗的总有效率较低,与其他类型药物联合用于精神疾病的治疗往往具有更好的疗效和安全性。本文就近年来关于氟哌啶醇联合用药治疗儿童抽动障碍及精神分裂症的情况进行综述,探讨氟哌啶醇联合用药用于儿童抽动障碍及精神分裂症方面的研究进展,为临床用药提供参考依据。     

Addition of lithium to haloperidol in non-affective,antipsychotic non-responsive schizophrenia: a double blind,placebo controlled,parallel design clinical trial

This double-blind placebo controlled, parallel design clinical trial compared the therapeutic effects of the addition of lithium or placebo to haloperidol in 21 seriously ill state hospital patients with DSM-III-R schizophrenia, who did not have concurrent affective disorders and who had not responded to previous trials of conventional antipsychotic medication. During a baseline period of 6 weeks, patients were switched to a stable dose of haloperidol (mean ± SD dose=13.6±8.1 mg/day). Patients were then randomized to receive either lithium or placebo in addition to haloperidol for 8 weeks (mean ± SD lithium level =0.98±0.13 mEq/1). Symptoms and side effects were assessed weekly. Improvement in symptoms correlated with the non-blind adjustment of antipsychotic dose, but not with lithium or placebo treatment. Side effects ratings did not differ between the two groups, but one patient developed a reversible delirium associated with combined lithium/haloperidol treatment. For these long-term, severely ill patients, combined treatment afforded no advantage over treatment with haloperidol alone.Supported by Grant MH 46700 from the National Institute for Mental Health. Lithium and lithium placebo capsules were supplied by Lilly Pharmaceuticals     

Sleeplessness in acute and chronic schizophrenia — Response to haloperidol and anti-Parkinsonism agents

Ten acute and seven chronic schizophrenics were longitudinally investigated in two separate double-blind studies. In both studies, after a washout and settling in period of two or more weeks, the patients were placed on placebo for about a month and then on individualized dosages of haloperidol for four months. During the haloperidol periods, the acute patients received two three-week courses of benztropine and the chronic patients, a single two-week course of trihexyphenidyl. The anti-Parkinsonism drugs were given non-blind. Nine times every night, the patients were rated for sleeplessness, and once every week they were rated for psychopathology.The results indicated that marked, predominantly early night sleeplessness was present in the patients studied. The acute subjects were more sleepless than the chronics but the pattern of sleeplessness was similar. The degree of sleeplessness seemed related to total psychopathology, hallucinations and thought disorder. No relationship was found with affective symptoms. Haloperidol reduced sleeplessness promptly and had the effect of normalizing sleep in these patients. Concurrently used anti-Parkinsonism medication seemed to have the opposite effect in chronic patients. These data did not support the notion that haloperidol was a stimulating neuroleptic, and the general distinction made between activating and sedative neuroleptics was questioned. It was suggested that the stimulating effect noticed with some neuroleptics may be attributable to the anti-Parkinsonism drugs often used with them.     

Procedural learning in schizophrenia after 6 months of double-blind treatment with olanzapine,risperidone, and haloperidol

Rationale First generation antipsychotics induce extrapyramidal motor symptoms (EPS), presumably through dopamine D₂ receptor blockade at the dorsal striatum. This may also produce impairment of cognitive processes, such as procedural learning, that are dependent on this region. Haloperidol and, to a lesser extent, risperidone, are active in the dorsal striatum and may induce EPS and impairment of procedural learning. In contrast, the prototypical second-generation antipsychotic, clozapine, is less active in the dorsal striatum and does not induce EPS or impair procedural learning. Olanzapine is pharmacologically similar to clozapine and has a low incidence of EPS induction.Objectives To assess the hypothesis that olanzapine would not have a deleterious effect on procedural learning.Methods Thirty-nine subjects with early phase schizophrenia were randomly assigned to double blind treatment with haloperidol, risperidone, or olanzapine. They were administered the Tower of Toronto test at an unmedicated baseline and again following 6 weeks and 6 months of treatment.Results Procedural learning, defined as the improvement observed between two blocks of five trials of the Tower of Toronto, was preserved after 6 weeks of all three treatments but showed a substantial decline after 6 months of treatment with haloperidol or risperidone.Conclusions These data are consistent with the differential activity of the three medications in dorsal striatum structures and suggest that the advantages of olanzapine over haloperidol and risperidone in relation to extrapyramidal syndromes may also generalize to procedural learning. The results also suggest that the procedural learning disadvantages of haloperidol and risperidone accrue slowly but are apparent after 6 months of treatment.A preliminary draft of this paper was presented at the 29th Annual Meeting of the International Neuropsychological Society, Chicago, February 14–18, 2001; and the 5th Biennial Mt Sinai Conference on Cognition in Schizophrenia, Whistler, BC, April 28 to May 2, 2001     

精神分裂症治疗前后单胺类神经递质分析及疗效评定

目的观察精神分裂症患者治疗前后血浆中单胺类神经递质含量变化及与疗效的相关性。方法采用放免法测定85例精神分裂症患者治疗前后血浆多巴胺(DA)、5-羟色胺(5-HT)、去甲肾上腺素(NE)和生长激素(GH)含量及简明精神病量表(BPRS)的减分率来评定疗效。结果治疗前后5-HT含量分别为(84.93±68.13)和(94.33±68.84)mmol/L,DA(34.14±10.24)和(32.89±9.63)mmol/L,NE(67.94±82.84)和(56.63±29.83)mmol/L,GH(3.69±10.02)和(2.28±4.20)mmol/L,前后对照均无统计学差异(P>0.05)。5-HT、DA、NE和GH含量变化与疗效无明显相关(P>0.05)。结论精神分裂症患者治疗前后血浆中单胺类神经递质未发现明显差异,与疗效是否相关需进一步细化精神症状。     

Improvement of acute exacerbations of schizophrenia with amisulpride: a comparison with haloperidol

Amisulpride is a substituted benzamide with high selectivity for dopaminergic D₂ and D₃ receptors. This study compared 800 mg/day amisulpride and 20 mg/day haloperidol in patients with acute exacerbations of schizophrenia. This multicenter, double-blind trial involved 191 patients allocated, after a 1 to 7-day wash-out period, to amisulpride (n = 95) or haloperidol (n = 96) for 6 weeks. Improvement of mean BPRS total score was 48% for amisulpride and 38% for haloperidol (NS), whereas improvement in the Negative PANSS subscale was greater in the amisulpride group (37%) compared to haloperidol (24%) (P = 0.038). CGI scores showed a higher number of responders in the amisulpride (62%) than in the haloperidol group (44%) (P = 0.014). More extrapyramidal symptoms measured with the Simpson-Angus scale were provoked in the haloperidol group (P = 0.0009). Amisulpride is at least as effective as haloperidol in the treatment of acute exacerbations of schizophrenia, and is more effective in the treatment of negative symptoms whilst causing less parkinsonism. Received: 13 December 1996/Final version: 12 March 1997     

利培酮对首发精神分裂症患者的疗效观察及与血浆催乳素水平的相关性研究

目的探讨非典型抗精神病药利培酮对首发精神分裂症患者血浆催乳素(PRL)水平的影响及其与疗效的关系。方法对30例符合CCMD-Ⅲ诊断标准的首发精神分裂症患者(治疗组) 在治疗前后及30例健康自愿者(对照组)的血浆PRL水平用放射免疫法进行检测。用利培酮治疗12 周,采用阳性和阴性症状量表(PAN SS)在治疗前后分别进行评定。结果患者组治疗前血浆PRL水平低于对照组,差异有统计学意义(P<0．05);治疗组治疗后血浆PRL水平明显高于治疗前(P< 0．01);治疗前、后在PAN SS总分及其因子分上差异均有显著性意义(P<0．05)。治疗后PRL水平较高、治疗前后差异较大或治疗前PRL水平较高者,疗效较好,尤其是阳性症状改善明显。结论利培酮治疗明显增加血浆PRL水平;且治疗前后血浆PRL水平与疗效相关,主要与阳性症状的疗效有关。