Prolactin and cortisol responses to acute intravenous clomipramine challenge in patients with mania, depression and healthy controls: evidence for reduced serotonergic responsivity.

Serotonergic dysregulation has been shown to be involved in the pathophysiology of unipolar and bipolar depression. Neuroendocrine challenge tests have been extensively used to investigate serotonin functioning in the brain. Although the role of serotonin has received a great deal of attention using neuroendocrine challenge paradigms, little effort has been made to explore the role of serotonin in mania. We assessed serotonergic neuroendocrine responsivity in patients with depression (n = 22), mania (n = 11) and 15 healthy controls by measuring the prolactin (PRL) and cortisol responses to i.v. clomipramine (CMI) and searched for possible differences among the groups. Blunted PRL responses to CMI in manic and depressed patients compared to healthy controls were found. The response to CMI disclosed similar results for the 2 patient groups. No significant differences were found among the 3 subject groups in the cortisol response to CMI. The blunted PRL responses to CMI in patients with mania and depression suggest that serotonergic functioning in mania and depression is similarly impaired, at least at the level of hypothalamus-hypophysis.

Provocation of neurocardiogenic syncope by clomipramine administration during the head-up tilt test in vasovagal syndrome.

OBJECTIVES: We sought to test the hypothesis that activation of the serotonergic system in patients with vasovagal syndrome during the head-up tilt test provokes syncope. BACKGROUND: Central serotonergic activation participates in the pathogenesis of neurocardiogenic syncope. Drugs increasing serotonin (5-HT) in the central nervous system have not been tested as drug challenges during the head-up tilt test with clomipramine (Clom-HUT). METHODS: The serotonergic re-uptake inhibitor clomipramine was infused (5 mg in 5 min) at the start of Clom-HUT in 55 patients (mean age 40 +/- 17 years) with a positive history of recurrent neurocardiogenic syncope and in 22 healthy control subjects (mean age 46 +/- 15 years). Blood samples were taken at 0, 5, 10 and 20 min for estimation of plasma prolactin and cortisol as neuroendocrine indicators of central serotonergic responsivity. All subjects had been previously tested with a basic 60 degrees head-up tilt test (B-HUT) for 30 min, and if negative, isoproterenol infusion was given at the end of the test. RESULTS: Twenty-nine (53%) of the 55 patients and none of the 22 control subjects had a positive result in the B-HUT. With Clom-HUT, the proportion of patients who experienced a positive response increased to 80% (n = 44), although this happened to only one control subject. Prolactin and cortisol plasma levels increased significantly in the positive Clom-HUT patient group only. CONCLUSIONS: The results indicate an increased responsivity of the central serotonergic neural system in subjects with vasovagal syndrome, the activation of which leads to sympathetic withdrawal. The use of clomipramine infusion with the tilt test seems to considerably improve its diagnostic value.

Neurochemical studies on tardive dyskinesia. I. Urinary homovanillic acid and plasma prolactin.

Forty-two schizophrenic patients under chronic neuroleptic treatment (11-24 years) were studied, 20 without and 22 with tardive dyskinetic symptomatology. Blood and urine samples were collected on 3 consecutive days. Plasma prolactin (PRL) and urinary homovanillic acid (HVA) values were higher in both tardive dyskinetic and nontardive dyskinetic groups, compared to normals. The increased PRL and HVA values were not related to tardive dyskinesia but to the actual neuroleptic dose. The subgroup of patients with actual dose under 900 chlorpromazine equivalents had normal PRL values and increased HVA at low significance level compared to normals, while the subgroup with doses over 900 equivalents had highly significant (p less than 0.001) increased PRL and HVA values. Thus, the actual neuroleptic dose determines plasma PRL and urinary HVA excretion in patients chronically treated with neuroleptics.

Neurochemical studies on tardive dyskinesia. II. Urinary methoxyhydroxyphenylglycol and plasma dopamine-beta-hydroxylase.

The noradrenergic correlates 3-methoxy-4-hydroxy-phenylglycol (MHPG) in urine and dopamine-beta-hydroxylase (DBH) in plasma were estimated on 3 consecutive days in chronic schizophrenic patients under neuroleptic treatment, 20 without and 22 with tardive dyskinetic symptomatology. Compared to normals, no differences in DBH activities were found, but MHPG excretion was higher in both patient groups. Dichotomy of DBH and MHPG values according to their medians for the 42 patients revealed a higher incidence of low DBH activities and low MHPG excretion in the tardive dyskinesia group, while there were no differences in relation to low or high actual neuroleptic dose.

Biogenic amine metabolites in plasma of drug-naive schizophrenic patients: associations with symptomatology.

The main metabolites of dopamine, noradrenaline, and serotonin, homovanillic acid, methoxyhydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA), were estimated in plasma of 20 drug-naive young male schizophrenic patients and 21 healthy controls. Although there were no significant differences between the two groups, multiple regression analysis revealed strong associations of the patients' 5-HIAA and MHPG plasma levels to their scores in the Brief Psychiatric Rating Scale items. 5-HIAA levels were mainly related positively to hostility and negatively to somatic concern, and MHPG positively to disorientation and negatively to emotional withdrawal and uncooperativeness. The results suggest that levels of the neurotransmitter metabolites may be related to certain psychological dysfunctions of the patients rather than to disease entities.

Prolactin and TSH responses to TRH and to ECT in pre- and postmenopausal women with major depression.

The patterns of prolactin and thyrotropin (TSH) release after thyrotropin-releasing hormone (TRH) (0.4 mg i.v.) and during the first session of a course of electroconvulsive treatment (ECT) were studied in women with major depression, 16 in pre- and 29 in postmenopausal status. The prolactin responses to both stimuli were lower in postmenopausal women, whereas the TSH responses were not different. The known correlation between the maximal prolactin response to ECT and the maximal response to TRH was significantly stronger in the group of premenopausal women (r = .8648, versus .4249 in the postmenopausal group, p < .02). A common underlying mechanism promoting prolactin release for both stimuli can be suggested, which diminishes after menopause, probably an influence of estradiol on the affinity of dopaminergic and serotonergic receptors. That mechanism does not interfere with the TSH release either by ECT or by TRH.

Effects of thyrotropin-releasing hormone administration on the electroconvulsive therapy induced prolactin responses and seizure time.

The effects of thyrotropin-releasing hormone (TRH) administration on electroconvulsive therapy (ECT)-induced prolactin (PRL) secretion and the duration of the seizure were studied in 14 depressed women. In a balanced order crossover design the patients were given 0.4 mg TRH or placebo intravenously 20 min before ECT during the first two sessions. In the third ECT session TRH was given just prior to ECT. ECT elicited the expected PRL response when given alone and when given 20 min after TRH when PRL plasma levels were high. During the coadministration design (third ECT session) PRL levels were raised not as a sum of the two stimuli but even significantly more. TRH failed to modify the duration of the seizure induced by ECT. Therefore, if TRH is involved in seizure modulation during ECT, our findings suggest a postictal rather than ictal role for TRH.

Neurochemical variables in delusional depression.

The authors assayed plasma dopamine beta-hydroxylase activity, platelet monoamine oxidase (MAO) activity, plasma prolactin, the urinary monoamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA), and urinary cAMP from 18 delusional and 22 nondelusional depressed inpatients. No significant differences between the two groups were found.

Hormonal responses during tilt-table test in neurally mediated syncope.

The hormonal profile during tilt testing was examined in syncopal patients. An increase in the growth hormones cortisol and prolactin was found during syncope, suggesting an implication of central serotonergic activation.

Left atrial function and atrial natriuretic factor/cyclic guanosine monophosphate changes in DDD and VVI pacing modes.

Left atrial systolic function and the plasma of atrial natriuretic factor (ANF) and cyclic guanosine monophosphate (cGMP) were investigated as possible markers for the development of pacemaker syndrome during VVI pacing. Patients who developed pacemaker syndrome during VVI pacing had a significant decrease in left atrial emptying fraction and a substantial increase in ANF and cGMP plasma levels.

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.

Gonadal axis hormones in male schizophrenic patients during treatment with haloperidol and after switch to risperidone.

RATIONALE: The atypical neuroleptic risperidone, in addition to its dopamine receptor blocking activity, has a high affinity for serotonergic receptors. Since both dopaminergic and serotonergic neuronal activities participate in regulation of the pituitary gonadal axis (PGA), it is expected that a switch from treatment with haloperidol to treatment with risperidone should influence plasma levels of PGA hormones. OBJECTIVE: To study the effects of a drug with dopamine and serotonin receptor blocking activity on PGA hormones in patients who were on treatment with a dopamine receptor blocker. METHODS: Plasma levels of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH), as well as prolactin and cortisol, were measured in 16 male schizophrenic patients during treatment with haloperidol (mean dose 23.3 mg daily, SD = 16.9) and 6 weeks later after switching to treatment with risperidone (mean dose 11.8 mg daily, SD = 2.9). Psychopathology was assessed by BPRS. RESULTS: After switching to risperidone, total BPRS score and the scores in its subscales for positive, negative, and general symptoms were all significantly reduced in the order of 35-45%. Prolactin levels were significantly increased from 39.5+/-22.3 to 58.9+/-28.5 ng/ml (F= 4.61, P = 0.04), while cortisol, testosterone, LH, and FSH remained unchanged. No significant correlations between prolactin increases and reduction in BPRS or in its subscale scores were found. CONCLUSIONS: The results show that blocking of both dopamine and serotonin receptors does not influence the pituitary gonadal axis but considerably increases prolactin release.

Ritanserin, a 5-HT2 receptor antagonist, does not modify ECT-induced prolactin release.

The effect of pretreatment with ritanserin, a potent and selective serotonin-S2 (5-HT2) receptor antagonist, on the prolactin (PRL) response to electroconvulsive therapy (ECT) was studied in seven female patients suffering from major depressive disorder. They were given either ECT alone, or ECT after 10 or 20 mg ritanserin PO, and PRL was estimated in blood samples taken at times -5, 0, +5, +15, +30 and +60 min. The PRL responses after drug administration were not different from the responses after ECT alone. We conclude that, if serotonergic mechanisms are involved in the ECT-induced PRL increase, this neuroendocrine response seems to be rather a 5-HT1 than 5-HT2 receptor mediated event.

Prolactin responses to acute clomipramine and haloperidol of male schizophrenic patients in a drug-free state and after treatment with clozapine or with olanzapine.

Atypical neuroleptics share a common feature, showing higher affinity for 5-HT2 receptors than for D2 dopamine receptors, but show considerable differences in their clinical and pharmacological properties. In clinical doses, they occupy serotonergic receptors near saturation, but show considerable differences regarding the D2 receptor occupancies, with clozapine showing the lowest degree of occupation. We assessed serotonergic and dopaminergic receptor responsiveness in two groups of male schizophrenic patients, one treated with the atypical neuroleptic clozapine (14 patients, doses 200-600 mg/d) and the other treated with olanzapine (11 patients, doses 10-30 mg/d). We measured the prolactin responses to the acute administration of a serotonergic drug, clomipramine, and a dopaminergic one, haloperidol. Tests were first performed in the drug-free state, and were repeated after the patients had been treated with stable doses of either drug for six weeks. Clomipramine administration induced significant increases of prolactin in the drug-free state. These responses were eliminated after treatment of the patients with either drug, thereby indicating a high 5-HT receptor occupancy by both clozapine and olanzapine. The prolactin responses to haloperidol were not altered after treatment with clozapine, but were significantly reduced after the olanzapine treatment. The baseline prolactin levels were not influenced by clozapine treatment, and were moderately but significantly increased after treatment with olanzapine. The results indicate that there is a difference between the two drugs in their capacity to block dopamine receptors at the hypothalamus-pituitary level, and match the results obtained by SPECT receptor binding studies for striatal dopamine receptors.

Altered serotonin uptake kinetics in multiple sclerosis.

Platelet serotonin uptake was studied in 20 patients with multiple sclerosis (MS) in acute relapse and in 20 age- and sex-matched controls. While there was no difference in the maximum velocity of the uptake, Michaelis constants were significantly higher and correlated positively with the Disability Status Scale score. The results suggest a competitive block of the serotonin uptake sites in platelets of MS patients.

Twenty four hour variation in plasma atrial natriuretic factor during VVI and DDD pacing.

OBJECTIVE: To investigate whether plasma atrial natriuretic factor (ANF) follows a pattern of circadian variation similar to that of other hormones in patients paced under VVI and DDD pacing modes and to determine if the known effect of pacing mode on ANF secretion is maintained throughout the 24 hour period. PATIENTS AND DESIGN: 20 patients were studied. They had complete atrioventricular block and had been paced for 17 (SD 3.5) months with a dual chamber multiprogrammable pacemaker. They were divided into two groups according to the duration of pacing in either VVI or DDD mode before the measurements: group A, n = 11 (8 men, 3 women, aged 65 (7) years), each paced for 24 h under each of VVI and DDD modes in random order; group B, n = 9 (7 men, 2 women, aged 63 (8) years), each paced for 60 d under each pacing mode before the measurements. Blood samples were taken and ANF concentrations measured every 4 h over a 24 h period, starting at 09.00. Measurements were also made of plasma cortisol, which has a known circadian pattern, so that the 24 h curve could be compared with that of ANF. RESULTS: In contrast to cortisol, ANF values indicated a pulsatile pattern of secretion throughout the 24 h period, with no clear circadian variation. In group B, ANF concentrations were significantly higher during VVI than during DDD pacing throughout the 24 h period, whereas in group A this difference was statistically significant only at certain times of day. CONCLUSIONS: ANF does not show the circadian pattern of variation shown by cortisol and other hormones. Dual chamber pacing contributes to an improvement not only in cardiac haemodynamics but also in the neuroendocrine system, especially in the long term.

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.

Neurochemical variables in schizophrenic patients during switching from neuroleptics to clozapine.

1. The study aimed to search for the effect of clozapine on the levels of the main metabolites of dopamine homovanillic acid (HVA), serotonin 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine 3-methoxy-4-hydroxyphenylglycol (MHPG) in urine as well as on plasma levels of HVA, 5-HIAA, prolactin (PRL) and cortisol. 2. Seventeen male patients diagnosed as suffering from DSM-IIIR schizophrenia completed the study. 3. The patients were switched from classical antipsychotics to clozapine. After six weeks treatment with clozapine the severity of psychopathology (total BPRS score) decreased significantly (p = 0.00004). pHVA and -5-HIAA did not change significantly. uMHPG increased significantly (p = 0.017). Both PRL and cortisol levels decreased significantly (p = 0.0002, p = 0.032 respectively). Patients with high HVA levels in both plasma and urine at baseline had a lower BPRS score at the end of treatment period (p = 0.0001, p = 0.049 respectively).

Biogenic amine metabolites in delusional (psychotic) depression and melancholia subtypes of major depression.

1. The levels of the urinary main metabolites of norepinephrine 3-methoxy-4-hydroxyphenylglycol (MHPG), of dopamine homovanillic acid (HVA) and of serotonin 5-hydroxyindoleacetic acid (5-HIAA) were measured in 84 patients with major depressive disorder, 34 delusional and 50 nondelusional. Melancholia subtype was also defined (N = 62). 2. MHPG was significantly higher in the delusional depressed group (p = 0.023). Female patients with delusional major depression also had significantly higher HVA excretion than female patients with non delusional major depression (p = 0.036). 5-HIAA excretion was similar in the two patient subgroups. 3. No significant differences in the three monoamine metabolites were found between the melancholic and nonmelancholic depressed patients.

Thyrotropin responses to TRH and MHPG excretion before and after an electroconvulsive therapeutic course in depressed patients.

1. TSH response to TRH, and urinary MHPG were investigated before and after an ECT course in 12 female patients with endogenous depression. 2. The changes caused by ECT treatment on these parameters were not significant. 3. A positive correlation (r = 0.75, p = 0.005) was found between the changes in TSH response and the changes in urinary MHPG excretion.