Effects of serotonin antagonists on m-chlorophenylpiperazine-mediated responses in normal subjects

The serotonin (5HT) agonist, m-chlorophenylpiperazine (MCPP), has been used as a challenge agent to assess central 5HT receptor sensitivity in normal subjects and patients with panic disorder, obsessive-compulsive disorder, and major depression. Adrenocorticotropin, cortisol, and prolactin responses to MCPP were among the variables measured. MCPP's usefulness as a probe of 5HT receptors, however, hinges on its 5HT selectivity. To address MCPP's selectivity for 5HT, this study tested whether two different 5HT antagonists, methysergide (4 mg p.o.) and metergoline (4 mg p.o.), could block the hormonal and behavioral effects of MCPP (0.5 mg/kg p.o.) in 10 normal male subjects in comparison to placebo. Both 5HT antagonists abolished the prolactin release to MCPP. Metergoline, the antagonist with the more potent 5HT binding affinity, significantly blocked MCPP's effect on cortisol release as compared to placebo, and methysergide showed a nonsignificant trend to that effect. MCPP alone did not have a significant effect on behavioral variables, perhaps explaining why neither 5HT antagonist affected these measures. The findings from this study suggest that both MCPP-induced prolactin release and cortisol release are indeed 5HT-mediated effects.     

Effects of ritanserin on the behavioral, neuroendocrine, and cardiovascular responses to meta-chlorophenylpiperazine in healthy human subjects.

Ten healthy male subjects were administered i.v. meta-chlorophenylpiperazine (MCPP) (0.1 mg/kg) after oral ritanserin (5-10 mg), a putative 5HT1c/5HT2 (serotonin) antagonist, or placebo. Behavioral responses, cardiovascular effects, and neuroendocrine responses (cortisol, growth hormone, and prolactin) were measured serially for 4 hours after MCPP infusion. Premedication with ritanserin attenuated the MCPP-induced increases in self-rated anxiety and prolactin, and completely antagonized MCPP cortisol elevations. In contrast, ritanserin did not significantly alter growth hormone response to MCPP. These findings suggest a role for 5-HT1c/5-HT2 receptors in the endocrine and behavioral responses to the mixed serotonin agonist MCPP in humans.     

Serotonin function in schizophrenia: effects of meta-chlorophenylpiperazine in schizophrenic patients and healthy subjects.

This study examined serotonin (5-hydroxytryptamine; 5HT) receptor responsivity in 22 chronic schizophrenic patients and 17 healthy control subjects. The 5HT agonist meta-chlorophenylpiperazine (MCPP) was used as a probe of serotonergic function. MCPP (0.35 mg/kg) or placebo was administered orally after a 3-week drug-free period in a randomized double-blind design. Hormonal (adrenocorticotropic hormone and prolactin), temperature, and behavioral responses and MCPP blood levels were assessed for 210 minutes after administration of the capsules. The schizophrenic patients had blunted temperature responses compared with those of the healthy control subjects: MCPP raised body temperature in the control subjects, but not in the patients. Behavioral responses also differed in the two groups: MCPP increased the total Brief Psychiatric Rating Scale (BPRS) score in the control subjects and tended to decrease it in the patients. In patients, MCPP decreased the BPRS psychosis subscore. Hormonal responses did not differ significantly in the two groups. These findings suggest that further exploration of 5HT function in schizophrenia is warranted.     

Serotonin function in obsessive-compulsive disorder. A comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects

To evaluate the role of serotonin (5-HT) function in obsessive-compulsive disorder (OCD), behavioral and biochemical responses to the 5-HT receptor agonist m-chlorophenylpiperazine (MCPP) and the 5-HT precursor tryptophan were examined in healthy subjects and patients with OCD. Baseline prolactin levels and the prolactin rise following MCPP were significantly reduced in female patients compared with female healthy subjects. In contrast, the increase in prolactin level following tryptophan administration was not significantly different between male or female patients with OCD and the respective sex-matched healthy subjects. The prolactin responses to MCPP and tryptophan were both significantly higher in female patients and healthy subjects than in their male counterparts. The cortisol and growth hormone responses to MCPP and tryptophan were similar in the patients and healthy subjects and were not related to gender. The behavioral responses to MCPP or tryptophan were not consistently different between patients and healthy subjects, and neither MCPP nor tryptophan had effects on obsessive or compulsive symptoms. These results lend only partial support to the hypothesis that 5-HT dysfunction may be linked to the pathophysiology of OCD and point to the need for the evaluation of other neurotransmitter systems in future investigations of OCD.     

Serotonin receptor sensitivity and aggression

This study investigated the relationship between increased serotonin (5-hydroxytryptamine, 5HT) receptor sensitivity and human aggression. A low oral dose of meta-chlorophenylpiperazine (MCPP), a postsynaptic 5HT receptor agonist, was administered in a placebo-controlled design to depressed (n = 22) and panic disorder (n = 20) patients classified with or without signs of outwardly directed aggression, patients with a history of suicide attempts (inwardly directed aggression) (n = 11), and normal controls (n = 19). Hormones under 5HT control were measured at 30-min intervals. Results were as follows: (1) MCPP did not induce or reduce anger, (2) patients with outwardly directed aggression did not have significantly greater MCPP-induced cortisol or prolactin release than did patients without signs of outwardly directed aggression, (3) patients with a history of suicide attempts did not have significantly greater MCPP-induced cortisol or prolactin release than did normal controls, and (4) MCPP-induced hormone release was unrelated to measures of aggression.     

Functional interrelationship of serotonin and norepinephrine: cortisol response to MCPP and DMI in patients with panic disorder, patients with depression, and normal control subjects.

The relationship between norepinephrine (NE) and serotonin (5-hydroxytryptamine; 5HT) functioning was explored in a neuroendocrine challenge paradigm. Ten normal control subjects, 17 patients with major depression, and 22 patients with panic disorder volunteered to participate in this study. Each subject received a challenge with meta-chlorophenylpiperazine (MCPP; 0.25 mg/kg, p.o.), a 5HT agonist, and desmethylimipramine (DMI; 75 mg, i.m.), an indirect NE agonist, in randomized order. The peak-minus-baseline cortisol response to MCPP was used as an indicator of 5HT function, and cortisol response at 75 minutes-minus-baseline to DMI was used as an indicator of NE function. The cortisol responses to DMI and MCPP were found to be highly negatively correlated in the total sample, in particular in the patients with major depression and panic disorder. This finding suggests that the functions (or dysfunctions) of the NE and 5HT systems may not be separate as is usually believed, and that the NE and 5HT disturbances observed in major depression and panic disorder may not be independent. Rather, there may be a joint disturbance of NE-5HT in these disorders.     

Neuroendocrine response to meta-chlorophenylpiperazine and ipsapirone in relation to anxiety and aggression

The aim of this study was to establish the association of trait anxiety and anger with hormonal responses to acute challenges with two different 5-HT agonists in a mixed group of patients with depressed mood. Fifteen patients and 16 normal controls received single oral doses of 0.5 mg/kg meta-chlorophenylpiperazine (MCPP), a 5-HT(2C) agonist, and 10 mg of ipsapirone, a 5-HT(1A) agonist, according to a double-blind, placebo-controlled, cross-over design. Dutch-adapted versions of the Spielberger Trait-Anxiety Inventory and the Spielberger Trait-Anger Scale administered assessed at study entry. Hormonal responses, expressed as drug-placebo differences, to MCPP and ipsapirone (changes in cortisol, ACTH and prolactin) were measured. Blood levels of MCPP and ipsapirone were also measured. MCPP and ipsapirone elevated cortisol, ACTH and prolactin. In the patient group, there was a significant correlation between trait anxiety and the cortisol response to MCPP. No significant correlations between the ACTH and prolactin responses to MCPP and levels of anxiety/anger were observed in the patients. No significant correlations could be established between levels of anxiety/anger and hormonal responses to ipsapirone. This study provided evidence for an association between measures of anxiety/aggression and the hormonal response to MCPP. Thus, in subjects with depressed mood, high levels of anxiety suggest a higher probability of 5-HT(2C) disturbances.     

Endocrine and behavioral responses to methylphenidate in normal subjects

Methylphenidate (0.3 mg/kg) was administered intravenously to 20 normal subjects. Behavioral responses varied considerably among individuals. Both cortisol and growth hormone showed significant increases (p less than 0.001). The adrenocorticotrophic hormone (ACTH) response seemed insufficient to explain the increase in cortisol. For men only, the increase in cortisol correlated positively with the increase in epinephrine (r = 0.77, p less than 0.05) and correlated negatively with baseline cortisol (r = -0.70, p less than 0.05), with increase in growth hormone (r = -0.70, p less than 0.05), and with the increase in "energy" (r = -0.83, p less than 0.01). The growth hormone response varied between the sexes, and for men, the growth hormone correlated with both an increase in "energy" (r = 0.70, p less than 0.05) and "friendliness" (r = 0.68, p less than 0.05). For all subjects, baseline heart rate correlated with the increase in "energy" (r = -0.69, p less than 0.002). In a separate study, six male subjects received, on different occasions, saline and a lower dose of methylphenidate. Together, these studies show that the increases in cortisol, growth hormone, and epinephrine, and the decrease in prolactin are dose-dependent.     

精神分裂症神经内分泌激发试验研究

目的：通过内分泌激发实验,探讨慢性精神分裂症中枢５－ＨＴ功能状态。方法：对７８例精神分裂症、１８例正常对照进行帕罗西汀激发实验研究,以皮质醇和催乳素作为激发实验的应答指标。同时,对病人进行阳性和阴性症状评定量表（ＰＡＮＳＳ）测查。结果：治疗前精神分裂症组催乳素基础值明显低于对照组,帕罗西汀激发实验后催乳素释放增高,曲线下面积（ＡＵＣ）与对照组无显著关异。病人治疗前皮质醇基础值明显高于对照组,帕罗西     

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.     

Dose-dependent growth hormone, prolactin and cortisol stimulation after i.v. administration of desimipramine in human subjects

In previous studies it was shown that the tricyclic antidepressant desimipramine (DMI) had different stimulatory effects on growth hormone (GH), prolactin (PRL), ACTH and cortisol secretion in healthy subjects, depending on the mode of administration. The present study examined the effects following i.v. administration of placebo and DMI (5, 15, 25, 50 and 75 mg) on GH, PRL and cortisol secretion in male subjects (n = 6). This primarily noradrenergic and secondarily serotonergic reuptake-inhibiting substance was found to stimulate the secretion of GH, PRL and cortisol in a dose-dependent manner. Compared to placebo, significant increases occurred in GH (p less than 0.05) and in PRL (p less than 0.05) from a dose of DMI 25 mg on, and in cortisol (p less than 0.05) from 15 mg on. The results indicate that, in addition to the dose, the method of administration influenced the effects of DMI on the three hormones.     

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.     

5-HT(1A) receptor dysfunction in female patients with schizophrenia.

BACKGROUND: Serotonin (5-HT)(1A) receptors are of interest in the pathophysiology of schizophrenia (SCH) and the mechanism of action of atypical antipsychotic drugs. To test the hypothesis that 5-HT(1A) receptor responsivity is significantly different in patients with SCH compared to normal control subjects, the neuroendocrine study was performed using ipsapirone (IPS), a 5-HT(1A) partial agonist, as a probe. METHODS: Ipsapirone 0.5 mg/kg, p.o. or placebo were administered, in random order, to patients with SCH (n = 43; 32 male) and normal controls (n = 33; 21 male). Blood samples for plasma cortisol and body temperature were obtained from 30 min before to 180 min after administration of IPS or placebo. RESULTS: Female normal control subjects had markedly greater increases in plasma cortisol following IPS than did male control subjects. The placebo response-corrected plasma cortisol response to IPS was significantly blunted in female SCH compared to female normal control subjects (p =.0001). The IPS-stimulated plasma cortisol response in male SCH did not differ from that of male normal control subjects or female SCH. There were no significant differences in the IPS-induced hypothermia in men and women or between patients with SCH and normal control subjects. Behavioral responses to IPS, including nausea, dizziness, irritability, and feeling less well, did not differ between groups. CONCLUSIONS: These results suggest that the post-synaptic 5-HT(1A) receptor mediated endocrine response is diminished in female SCH compared to female normal control subjects, possibly secondary to an abnormality in intracellular signal transduction mechanism.     

Circadian and sleep-related endocrine rhythms in schizophrenia.

Plasma levels of prolactin, growth hormone, corticotropin, and cortisol were measured at 15-minute intervals for 24 hours in nine unmedicated male schizophrenic patients and in nine age-matched normal male subjects. Each study was preceded by 3 days of habituation to the laboratory environment. Sleep was polygraphically recorded. The circadian and pulsatile variations present in each hormonal profile were quantitatively characterized with the use of computer algorithms specifically designed for analyses of hormonal fluctuations. The major abnormality of neuroendocrine release that was observed in the schizophrenic patients was an almost threefold enhancement of the sleep-related increase in the prolactin level, associated with an intensified frequency of nocturnal prolactin pulses. This increased stimulatory effect of sleep on prolactin secretion was evident immediately after sleep onset. The normal inhibition of cortisol secretion during early sleep was absent in schizophrenic patients. The major sleep abnormalities were a prolonged sleep latency and a reduction in total rapid eye movement stage sleep. During wakefulness, prolactin and cortisol levels were normal. The 24-hour profile of growth hormone was unaltered in schizophrenic patients, and a sleep-onset growth hormone pulse was observed in all patients. No abnormalities were noted in the levels or temporal organization of corticotropin secretion. Both the amplitude and the timing of the cortisol rhythm were normal. We conclude that, in schizophrenic men, pituitary-adrenal function and circadian time-keeping are normal but prolactin secretion is hyperresponsive to the physiologic stimulus of sleep onset. Schizophrenia thus appears to be characterized by a subset of neuroendocrine disturbances distinct from that observed in major endogenous depression.     

Prolactin responses to domperidone in chronic schizophrenia.

The prolactin response to 20 mg of domperidone, a peripheral dopamine receptor antagonist, was evaluated in a group of 17 male, drug-free, elderly, chronic schizophrenic patients and 8 age-matched male normal control subjects. Both groups of subjects were receiving a variety of nonpsychotropic medications not known to affect the prolactin response to dopamine receptor antagonists. Basal plasma prolactin levels did not differ between the two groups. However, the prolactin response following domperidone was significantly greater in the schizophrenic patients, although plasma domperidone levels did not differ between the two groups. This effect is opposite to the previously reported effect of domperidone in young schizophrenic patients compared with age-matched control subjects (Nerozzi et al., 1990). The prolactin response to domperidone was markedly smaller in the old compared with the young normal control subjects, whereas the young and old schizophrenic patients had identical responses. Possible explanations for these results are considered, especially the possibility of abnormalities in the release of dopamine and pituitary D2 dopamine receptors in the elderly schizophrenic patients compared with age-matched normal control subjects.     

Pituitary hormone responses to meta-chlorophenylpiperazine in panic disorder and healthy control subjects.

The present study reports adrenocorticotropic hormone (ACTH) and prolactin responses after oral administration of 0.25 mg/kg of the serotonin agonist, meta-chlorophenylpiperazine (MCPP), in patients with panic disorder (PD) and in healthy subjects. MCPP blood levels were similar for the two groups, but almost twice as high in males as in females. Female patients had augmented ACTH and prolactin release as compared to healthy females, while ACTH and prolactin release in male patients was similar to that of male controls. These results suggest that female PD patients have hypersensitive serotonin receptors. Moreover, they indicate that pharmacokinetic gender differences may affect challenge studies, and that different doses may be required to study neuroendocrine responses in males and females.     

Prolactin and growth hormone responses to growth hormone-releasing hormone in acute schizophrenia

Growth hormone (GH), and prolactin (PRL) responses to the administration of growth hormone-releasing hormone (GHRH) (1 microgram/kg) were evaluated in a group of 18 drug-free, acute, young male schizophrenics and in a group of age-matched normal controls. Cortisol responses were also evaluated. No difference in mean plasma GH, PRL and cortisol plasma basal values or in GH and PRL responses to GHRH between schizophrenics and controls was observed. Our failure to demonstrate a difference in GH response to GHRH between schizophrenics and controls would seem to indicate that GH secretory pituitary reserve is intact in young acute male schizophrenics. Cortisol values did discriminate between schizophrenics and controls (p less than 0.05). In our sample, both schizophrenics and normal controls showed a slight but significant (p less than 0.03) and transitory increase in plasma PRL response to GHRH.     

Serum cholesterol and serotonergic function in major depressive disorder

Studies have revealed a relationship between serum cholesterol levels and serotonergic (5HT) function in healthy young adults. Patients with major depressive disorder (MDD) may have significant differences in cholesterol levels compared with healthy adults, while MDD patients with elevated cholesterol have a poorer prognosis for treatment response. The goal of the present study is to examine (1) the relationship between serum cholesterol levels and central 5HT function by way of the cortisol and prolactin response to the 5HT-selective agonist DL-fenfluramine in MDD patients and (2) differences in 5HT-function between MDD patients who present with and without elevated cholesterol. Fasting serum cholesterol levels were measured in 21 outpatients with MDD. After oral administration of 60 mg of DL-fenfluramine in these patients, cortisol and prolactin responses were measured to test whether cholesterol levels predicted the degree of cortisol or prolactin response. Cortisol and prolactin responses were compared between patients with and without elevated cholesterol levels, defined as >/=200 mg/dl. MDD patients with elevated cholesterol levels were more likely to demonstrate an attenuated cortisol response. There was no relationship between cholesterol levels and cortisol or prolactin response. Excess cholesterol may adversely affect the function of membrane-bound serotonergic structures, and this may explain why MDD patients with elevated cholesterol are more likely to exhibit attenuated neuroendocrine responses, less likely to respond to treatment and more likely to relapse.     

Neuroendocrine responses in chronic schizophrenia: Evidence for serotonergic dysfunction

Neuroendocrine and mood responses to a 60 mg oral dose of the serotonin-releasing agent, fenfluramine, were assessed in ten neuroleptic-free, chronic schizophrenic patients and in age- and sex-matched normal control subjects. The prolactin (PRL) response to fenfluramine was significantly blunted in the schizophrenic subjects. Growth hormone and cortisol levels were not differentially affected by the challenge. There was no significant effect of fenfluramine on mood in either group. The blunted PRL response in the schizophrenic group suggests serotonergic dysfunction; possible mechanisms of this finding and implications for treatment are considered.     

Effect of the anesthetic agent propofol on hormonal responses to ECT

Propofol is a new anesthetic induction agent that reduces electroconvulsive therapy (ECT) seizure duration. To indirectly investigate the effect of propofol on ECT-induced acute central neurotransmitter changes, we studied neuroendocrine responses in 25 primary depressed subjects treated with ECT under either propofol or thiopentone anesthesia. Blood samples were taken prior to ECT, and then at regular intervals for 2 hr. Only the prolactin response correlated significantly with seizure duration (r = 0.52, p less than 0.01). Subjects given propofol had significantly reduced adrenocorticotropin (ACTH) (p less than 0.01) and cortisol (p less than 0.05) responses compared to thiopentone, which were independent of seizure duration. There was a trend towards a reduction in the prolactin response with propofol compared to thiopentone, but this was dependent upon the diminished seizure duration. The results indicate that propofol affects endocrine responses to ECT by two distinct mechanisms: decreasing prolactin by reducing the seizure duration and decreasing ACTH and cortisol by another process, possibly via a reduction in central noradrenergic activation.