Neuroendocrine serotonergic and dopaminergic responsivity in male schizophrenic patients during treatment with neuroleptics and after switch to risperidone

RATIONALE: 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. OBJECTIVE: To assess the responsivity of serotonergic and dopaminergic receptors during treatment with neuroleptics and after switch to risperidone, using neuroendocrine paradigms. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.     

Comparison of prolactin concentrations between haloperidol and risperidone treatments in the same female patients with schizophrenia

The present study aimed to investigate intraindividual changes in plasma prolactin concentrations by switching from haloperidol treatment to risperidone treatment. The subjects were 15 female schizophrenic inpatients who received firstly haloperidol 12 mg/day for at least 2 weeks and, thereafter, risperidone 6 mg/day. Prolactin concentration in plasma during risperidone treatment (median 87.5 ng/ml, range 5.3-298.1 ng/ml) was significantly ( P<0.01) higher than during haloperidol treatment (median 50.7 ng/ml, range 11.6-226.6 ng/ml). In contrast, the ratio of prolactin concentration to nmol/l unit drug concentration (the active moiety: the sum of risperidone and 9-hydroxyrisperidone) during risperidone treatment (median 1.10, range 0.02-3.73) was significantly lower ( P<0.001) than that of haloperidol (median 1.81, range 0.41-8.24). Prolactin concentrations during both treatment phases correlated well in individuals (r=0.619, P<0.05), whereas better correlation was found in the ratio of prolactin concentration to drug concentration (r=0.779, P<0.01). These findings suggest the higher risk of hyperprolactinemia during risperidone treatment than during haloperidol treatment at clinically used dosages. However, from a purely pharmacological point of view, prolactin response per drug concentration was more sensitive during haloperidol treatment than risperidone treatment, probably resulting from the potent and selective antagonistic effect of haloperidol on dopamine D(2) receptor, compared with the broader pharmacological spectrum of risperidone.     

Switch from neuroleptics to clozapine does not influence pituitary–gonadal axis hormone levels in male schizophrenic patients

Hypothalamic dopaminergic and serotonergic inputs participate in the regulation of pituitary hormones, and drugs that block central dopamine and serotonin receptors are expected to influence the hypothalamus–pituitary–gonadal (HPG) and –adrenal (HPA) axes. In schizophrenic patients, the switch from neuroleptics to clozapine influences prolactin and cortisol secretion, but there is no information on possible changes on HPG-axis hormones. We measured the plasma levels of testosterone (TST), LH, FSH, as well as of prolactin (PRL) and cortisol (CORT), in a group of male patients with schizophrenia during treatment with classical neuroleptics with no satisfactory therapeutic response (31 pts, age 30.3±8.5, range 18–50), and 6 weeks later, after switch to treatment with clozapine (CLZ) in doses from 100 to 600 mg daily (mean 328 mg). Psychopathology was assessed using the Brief Psychiatric Rating Scale. The hormone levels were also compared to those of a control group of 38 healthy males. Treatment with CLZ resulted in a reduction in the BPRS score by 30% in the mean. Plasma PRL was reduced from 39.9±26.1 to 8.3±5.0 ng/ml (P<0.001), CORT from 150±42 to 118±39 ng/ml (P<0.003), while LH, FSH, and TST remained unaltered. Compared to healthy controls, patients had higher PRL and CORT levels while on neuroleptics, and no significant differences to any of the estimated hormones, after switch to clozapine. The results show that switching from classical neuroleptics to treatment with clozapine does not have any substantial effect on the HPG-axis hormone plasma levels, although it reduces substantially the levels of prolactin and cortisol.     

The effects of antipsychotic drugs on serotonergic activity in the rat hippocampus.

The serotonergic activity in hippocampus was investigated following acute and chronic treatment with the antipsychotic drugs haloperidol and risperidone. Acute administration of risperidone, the serotonin(2) (5-HT(2)) receptor antagonist ketanserin, and the dopamine (DA)-D(2) receptor antagonist raclopride increased the 5-hydroxyindoleacetic acid/serotonin (5-HIAA/5-HT) ratio. In contrast, acute administration of haloperidol did not affect this ratio. Chronic administration of risperidone maintained the increased 5-HIAA/5-HT ratio; a challenge dose of risperidone after the chronic treatment and the subsequent washout period also maintained the increased ratio. Chronic administration of haloperidol as well as a challenge dose of haloperidol following chronic treatment did not affect the serotonergic activity in hippocampus. Administration of ketanserin or raclopride after chronic treatment and the washout period induced an additional increase in the 5-HIAA/5-HT ratio in risperidone-treated rats. Moreover, a challenge dose of ketanserin, but not raclopride, increased the 5-HIAA/5-HT ratio in haloperidol-treated rats. The present results indicate that acute and chronic treatment of haloperidol or risperidone modified serotonergic activity in the hippocampus in a different way. Moreover, the augmentation of serotonergic activity induced by risperidone did not seem to be solely related to dopaminergic or serotonergic properties and may be of particular relevance for the amelioration of schizophrenia symptoms.     

The atypical antipsychotics olanzapine and quetiapine, but not haloperidol, reduce ACTH and cortisol secretion in healthy subjects

Rationale Increased activity of the hypothalamic–pituitary–adrenal (HPA) axis is an important aspect of the pathophysiology of major depression and schizophrenia. Despite the usefulness of atypical antipsychotics in the treatment of depression and their positive influence on cognitive functioning possibly related to their impact on cortisol, little is known about their effect on HPA axis function. Objective Therefore, this double-blind, placebo-controlled, randomized cross-over study investigated the influence of the atypical antipsychotics quetiapine and olanzapine in comparison with haloperidol and placebo on plasma adrenocorticotropic hormone (ACTH), cortisol, and prolactin levels. Eleven healthy male volunteers were studied during four sessions one week apart, orally receiving placebo, quetiapine (50 mg), olanzapine (5 mg), or haloperidol (3 mg). Blood samples were taken at hourly intervals from 0900 until 1700 hours. For ACTH, cortisol, and prolactin a significant effect of treatment condition (p≤0.005; p≤0.035; p≤0.0001, respectively) for area under the curve (AUC) was found. In comparison to placebo, quetiapine and olanzapine significantly reduced ACTH (p≤0.002; p≤0.05, respectively) and cortisol (p≤0.005; p≤0.03, respectively). No effect of haloperidol on AUC of ACTH or cortisol levels was observed. In comparison with placebo, haloperidol (p≤0.0001) and olanzapine (p≤0.0001) elevated AUC of prolactin plasma levels, whereas no significant effect was observed for quetiapine as a main effect of treatment condition. The atypical antipsychotics’ strong influence on HPA-function with pronounced ACTH and cortisol lowering is possibly related to the atypicals’ blockade of serotonergic receptors, but blockade of adrenergic or histaminergic receptors may play a role as well. The observed HPA-axis down-regulation may be clinically important for the atypicals’ effects on depressive symptomatology and cognitive functioning.     

Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine — a123 IBZM single photon emission tomography (SPET) study

We have studied striatal D₂ dopamine binding in schizophrenic patients treated with the novel atypical antipsychotic drug, olanzapine.¹²³I iodobenzamide (IBZM) single photon emission tomography (SPET) was used to estimate striatal dopamine D₂ receptor binding in vivo. Patients were recruited from a prospective, double blind controlled trial of olanzapine versus haloperidol treatment. In vivo striatal D₂ binding data from olanzapine treated patients (n=6) were compared with previously reported data from typical antipsychotic responsive (n=10); clozapine (n=10); and risperidone (n=6) treated patient groups. Mean % Brief Psychiatric Rating Scale score (BPRS) improvement following olanzapine treatment was 49% (SD 44). The hypothesis that clinical improvement in olanzapine treated patients would be associated with higher mean striatal D₂ binding of¹²³I IBZM (reflecting lower levels of D₂ occupancy) than typical antipsychotic (1.25±0.05) or risperidone (1.24±0.04) treatment was confirmed. Olanzapine treated patients had similar levels of striatal D₂ binding in vivo (1.41±0.06) as those treated with clozapine (1.49±0.04). This preliminary evidence suggests olanzapine is another atypical antipsychotic drug in which therapeutic response is not associated with a high degree of striatal D₂ receptor occupancy in vivo.     

Prolactin levels in male schizophrenic patients treated with risperidone and haloperidol: a double-blind and randomized study

Rationale There are few data from systematic, double-blind clinical trials that have compared the effect of the typical and the atypical antipsychotics on serum prolactin (PRL) levels in patients with schizophrenia.Objectives The goal of this study was to compare the effect of risperidone and haloperidol on serum PRL and investigate the relationship between serum PRL levels and clinical response in patients with schizophrenia.Methods Seventy-eight inpatients with a diagnosis of schizophrenia (according to DSM-III-R) were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol after a 2-week washout period, using a randomized, double-blind design. Clinical efficacy was determined using the positive and negative syndrome scale (PANSS). Their serum PRL was assayed by means of radioimmunometric assay (RIA) between pre-treatment and post-treatment, and compared with 30 sex-matched and age-matched normal subjects.Results Both risperidone and haloperidol treatment significantly increased serum PRL levels in drug-free chronic schizophrenia patients (both P<0.001). Hyperprolactinemia induced by risperidone 6 mg/kg was comparable to levels produced by haloperidol 20 mg/day. Considering dose-adjusted serum PRL levels, risperidone treatment induced a significant elevation of PRL levels compared with haloperidol treatment at the haloperidol equivalent (P<0.001). Change in PRL levels at pre-treatment and post-treatment were related to positive symptom improvement seen in the risperidone group (r=0.51, P=0.016), but not in the haloperidol group (P>0.05). Female patients showed both a higher baseline and post-treatment PRL level and a greater increase in PRL than men (all P<0.05).Conclusions Risperidone is associated with a robust effect on prolactin secretion in contrast to the conventional antipsychotic haloperidol. Prolactin monitoring during risperidone treatment should be performed.     

Amisulpride improves depressive symptoms in acute exacerbations of schizophrenia: comparison with haloperidol and risperidone.

The Brief Psychiatric Rating Scale (BPRS) anxiety/depression subscore has been used to assess affective symptoms in three studies (n = 612) comparing amisulpride (400-800 mg/day, n = 339) with haloperidol (15-20 mg/day, n = 160) and risperidone (8 mg/day, n = 113) in the treatment of acute exacerbations of schizophrenia. At endpoint, the mean improvement in the anxiety/depression subscore showed a significant (P = 0.011) difference in favour of amisulpride (5.6+/-6.1) compared with haloperidol (4.4+/-5.5) and risperidone (3.7+/-4.7). Amisulpride provided a significantly greater improvement compared both to haloperidol and risperidone in more severely depressed patients (BPRS anxiety/depression subscore > or = 16 at baseline, P = 0.001). This significant advantage in favour of amisulpride is seen from the 2nd week of treatment.     

IBZM SPECT imaging of striatal dopamine-2 receptors in psychotic patients treated with the novel antipsychotic substance quetiapine in comparison to clozapine and haloperidol

We investigated the striatal dopamine-2 (D₂) receptor occupancy caused by different antipsychotic substances in 18 psychotic patients (16 with schizophrenic and two with schizoaffective disorder according to DSM-IV) with single photon emission computed tomography (SPECT) using ¹²³I-iodobenzamide (IBZM) as tracer substance. Four patients were treated with the novel antipsychotic compound quetiapine (300–700 mg/day), six with clozapine (300–600 mg/ day) and eight with haloperidol (10–20 mg/day). They were compared with eight healthy controls. Measurement of S/F ratios and consecutive calculation of D₂ receptor occupancy revealed a significantly lower striatal D₂ occupancy rate with quetiapine and clozapine in comparison to haloperidol. In correspondence with the low striatal D₂ receptor occupancy rates and again in contrast to the haloperidol treatment group, there were no extrapyramidal motor side-effects (EPS) in the quetiapine and clozapine treatment groups. Therefore, the reported data support the position that quetiapine can be considered to be an atypical antipsychotic substance due to its relatively weak striatal D₂ receptor blocking property and therefore its low propensity to induce EPS. Received: 12 August 1996/Final version: 11 May 1997     

9‐Hydroxyrisperidone‐Induced Hyperprolactinaemia in Thai Children and Adolescents with Autism Spectrum Disorder

Although our previous study revealed an association between prolactin level and risperidone dosage, data regarding the plasma concentration of risperidone are lacking. Therefore, this study aimed to investigate the association between plasma drug concentrations of risperidone, 9‐hydroxyrisperidone and serum prolactin level in Thai children and adolescents with autism spectrum disorder (ASD). The individuals for this study were 103 children and adolescents with ASD (90 males and 13 females). In the 12th hour after the last risperidone dose, blood samples were collected for analysis. Serum prolactin, plasma risperidone and 9‐hydroxyrisperidone levels were measured. Patients' clinical data were collected from medical records – age, weight, height, body mass index, dose of risperidone and duration of treatment. Serum prolactin level was significantly positively correlated with plasma 9‐hydroxyrisperidone level (r_s = 0.355, p < 0.001). The median concentration of 9‐hydroxyrisperidone in individuals with hyperprolactinaemia (7.59 ng/ml; IQR 4.86–15.55) was significantly higher than non‐hyperprolactinaemic individuals (5.18 ng/ml; IQR 2.10–8.99) after risperidone treatment (p = 0.006). By multivariate analysis, high prolactin level was correlated to high 9‐hydroxyrisperidone level (p = 0.010). The results of this study showed that serum prolactin levels, especially in autistic individuals with hyperprolactinaemia during risperidone treatment, were significantly correlated with the level of 9‐hydroxyrisperidone. These results suggest that hyperprolactinaemia may develop during risperidone treatment.     

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     

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     

Acute hormonal changes after IV citalopram and treatment response in OCD

Rationale Serotonergic pharmacological challenges have failed to produce consensual results in patients with obsessive–compulsive disorder (OCD), suggesting a heterogeneous 5-hydroxytryptamine (5-HT) activity in this disorder. Objectives The aim of this study was to compare the neuroendocrine response to a serotonergic challenge in OCD patient responders (RP) and nonresponders (NR) to serotonin reuptake inhibitors treatment and healthy volunteers. Materials and methods Thirty OCD treatment NR, 30 RP, and 30 controls (CN) matched for sex and age were included. Each subject received 20 mg of intravenous citalopram. Prolactin, cortisol, and growth hormone plasma concentration were measured at times—20, 0, 20, 40, 60, 80, 100, 120, 140, and 160 min after the onset of citalopram infusion. Results Citalopram did not induce anxiety or OCD symptoms in patients. Citalopram was associated with stronger prolactin response in the CN group (maximal percentage variation [max%Δ] = 65.76 ± 105.1) than in NR (max%Δ = 17.41 ± 31.06) and RP groups (max%Δ = 15.87 ± 31.71; p = 0.032; Friedman χ ² = 6.87; df = 2). On the other hand, cortisol response did not differ between CN and RP groups and was blunted in the NR group (NR max%Δ = 20.98 ± 58.14 vs RP max%Δ = 47.69 ± 66.94; CN max%Δ = 63.58 ± 88.4; p = 0.015; Friedman χ ² = 8.60; df = 2). Conclusions Compared to CN, both treatment RP and NR patients showed blunted prolactin response to citalopram, but only NR patients showed an attenuated cortisol response, suggesting a more disrupted central serotonergic transmission in this group.     

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     

Elevated prolactin responses to <Emphasis Type="SmallCaps">l</Emphasis>-tryptophan infusion in medication-free depressed patients

Rationale Several previous neuroendocrine studies have demonstrated reduced 5-HT_1A receptor function in major depressive disorder (MDD). However, hypercortisolaemia or previous drug treatment may have been significant confounds. Objectives To replicate previous studies in subjects with MDD who had been drug free for at least 8 weeks and to relate the findings to measures of HPA axis function. Methods Hormonal responses to l-tryptophan infusion were measured in patients with MDD (n=20) and healthy controls (n=20). Basal salivary cortisol and DHEA were also profiled. Results No attenuation of 5-HT_1A receptor-dependent neuroendocrine responses (growth hormone, prolactin) was observed in patients with MDD. The prolactin response to l-tryptophan was significantly greater in MDD patients than in healthy controls (P=0.008). There was a significant negative correlation between prolactin response and basal salivary cortisol secretion over the 3 days prior to the test. Conclusions These data do not support previous findings of reduced 5-HT_1A function in MDD and suggest that hypercortisolaemia or psychotropic medication may have accounted for the attenuation. Basal cortisol, DHEA and the cortisol-DHEA ratio did not differ between patients and controls, and all patients were psychotropic medication-free. The greater prolactin response to l-tryptophan infusion in depressed subjects may be the result of an increase in dopamine receptor sensitivity, secondary to reduced dopamine levels.     

Effects of the dopamine stabilizers (<Emphasis Type="Italic">S</Emphasis>)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and monoamine-depleted rats

Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-dl-p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.     

Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol – a 123I-IBZM SPECT study

The striatal D₂ dopamine binding was studied in schizophrenic patients treated with the novel atypical antipsychotic drug sertindole (n = 10). Comparisons were obtained with haloperidol (n = 8), clozapine (n = 6), risperidone (n = 11) and untreated healthy controls (n = 8) of a dataset which has partly been reported previously. ¹²³I-Iodobenzamide (IBZM) single photon emission computerized tomography (SPECT) was used for estimation of striatal dopamine D₂ receptor binding. Sertindole-treated patients exhibited significantly (P < 0.001) lower levels of striatal D₂ binding (BG/FC ratio:1.28) compared with those treated with haloperidol (BG/FC ratio:1.09) and risperidone (8 mg:1.18) but significantly (P < 0.005) higher levels compared with clozapine (BG/FC ratio:1.49). However, if patients were pretreated with a depot neuroleptic, significantly (P < 0.05) higher striatal D₂ binding (BG/FC ratio:1.12) has been obtained. Since sertindole has been shown to exert distinct clinical efficacy for treatment of positive and negative symptoms, our data are indicative that antipsychotic efficacy is not associated with a high degree of striatal D₂ receptor occupancy in schizophrenic patients. Received: 21 July 1997/Final version: 27 October 1997     

Hormonal and temperature responses to the 5-HT1A receptor agonist flesinoxan in normal volunteers

Abstract Rationale. Flesinoxan is a highly potent and selective 5-HT_1A agonist and appears to be a potentially interesting neuroendocrine serotonergic probe. Objectives. We assessed hormonal (ACTH, cortisol, prolactin and growth hormone) and temperature responses to flesinoxan in normal volunteers. Methods. In a double-blind placebo-controlled study, single doses of 0.5 mg and 1 mg were injected over 10 min into 12 healthy male volunteers at 1-week intervals. Temperature and hormonal responses were measured at times –30, 0, 15, 30, 60, 90, and 120 min. Results. Flesinoxan induced a significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature. Tolerance to flesinoxan was excellent. Conclusions. These results showed the role of 5-HT_1A mechanisms in the PRL, ACTH, cortisol, GH, and temperature responses to flesinoxan. In the present study, flesinoxan appears a very promising serotonergic neuroendocrine probe. Electronic Publication     

Current treatment options for hyperprolactinemia

Introduction: Hyperprolactinemia is a prevalent cause of oligo-amenorrhea, and prolactinomas are the most common type of functional pituitary tumor. Untreated hyperprolactinemia can lead to bone loss and impair gonadal function and fertility. Normalization of prolactin improves bone mass and restores gonadal function in a majority of patients.

Areas covered: This article contains an overview of hyperprolactinemia with an emphasis on pharmacologic, surgical and radiation treatment options. Discussion focuses on the efficacy and safety of available treatments and comments on new and emerging therapies.

Expert opinion: Dopamine agonists, usually cabergoline, remain the primary choice for initial treatment of hyperprolactinemia. Surgery may also be an appropriate alternative in certain circumstances. Monotherapy with dopamine agonists is often successful at controlling prolactin levels and tumor size, but adjunctive treatments may be necessary for resistant or aggressive prolactinomas.     

Effects of AMPA receptor antagonists on dopamine-mediated behaviors in mice

 Current data indicate that dopaminergic and glutamatergic neurotransmitter systems interact. The role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor subtypes in modulating dopamine neurotransmission, however, remains unclear. The noncompetitive AMPA antagonists, GYKI 52466 (5–40 mg/kg) and LY300164 (1–6 mg/ kg), and the competitive AMPA antagonists, LY326325 (5–80 mg/kg) and NBQX (10–80 mg/kg), were compared to the dopamine antagonist, haloperidol (0.03– 1.0 mg/kg), for their ability to inhibit dopamine-mediated behaviors after IP administration in mice. The behavioral paradigms included amphetamine- or dizocilpine-induced hyperactivity, amphetamine-induced stereotyped sniffing, and apomorphine-induced climbing and stereotyped sniffing. All four AMPA antagonists and haloperidol attenuated amphetamine- and dizocilpine-induced hyperactivity and decreased spontaneous locomotion. Haloperidol and GYKI 52466 were more potent against amphetamine than against dizocilpine. In contrast, LY326325 was more potent against dizocilpine than against amphetamine. The hyperactivity decreases by LY300164 and NBQX were most likely due to non-specific effects on motor behavior. The AMPA antagonists and haloperidol also attenuated amphetamine- induced stereotypy. Unlike haloperidol, however, GYKI 52466, LY300164, and NBQX failed to attenuate apomorphine-induced climbing and stereotyped sniffing. LY326325, on the other hand, attenuated apomorphine-induced stereotypy, but not climbing. These results indicate that AMPA receptor antagonists can attenuate the behavioral effects of drugs, such as amphetamine and dizocilpine, that increase dopamine neurotransmission. However, the behavioral effects of the direct dopamine agonist apomorphine are not consistently attenuated by AMPA antagonists. The competitive AMPA receptor antagonist LY326325 appears to have a profile distinct from both haloperidol and the other AMPA antagonists tested. Received: 23 December 1996/Final version: 8 September 1997