Dopamine receptor responsivity in schizophrenic patients before and after switch from haloperidol to risperidone

The increases that occur in plasma prolactin (PRL) levels after i.m. administration of 5 mg of haloperidol (the HAL test) provide information about the responsivity of D2 dopamine receptors in the hypothalamus-hypophysis, and may be a measure of their occupancy during the neuroleptic treatment of schizophrenic patients. We studied these responses during treatment with haloperidol (doses 7.5-60 mg daily, mean = 20.6) in 12 male schizophrenic patients who did not have a satisfactory therapeutic response to the drug, and the test was repeated 6 weeks later, after the patients were switched to therapy with the atypical neuroleptic risperidone (8-16 mg daily, mean = 11.7). After the institution of risperidone treatment, the total score on the Brief Psychiatric Rating Scale (BPRS) fell by 38% (from a mean score of 47.2 to 29.3). BPRS subscale scores for positive, negative, and general symptoms were reduced by 38, 35, and 40%, respectively. Moderate PRL responses to the HAL test were found during haloperidol treatment and no responses at all during treatment with risperidone. Baseline PRL increased significantly from a mean of 35.0 (S.D. = 16.0) to a mean of 55.7 ng/ml plasma (S.D. = 19.6). This high potency of risperidone to increase PRL levels cannot be explained by the serotonergic blocking activity of the drug, and seems not to be restricted to its D2 receptor blocking capacity.     

Dopamine receptor responsivity in schizophrenic patients in a drug-free state and after treatment with olanzapine

1. Olanzapine is a novel atypical antipsychotic with affinity for a number of neurotransmitter receptors including dopamine D1, D2, D4, serotonin 5HT2A, 5HT2C, histamine H1, a1-adrenergic, and muscarinic receptors. 2. A neuroendocrinological method to check the degree of dopamine receptor blocking is by measuring the prolactin (PRL) responses to acute (i.m.) administration of haloperidol (HAL). The authors applied this test in a group of male patients with DSM-IV schizophrenia in the drug-free state. The patients were subsequently treated with olanzapine (OLZ) (mean daily dose: 22.5+/-5.8) and the test was repeated six weeks later. For the HAL-test, 5mg HAL were injected i.m. and blood samples were taken at times 0, 30, 60, 90 and 120 minutes. Fourteen patients enrolled in the study. Psychopathology was assessed by means of the Brief Psychiatric Rating Scale (BPRS). 3. Six weeks treatment with OLZ resulted in significant decreases in the total BPRS score and on the score of its subscales for positive, negative, and general psychopathology. Comparison of the PRL response patterns, after HAL administration by analysis of variance for repeated measures (ANOVAR) for drug treatment and time, revealed a highly significant time effect (F=28.98, p=0.000) and a significant treatment by time interaction (F=8.27, p=0.000008). Namely, in the drug-free state significant increases were found in the PRL levels after i.m. HAL administration which were significantly reduced during treatment with OLZ, indicating moderate receptor blockade.     

Neuroendocrine responsivities of the pituitary dopamine system in male schizophrenic patients during treatment with clozapine, olanzapine, risperidone, sulpiride, or haloperidol

Background Atypical antipsychotic drugs, in clinical doses, occupy 5-HT2 receptors near saturation, while D2 dopamine receptors, assessed usually in striatum by SPECT or PET methods, are occupied to different degrees. We hypothesized that these differences in D2 receptor occupancies may also be evaluated by a neuroendocrine approach, namely by measuring the plasma prolactin responses to i. m. administered haloperidol, since the expected elevations depend mainly on the free remaining D2 receptors in the tuberoinfundibular tract. Methods We measured the plasma prolactin levels at 0, 30, 60, 90, and 120 minutes after administration of 5 mg haloperidol i. m. in six groups of male patients with schizophrenia: a) 33 patients in a drug-free state, b) 15 patients on treatment with clozapine (range 200–600 mg/day), c) 15 patients on olanzapine (10–30 mg/day), d) 14 patients on risperidone (8–16 mg/day), e) 23 patients on haloperidol (10–40 mg/day), f) 14 patients on sulpiride (600–1600 mg/day). Data were also obtained from a group of 14 healthy male control subjects. The differences in baseline prolactin levels and in the responses to acute haloperidol of the seven groups were compared. Results The baseline prolactin levels did not differ significantly in the groups of controls (8.3±3.8 ng/ml), drug-free patients (8.0±3.6) and patients treated with clozapine (7.7±3.8), they were moderately elevated in patients treated with olanzapine (16.8±8.9), elevated in patients on haloperidol (34.4±17.3), and they were even higher in the groups of patients treated with risperidone (54.9±22.4) or sulpiride (58.8±27.0). All groups of patients gave attenuated prolactin responses to i. m. haloperidol compared to healthy controls. During treatment with haloperidol, risperidone, or sulpiride, no significant prolactin increases after i. m. haloperidol were observed. The group treated with olanzapine gave significant prolactin increases, which were lower than those obtained in the group of patients treated with clozapine, who gave responses similar to that of the drug-free patients. Conclusions Plasma prolactin levels and responses to i. m. haloperidol of patients on treatment with antipsychotic drugs, reflect the prolactin release potencies of the drugs, which are related, but not restricted, to their affinities to D2 dopamine receptors. According to the prolactin baseline levels and responses to i. m. haloperidol, the drugs of this study can be categorized for their potency to the pituitary dopamine system that controls prolactin release, as follows: sulpiride > risperidone > haloperidol > olanzapine > clozapine. This categorization is similar to that obtained by binding studies in striatal D2 dopamine receptors using brain imaging techniques. Received: 26 March 2001 / Accepted: 21 June 2001     

Changes in central serotonergic function as a correlate of duration of illness in paranoid schizophrenia

There is evidence that the duration of untreated psychosis may affect both the course and outcome of treatment in schizophrenic patients. In the present study, we used neuroendocrine probes to test the hypothesis that untreated psychosis may induce time-dependent changes in central serotonergic and dopaminergic neurotransmission. Prolactin responses to the administration of clomipramine (i.v.) and haloperidol (i.m.) were measured in healthy control subjects and in 16 never-treated male patients with DSM-IV diagnoses of schizophreniform or schizophrenic disorders of paranoid subtype, both before and after 5 weeks of treatment with haloperidol. In the drug-free state, schizophrenic patients exhibited significantly increased prolactin responses to clomipramine administration compared with both the healthy control subjects and the schizophreniform patients. Maximum prolactin responses to clomipramine in the total group of patients were positively correlated with the duration of psychotic illness and negatively correlated with changes in Positive and Negative Syndrome Scale (PANSS) total, negative symptoms and general psychopathology scores after 5 weeks of treatment with haloperidol. Prolactin responses to haloperidol challenge in the drug-free state were lower in the schizophreniform group than in the control and the schizophrenic groups, but the differences did not reach statistical significance. The results provide evidence that the persistence of psychotic psychopathology induces secondary neuroadaptive effects, which seem to involve changes in central serotonergic function.     

Increased dopamine d(2) receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine

OBJECTIVE: The authors added haloperidol, a potent D(2) blocker, to ongoing treatment with clozapine in patients with schizophrenia to determine the effects of this combination on dopamine D(2) receptor blockade, prolactin level, and extrapyramidal side effects. METHOD: At baseline and 4-8 weeks after the addition of haloperidol (4 mg/day) to ongoing clozapine treatment, five patients were examined for prolactin elevation, extrapyramidal side effects, drug plasma levels, and D(2) receptor occupancy measured with [(11)C]raclopride and positron emission tomography imaging. RESULTS: Adding haloperidol significantly increased D(2) receptor occupancy, from a mean of 55% to 79%, and significantly increased the prolactin level. One patient developed akathisia, and another manifested mild extrapyramidal side effects. CONCLUSIONS: Adding a modest dose of haloperidol to clozapine results in the high D(2) receptor occupancy and sustained prolactin elevation usually associated with typical antipsychotics. These findings suggest that the lack of prolactin elevation associated with clozapine derives mainly from low D(2) receptor occupancy and not from the medication's effects on other receptors.     

抗精神病药对老年精神分裂症患者血清催乳素的影响

目的：探讨几种抗精神病药对老年精神分裂症患者血清催乳素（PRL）的影响。方法：随机选取抗精神病药治疗老年精神分裂症患者121例,分别在治疗前后测定血清PRL水平。结果：患者经舒必利、奋乃静、氟哌啶醇和利培酮治疗后血清PRL明显升高,各药物之间以及治疗前后比较差异均有显著性（F=15．95,P〈0．01）。PRL水平的升高与药物剂量呈正相关。氯氮平对PRL水平影响不明显。结论：典型和非典型抗精神病药对老年精神分裂症患者血清PRL水平的影响同样明显,强弱的顺序依次是舒必利、奋乃静、氟哌啶醇和利培酮。     

Effects of olanzapine and haloperidol on serum prolactin levels in male schizophrenic patients

It has been proposed that new atypical antipsychotics cause minimal prolactin (PRL) elevation compared to traditional antipsychotic agents because they spare dopamine blockade within the brain's tuberoinfundibular tract. The aim of this study was to compare the effects of olanzapine and haloperidol on PRL secretion in male schizophrenic patients. Twenty-nine male schizophrenic inpatients were included in the study. Fifteen of them were given olanzapine in a fixed dose of 10 mg/day PO and 14 of them were given haloperidol in a fixed dose of 10 mg/day PO for 6 weeks after a 2-week drug washout period. Fifteen age-matched healthy control subjects were used as control group. PRL levels were measured both before and after the 6-week treatment period in the patients. At the end of the 6th week, the PRL values observed with olanzapine treatment were significantly less than those observed with haloperidol, but not different from those of the controls. There was a significant positive correlation between the PRL values and the severity of extrapyramidal side effects in only the haloperidol group after the six week's treatment period. Our data indicate that short-term olanzapine treatment at doses of 10 mg/day PO causes minimal elevations in PRL secretion in male schizophrenic patients in contrast to haloperidol. This finding is consistent with the previous reports and may be attributed to olanzapine's differential effects on dopamine neurotransmission.     

Effects of treatment with various doses of haloperidol on the pituitary-gonadal axis in male schizophrenic patients

Fifteen male paranoid schizophrenics underwent an initial 4-week therapy with haloperidol 7.5 mg/day, and a subsequent 4-week treatment with haloperidol 15 mg/day, p.o. (group I). Another 15 male paranoid schizophrenics received an initial 4-week treatment with haloperidol 30 mg/day, and a subsequent 4-week therapy with haloperidol 60 mg/day, p.o. (group II). In each group of patients, serum prolactin (PRL), luteinizing hormone (LH) and testosterone (T) levels were measured before treatment and at the end of the two consecutive periods of treatment. A dose-related increase in serum PRL levels was found in both groups of medicated patients. Serum LH levels were not significantly affected by haloperidol treatment. A significant decrease in serum T levels was detected only in group II medicated patients, i.e., in the patients who were treated with relatively high daily doses (30 or 60 mg/day) of haloperidol.     

Dopaminergic factors in human prolactin regulation: Effects of neuroleptics and dopamine

(1) We have recently suggested that the plasma prolactin (PRL) response to the administration of a neuroleptic drug may serve as a measure of dopaminergic blockade in man. (2) In four normal men the PRL concentration remained elevated above baseline for at least seven hr following a single i.m. administration of haloperidol 1 mg; this is consistent with reported data on the plasma half-life of haloperidol. (3) With six normal men as their own controls, dose-PRL response curves of haloperidol, prochlorperazine and thiothixene were shown to be essentially parallel, suggesting a common antidopaminergic mechanism of action when releasing PRL. (4) In two studies, dopamine hydrochloride was infused at a constant rate of 0.3 mg/min; the DA infusion was started either immediately after a neuroleptic had been given i.v. or 30 min later. In the first study DA totally antagonized the neuroleptic induced PRL response; in the second study DA suppressed the neuroleptic-induced high PRL concentration to baseline level within one hr. (5) These findings provide further support for the hypothesis that the PRL response to a neuroleptic is a valid test of dopaminergic blockade in man.     

Tardive dyskinesia model in the common marmoset.

Thirteen adult common marmosets (Callithrix jacchus) were given once-monthly injections of haloperidol decanoate (5-15 mg/kg i.m.) for one year. Thereafter, drug-free and treatment periods alternated at 3-month intervals. After 2.5 to 14 months, 12 monkeys showed symptoms of tardive dyskinesia (TD), such as periocular and perioral twitchings, tongue protrusions, masticatory movements, and choreic movements in arms and legs. When TD symptoms were evident, the periodic treatment was interrupted and symptoms persisted for at least 5 months after the last haloperidol dose, worsened by injection of the anticholinergic drug biperiden. An injection of nondepot haloperidol (0.12 or 0.25 mg/kg) produced a reduction of TD symptoms. At the end of the study, nondepot haloperidol was injected once a week at two doses (0.12 and 0.25 mg/kg i.m.). A syndrome of excitation with peculiar behavior, interpreted as acute dystonia, was precipitated in all animals. The animals showed sustained retrocollis, climbing upside down, biting the perch, repetitive turnings, and frequent backward movements. The dystonic movements lasted approximately 6 hours and were reduced but not completely extinguished by biperiden (0.1 mg/kg). The TD syndrome registered in marmosets may provide a useful model for screening new antipsychotics for their propensity to induce TD.     

Neuroleptic bioavailability,psychosocial factors,and clinical status: A 1-year study of schizophrenic outpatients after dose reduction

Serum neuroleptic levels, prolactin levels, and clinical state were assessed for 1 year in 29 schizophrenic outpatients whose clinically determined neuroleptic dose had been reduced by 50%. Fifty-five percent of the subjects remained stable. Neuroleptic dose did not differ between relapsed and stable patients. Serum prolactin (PRL) assessed 2 weeks after dose reduction and mean PRL after reduction were significantly lower among relapsers. Serum neuroleptic levels were significantly lower for relapsers in patients on haloperidol. Among relapsers, there were no serum PRL or neuroleptic level differences between stable periods and the relapse episode. Among patients with relatively low neuroleptic bioavailability, relapsers reported lower levels of social activity and had social networks that were less enjoyable, more aversive, and less helpful than those of stable patients.     

Prolactin response to morphine in intact and adrenalectomized lactating rats.

To examine the hypothesis that the increased adrenocortical activity during lactation induced the loss of the prolactin (PRL) -releasing effect of morphine, we studied the effect of morphine in adrenalectomized (ADX) and sham-operated primiparous lactating Wistar rats. Animals were adrenalectomized 4 days after delivery. On day 11 of lactation (7 days after ADX), pups were separated from their mother 2 h before morphine or haloperidol injection. Intravenous injection of 5 mg/kg morphine did not change plasma PRL levels in the sham-operated lactating rats, but it resulted in a significant increase of plasma PRL levels in ADX lactating animals, with or without corticosterone replacement. Catalepsy following 10 mg/kg i.v. morphine was also markedly enhanced in ADX lactating animals. The PRL response to 0.5 mg/kg haloperidol was higher in ADX lactating animals than that in the controls. Morphine given 2 h after haloperidol treatment resulted in a further increase of plasma PRL in ADX, but not in the sham-operated lactating animals. These results suggest that adrenal hyperfunction may lead to a loss of sensitivity to morphine during lactation.     

Risperidone-induced increase in serum prolactin is correlated with positive symptom improvement in chronic schizophrenia

The elevation in serum prolactin (PRL) concentration in schizophrenic patients treated with typical antipsychotic drugs is well documented. Recently, increased prolactin levels have been reported in patients taking risperidone. The purpose of this study was to explore the effect of the atypical antipsychotic drug risperidone on serum prolactin, and to investigate the relationship between the change in PRL and the therapeutic outcome. In this study, 30 male inpatients with a diagnosis of chronic schizophrenia (DSM-III-R) were assigned to 12 weeks of treatment with risperidone after a 2-week washout period. The risperidone dose was fixed at 6 mg/day. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS). Serum PRL was assayed in serum by radioimmunometric assay in schizophrenic patients before and after 12-week treatment, as compared to 30 age-matched normal male subjects. The results showed that risperidone treatment significantly increased the serum PRL. A significant and positive relationship between the change in PRL at pre- and post-treatment and the reduction rate of PANSS positive subscore was observed. Risperidone treatment significantly increased the serum PRL levels of schizophrenic patients. There was a close relationship between the improvement in positive symptoms and the change of serum PRL level before and after risperidone treatment. The serum PRL levels at baseline could be used to predict the responses of schizophrenic patients to risperidone.     

氟哌啶醇对慢性精神分裂症患者泌乳素的影响

目的：探讨氟哌啶醇对泌乳素的影响及其与临床疗效的关系。方法：采用固定剂量氟哌啶醇治疗慢性精神分裂症４５例,疗程１２周,在治疗前后评定阳性与阴性症状量表（ＰＡＮＳＳ）,并用放射免疫法测查血浆中泌乳素（ＰＲＬ）浓度。     

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.     

Effects of neuroleptics on platelet monoamine oxidase activity

Platelet MAO activity in schizophrenics was significantly decreased, by about 15%, after 3 weeks of treatment with haloperidol. Treatment with thioridazine or butaperazine also tended to decrease platelet MAO activity. The neuroleptic-induced decrease began to appear within a few days of treatment and did not show tolerance over 1-2 months of treatment with haloperidol. Platelet MAO activity of schizophrenic patients measured during drug-free base-line was not significantly different from that of normal controls, but MAO activity of schizophrenics was significantly lower than normals after 3 weeks of treatment with neuroleptics. The extent of decrease in platelet MAO activity correlated negatively with base-line prolactin and its increase after 24 hr. With PEA as substrate, the decrease in activity correlated positively with steady state plasma haloperidol.     

Bromocriptine therapy in chronic schizophrenia: effects on symptomatology, sleep patterns, and prolactin response to stimulation

Ten chronic schizophrenic patients were given bromocriptine in doses increasing from 1.25 to 5 mg over 6 days (the low-dose therapy) and then up to 40 mg over 15 days (the high-dose therapy). Psychopathological status was assessed using the Brief Psychiatric Rating Scale, twice daily the first 6 days, and every 2 days thereafter. The prolactin (PRL) response to haloperidol stimulation (1 mg i.v.) was measured in five cases before and 3 days after the end of high-dose therapy, and in one patient before and 3 days after the end of low-dose therapy. Electroencephalographic sleep studies were carried out before therapy and every 2 nights during low-dose therapy in five patients, and in two cases during high-dose therapy. Bromocriptine therapy modified neither clinical symptomatology nor sleep patterns. The PRL response to haloperidol after therapy was markedly lower than that before therapy in the five patients treated with high doses, and markedly higher in the single patient tested who was treated only with low-dose therapy.     

Prolactin responses to haloperidol in normal young women

The prolactin (PRL) responses to intramuscular haloperidol (HPD) (0.5, 1.0, and 1.5 mg) were evaluated in six normal premenopausal women during the follicular and luteal phases of their menstrual cycles. These were compared to the PRL responses to these doses of HPD in normal young men. PRL responses to HPD did not differ between the follicular and luteal phases. The mean log-transformed PRL response to the lowest HPD dose (0.5 mg) in women was less than that in the men, but the women had greater PRL responses than the men to the higher haloperidol doses (1.0 mg and 1.5 mg).     

Intramuscular ziprasidone compared with intramuscular haloperidol in the treatment of acute psychosis. Ziprasidone I.M. Study Group

BACKGROUND: This 7-day, randomized, open-label, multicenter, international study compared the efficacy and tolerability of intramuscular (i.m.) ziprasidone with haloperidol i.m. and the transition from i.m. to oral treatment in hospitalized patients with acute psychotic agitation (related to DSM-III-R diagnoses). METHOD: Patients received up to 3 days of flexible-dose ziprasidone i.m. (N = 90) or haloperidol i.m. (N = 42) followed by oral treatment to day 7. After an initial ziprasidone i.m. dose of 10 mg, subsequent i.m. doses of 5 to 20 mg could be given every 4 to 6 hours (maximum daily dose = 80 mg) if needed, followed by oral ziprasidone, 80-200 mg/day. Haloperidol i.m. doses of 2.5 to 10 mg were given on entry, followed by 2.5 to 10 mg i.m. every 4 to 6 hours (maximum daily dose = 40 mg) if needed, then by oral haloperidol, 10-80 mg/day. RESULTS: The mean reductions in Brief Psychiatric Rating Scale (BPRS) total, BPRS agitation items, and Clinical Global Impressions-Severity scale scores were statistically significantly greater (p < .05, p < .01, and p < .01, respectively) after ziprasidone i.m. treatment compared with haloperidol i.m. treatment. Further reductions in these scores also occurred in both groups following transition to oral treatment. Ziprasidone was associated with a lower incidence of movement disorders and a reduced requirement for anticholinergic medication during both i.m. and oral treatment compared with haloperidol. Movement disorder scale scores improved with ziprasidone i.m. and oral treatment, but deteriorated with haloperidol. Other adverse events were rare with both treatments. CONCLUSION: Ziprasidone i.m. was significantly more effective in reducing the symptoms of acute psychosis and was better tolerated than haloperidol i.m., particularly in movement disorders. The transition from ziprasidone i.m. to oral ziprasidone was effective and well tolerated.     

Hormone response to repeated electroconvulsive therapy: effects of naloxone

Plasma prolactin (PRL), cortisol, and growth hormone (GH) were measured before, and at 15-min intervals for 1 hr after, electroconvulsive therapy (ECT). This was repeated over a series of 6 consecutive treatments for each of 12 depressed drug-free inpatients. Patients received naloxone, 2 mg or 20 mg, by intravenous infusion before the third and fifth treatment. ECT was consistently followed by a release of PRL and cortisol, although two patterns of PRL response could be distinguished. In eight patients, the PRL response did not change significantly with repeated ECT, whereas in four patients, the plasma PRL increased tenfold after the first treatment and decreased after each successive treatment. The GH level varied widely, with no evidence of a reliable response to ECT. Opiate receptor blockade with low- or high-dose naloxone did not alter the release of PRL or cortisol after ECT. These findings demonstrate a reliable PRL and cortisol response to ECT, but do not support a role for endogenous opiates in these hormonal changes.