Prolactin responses to haloperidol in drug-free and treated schizophrenic patients

Summary The prolactin response to 5 mg haloperidol i.m. was studied in 12 schizophrenic patients in a drug-free state and after a month treatment with haloperidol, as a possible index of dopamine receptor sensitivity and occupancy. Blood samples were taken at times 0, 60, 90 and 120 minutes. The increase in PRL observed in the drug-free state disappeared after drug treatment. The PRL plasma levels after treatment with 60 mg haloperidol per os were higher than the maximal PRL responses after 5 mg i.m. The increases in baseline PRL caused by the treatment correlated positively to the reduction in the BPRS score. The test was also performed in a group of 11 patients chronically treated with haloperidol during a daily dose of 60 mg, and 15 days after reduction of the dose to 30 mg. PRL increases after 5 mg haloperidol i.m. were observed only after reduction of the dose. It is suggested that the prolactin response to haloperidol is an index of the occupancy of receptors that are involved in the PRL releasing mechanisms, and could be used to verify their blockade by the neuroleptics, especially in patients that do not respond positively to drug treatment.     

Evolution of plasma homovanillic acid (HVA) in chronic schizophrenic patients treated with haloperidol

In a 4-week study of 14 drug-free schizophrenic patients (according to DSM-III-R), free and conjugated fractions of plasma homovanillic acid (pHVA) were repeatedly measured. Free HVA levels decreased during the first 2 h of haloperidol intake (P<0.03). Conjugated HVA levels slowly decreased during the following weeks (P<0.05), while free HVA levels remained stable. After 4 weeks, free HVA levels remained unchanged 2 h after morning haloperidol intake, but conjugated HVA levels tended to increase. In haloperidol responders, at baseline the free/total HVA ratio was significantly higher than that in non-responders (P<0.01). Tolerant patients, i.e. those whose post-treatment free HVA levels decreased below pre-treatment levels, were not found to respond better to haloperidol than non-tolerant patients. The balance between free and conjugated pHVA may be a better reflection of the action of haloperidol than free pHVA levels and it may be of prognostic value in terms of drug response.     

19F-magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate

Haloperidol decanoate is widely used in the maintenance treatment of schizophrenia and other psychotic disorders, but knowledge concerning its pharmacokinetics at the injected region is very limited. Because the chemical structure of haloperidol contains fluorine, in vivo 19F-magnetic resonance (MR) spectroscopy (repetition time (TR) = 1 s) and chemical shift imaging (CSI; TR = 1 s, pixel size = 15 x 15 mm) were performed in schizophrenic patients who were treated with haloperidol decanoate (three men and one woman) to measure its diachronic change at the injection point and visualize its local distribution after intramuscular injection. 19F signals (T1 time = 365 ms) were obtained at the haloperidol decanoate-injected region. The decrease rate of the signal-to-noise ratio (SNR) by 19F-MR spectroscopy seemed large in comparison with that of the plasma haloperidol concentration. The distribution was clearly visualized by 19F-CSI for a few days after the injection, but after 1 week could no longer be seen. Although the slow-release characteristics of depot neuroleptics have been explained by the slow diffusion of esterified neuroleptics from the oil vehicle, this result may suggest that there are other mechanisms involved in maintaining the plasma haloperidol concentration. In vivo 19F-MR spectroscopy and CSI are potentially applicable for the pharmacokinetic analysis of haloperidol and other drugs containing fluorine in their structure.     

帕利哌酮与氟哌啶醇治疗精神分裂症患者的随机对照研究

目的:探讨帕利哌酮缓释片对急性期精神分裂症患者精神病性症状、认知功能、生活质量及社会功能改善作用。方法:以开放、随机的方法将60例门诊急性期精神分裂症患者分为两组,分别给予帕利哌酮和氟哌啶醇治疗,疗程16周。分别于治疗前及治疗8、12、16周采用阳性与阴性症状量表(PANSS)评估精神症状,采用威斯康星卡片分类测验(WCST)、持续性操作测验(CPT)、成人韦氏智力量表(WAIS)中的数字广度测验评估认知功能,采用生活质量和满意度自评问卷(Q-LES-Q)评估生活质量,采用个人和社会功能量表(PSP)评估社会功能;并进行组间比较。结果:治疗后两组各时点PANSS评分明显低于治疗前(P均0.01),两组间比较差异无统计学意义。治疗后帕利哌酮组WCST、CPT成绩明显好于治疗前及氟哌啶醇组(P0.05或P0.01);Q-LES-Q评分较治疗前明显提高(F=8.71,P0.01),且治疗第12及16周时明显高于氟哌啶醇组(t=2.58,2.84;P均0.01)。治疗后两组PSP评分明显高于治疗前,且帕利哌酮组明显高于氟哌啶醇组(P0.05或P0.01)。结论:帕利哌酮和氟哌啶醇对精神分裂症急性期精神症状的改善作用相当,但帕利哌酮对患者的认知功能、生活质量及社会功能也有较好的改善作用。     

Measurement of haloperidol reductase activity in red blood cells and reduced haloperidol/ haloperidol ratios in plasma in oriental psychiatric patients

Shibaski Morikazu, Toshiyuki Someya, Tadafumi Kato, Toshifumi Noguchi, Nobuya Ishida and Saburo Takahashi: Measurement of Haloperidol Reductase Activity in Red Blood Cells and Reduced Haloperidol/ Haloperidol Ratios in Plasma in Oriental Psychiatric Patients. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, : 941–947.

1. 1. The authors established a method for measuring haloperidol (HAL) reductase activity in human red blood cells.

2. 2. Characteristics of the HAL reductase in red blood cells were examined. This enzyme reaction was NADPH dependent, and the optimum pH was at 8.2–8.9. Vmax and Km were calculated as 25–150 pmol/hr/10⁶RBC and 160–2600 μM respectively.

3. 3. HAL reductase activities in red blood cells from 14 patients treated with HAL were in a range of 9.7–20.8 pmol/hr/10⁶ RBC. So far we did not find any significant correlation between HAL reductase activities and reduced HAL/HAL ratios in plasma.

Prolactin secretion in response to haloperidol challenge in delusional (psychotic) and non-delusional depression

Certain studies on measures related to central neurotransmitter activity have demonstrated that in delusional (psychotic) depression there is a dopaminergic dysregulation which distinguishes it from non-psychotic depression. A neuroendocrinologic method to check the degree of DA receptor responsivity is by measuring the prolactin responses to acute intramuscular administration of haloperidol. We studied this possibility by applying the haloperidol test in seven delusional and ten non-delusional depressed patients. All patients met DSM-IV criteria for a major depressive episode, single or recurrent, with or without psychotic features. After a three-week washout period, 5 mg of haloperidol were injected i.m. and blood samples were taken at 0, 30, 60, 90 and 120 minutes. In both trials, significant time effects were observed (elevated prolactin levels, F = 11.36, P = 0.000). However, the prolactin responses to haloperidol did not differ significantly between the two patient groups (F = 0.12, P = 0.97). These data do not show a difference in D(2) receptor responsivity, at least at the hypothalamus-pituitary level, between psychotic and non-psychotic depression.     

Clinical implications of determination of plasma haloperidol levels

The aim of this study was to analyze the clinical utility of monitoring plasma levels, since the utility of monitoring is not yet well established. After a washout period, 30 schizophrenic patients were given fixed doses of haloperidol for 3 weeks. A U-shaped second-grade polynomic relationship (R = 0.69) was found between steady state of haloperidol and percentage improvement in total score on the Brief Psychiatric Rating Scale. The interval of effective concentrations was between 12 and 59 ng/ml. Fourteen of the 15 patients who had a steady state of haloperidol within that therapeutic interval were responders: only 5 out of the 15 patients below the therapeutic interval were responders. None of the 5 patients who had concentrations below 8 ng/ml was a responder. Furthermore, responder patients showed a steady-state level of haloperidol significantly higher than that of nonresponders. These data suggest that plasma levels of haloperidol are predictors of therapeutic response in schizophrenic disorders.     

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50例,氟哌啶醇组48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:阿立哌唑是一有效安全的抗精神病药。     

Reduced haloperidol in the post-mortem brains of haloperidol-treated patients

We measured the concentrations of haloperidol and its reduced alcohol metabolite in human post-mortem tissues with high-performance/liquid chromatography using electrochemical detection. Both haloperidol and reduced haloperidol were detected and quantified in the occipital cortex of nine schizophrenic patients with a history of haloperidol treatment, but not in six samples from nontreated subjects. Reduced haloperidol concentrations were below the detection limit of the assay in several tissues of rats and mice even after 10 days of haloperidol treatment. The results suggest that reduced haloperidol is present in the brains of haloperidol-treated patients at slightly higher concentrations than haloperidol itself. Further studies are warranted to establish the possible biological importance of this haloperidol metabolite.     

利培酮对精神分裂症患者生活质量的影响

目的：比较利培酮与氟哌啶醇对精神分裂症患者生活质量的影响。方法：对门诊72例服用氟哌啶醇及74例服用利培酮的精神分裂症患者用生活质量综合评定问卷（GQOLI）、阳性与阴性症状量表（PANSS）、副反应量表（TESS）进行评定。结果：利培酮组患者治疗后生活质量有所提高,而氟哌啶醇组患者生活质量有所下降。结论：利培酮治疗有利于患者提高生活质量。     

Effects of haloperidol on antioxidant defense system enzymes in schizophrenia

Dysregulation of free radical metabolism as reflected by abnormal erythrocyte activities of three critical enzymes of the antioxidant defense system (AODS), i.e. superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), has been reported in schizophrenic patients. The present study examined the effects of haloperidol, a standard antipsychotic agent, on the AODS enzymes, using a within-subject, repeated-measures, on–off haloperidol treatment design. The mean drug free period was 40 days. At baseline, there were no significant differences for all three enzymes between patients and age and sex-matched normal volunteers. During the drug-free condition, SOD activity, but not GSH-Px and CAT activities, was significantly higher relative to normal control subjects. However, within-subjects both SOD and GSH-Px activities, but not CAT activity, were higher in the drug-free condition compared to the treatment condition. No significant correlation was observed between SOD activity and plasma haloperidol (or daily haloperidol dose) levels. Smoking status, as assessed by the cotinine level, was unrelated to enzyme activities. In addition, none of the major AODS enzymes showed significant differences between relapsed and clinically stable patients. These findings suggest that haloperidol may not have direct regulatory effect on AODS enzyme activities and that SOD and GSH-Px activities may change in response to other factors such as change in symptom severity.     

Dopamine receptor sensitivity in the hypothalamus of chronic schizophrenics after haloperidol therapy: Growth hormone and prolactin response to stimuli

(1) The present investigation deals with a study of the hypothalamic dopamine-receptor sensitivity in schizophrenics, before and after haloperidol therapy, examined by investigation of basal GH and PRL levels and responses to an l-DOPA stimulation test. (2) Ten chronic schizophrenics, 8 males and 2 females, aged 27–53 yr, with a duration of illness from 4 to 32 yr, were studied after they were off therapy for at least 10 days. (3) The l-DOPA stimulation test was done at the beginning of the study and again 3 and 6 days after withdrawal of haloperidol which had been administered in increasing doses from 5 to 10 mg a day for 30 days. l-DOPA was given orally at a dose of 500 mg plus carbidopa 100 mg. (4) Patients were tested psychologically before and after haloperidol therapy by the Asberg Psychopathological Rating Scale and typed genetically for the HLA-SD system. (5) Basal prolactin levels before and after haloperidol therapy were low. GH secretion in response to l-DOPA was normal before haloperidol therapy. (6) After treatment the patients could be divided into two groups according to the HLA types; one group showing an increased response to the stimuli as compared with the other. The data are correlated with the psychological effectiveness of the therapy.     

A double-blind comparison of raclopride and haloperidol in the acute phase of schizophrenia

This is the first comparative double-blind study of raclopride. Ninety-one patients with acute schizophrenia received either raclopride 2-8 mg twice daily or haloperidol 5-20 mg twice daily for 4 weeks. Both neuroleptics produced clinical improvements. There were no significant between-drug differences in overall efficacy measurements as assessed by the schizophrenia change sub-scale of the Comprehensive Psychopathological Rating Scale and the Krawiecka (Manchester) Rating Scale. Assessment by the Clinical Global Impression scale found haloperidol to be more effective. There were significantly fewer extrapyramidal symptoms with raclopride and a significantly lower incidence of acute dystonia. The results suggest that raclopride has an antipsychotic effect with a low incidence of extrapyramidal side effects.     

Prolactin studies in normals: implications for clinical research

Dopaminergic (DA) transmission is a major regulator of pituitary prolactin (PRL) secretion. Strategies to assess abnormalities of DA regulation in mental illness have thus included comparisons of patients' and normals' serum PRL levels before and after the administration of DA agonists and antagonists. These clinical research strategies suffer from a number of shortcomings. There is a wide interindividual variability of normal basal PRL levels, and intraindividual variability has been little studied. Large interindividual variability of PRL responses to DA antagonist challenges has also been observed in normals and reported to be strongly correlated to variation in serum levels of the challenge drug. Assessment of DA agonist challenges is hampered by the fact that low basal levels of serum PRL make suppression difficult to measure; a further problem is the confounding effect of nausea when these drugs are given in high doses. In this study of normals, individual basal serum PRL levels were found to be stable over a mean period of 10 months, with interindividual variance vastly greater than intraindividual variance. Thus, state alterations in mental illness may best be studied using a longitudinal design for measurements of PRL levels in patients, thereby avoiding confounding interindividual variability. Moreover, it appears that alterations of PRL levels between groups or within patients, even though within the normal range, may have individual physiological significance. A study of the PRL responses to haloperidol (hal) and hal + apomorphine (apo) challenges in normals revealed a strong correlation despite a highly significant 51% reduction in PRL response with the addition of apo. Because this correlation is dependent upon a normal or limited range of DA regulation, the study of these two responses in abnormal populations may be more revealing of DA abnormalities than the study of PRL responses to single DA agonist or antagonist challenges.     

Prolactin response to low-dose haloperidol challenge in schizophrenic, non-schizophrenic psychotic, and control subjects

Haloperidol was administered IV to 46 male psychotic inpatients and 28 male control subjects. A two-way analysis of covariance, with age as the covariate, revealed that DSM-III schizophrenics (n = 27) had a lower prolactin response to haloperidol than did the controls (n = 28). There were no significant differences between the prolactin responses in schizophrenics, patients with affective disorders (n = 7), and those with other psychoses (n = 12), which included patients with paranoia, schizophreniform, schizoaffective disorder, and atypical psychoses. These findings support the proposition that tuberoinfundibular dopaminergic dysfunction may occur in certain patients with DSM-III schizophrenia.     

Slower theta activity over the midfrontal cortex in schizophrenic patients

Disturbances of the topographical distribution of theta activity in the EEG spectra before and during voluntary movements were investigated in 31 neuroleptic-treated and in 13 untreated schizophrenics and matched controls as well as in 15 normals medicated with haloperidol. All 4 groups demonstrated similar topographical distribution of theta mean power density, with highest values over the midfrontal region. In the center frequency of the theta band, however, treated and untreated schizophrenics had lower values over the midfrontal region than at parietal electrodes. In controls and normals medicated with haloperidol, this frontoparietal "gradient" demonstrated the inverse picture, with highest values at the frontal midline electrode. Patients and controls differed significantly in this gradient. The slower theta activity over the midfrontal cortex in the schizophrenic patients is related to the hypofrontality hypothesis.     

氟哌啶醇治疗精神分裂症的增效作用

目的:评价奎硫平合并氟哌啶醇治疗精神分裂症的疗效与不良反应。方法:对110例单纯口服奎硫平的精神分裂症患者疗效不佳者合并氟哌啶醇治疗12周。用阳性症状和阴性症状量表(PANSS)评定疗效,用UKU不良反应评定量表评定不良反应。结果:治疗12周末PANSS量表总分及各分量表评分较治疗前均有显著下降(P<0.05或P<0.01);有效率达71.82%;不良反应无明显增加(P>0.05)。结论:奎硫平合并氟哌啶醇治疗精神分裂症疗效肯定,不良反应较轻。     

Clonazepam/haloperidol combination therapy in schizophrenia: A double blind study

Clonazepam (CLN), a benzodiazepine originally used as an antiepileptic, was tested in schizophrenia in a double blind comparison in combination with haloperidol (HL). Twenty-four schizophrenic inpatients, diagnosed according to DSM III were treated with HL and CLN (Group 1) or HL and placebo (Group 2) for 4 weeks. The Brief Psychiatric Rating Scale (BPRS) and the Extrapyramidal Side Effect Scale (EPSE) were used for assessing psychopathological features and extrapyramidal side-effects before treatment and then weekly. No differences in specific schizophrenic symptoms were detected between the two groups, but in Group 1 an early significant BPRS amelioration was noticed compared to Group 2. Moreover, the excitement item improved significantly in Group 1 only, from the second week. Less severe EPSE scores were observed in Group 1 in comparison to Group 2. In conclusion the combination of CLN and HL seems to be preferred to HL alone in cases of psychotic excitement and in order to reduce the severity of extrapyramidal side-effects.     

Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double-blind comparative study.

Forty-four chronic schizophrenic inpatients participated in this multicentre 12-week parallel-group double-blind trial. After a run-in period of 2 weeks and a single-blind placebo wash-out of 1 week, they were randomly assigned to treatment with either the serotonin2 and dopamine-D2 antagonist risperidone or haloperidol. Two patients were excluded from the efficacy analysis. Five patients dropped out in the haloperidol group and 1 in the risperidone group. At the end of the trial, the mean daily dose was 12 mg for risperidone and 10 mg for haloperidol. The risperidone group showed greater improvement on the Positive and Negative Syndrome Scale for Schizophrenia, the Schedule for Affective Disorders and Schizophrenia-change version, and the Nurses' Observation Scale for Inpatient Evaluation. The improvement of negative symptoms was more pronounced in the risperidone group until week 8 of double-blind treatment. The consumption of antiparkinsonian medication was 10 times lower with risperidone. Both drugs were well tolerated and the laboratory, endocrinological and cardiovascular safety parameters were comparable. This study suggests that risperidone is comparable to haloperidol as an antipsychotic, but that it has a safer EPS profile.     

Haloperidol and lithium carbonate treatment did not influence serum immunoglobulin levels in schizophrenic and affective patients

Serum immunoglobulin levels were studied in 153 psychiatric patients (87 schizophrenic, 48 bipolar and 18 unipolar patients), and 35 healthy controls. Psychotropic treatments (haloperidol in the schizophrenic patients and lithium in the bipolar affective patients) did not alter serum immunoglobulin levels. Decreased mean IgM serum level was detected in the major affective patients (unipolar and bipolar) compared with normal controls. Nonspecific environmental, infectious, autoimmune and emotional factors that can play a role in the alterations obtained in psychiatric patients are discussed.