John Hatzimanolis

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.

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.

Plasma dopamine-beta-hydroxylase in familial and sporadic paranoid schizophrenia

This study was designed to check the hypothesis of low DBH activities in paranoid schizophrenia (PS), controlling for the influence of positive family history

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.

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).

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 harmone (LH) and follicle stimulating harmone (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.

Changes in dopamine receptor responsivity during alcohol detoxification may predict relapse

In the search for clinical and biological variables that may predict relapse of alcohol dependent patients after detoxification, we followed up for 1 year male patients that had undergone successful detoxification. The patients had been tested earlier during their usual alcohol consumption and immediately after detoxification for the responsivity of D2 dopamine receptors (as measured by the increases in prolactin plasma levels caused by intramuscular administration of 5 mg of the dopamine receptor blocker haloperidol). Of the 18 patients, eight had not consumed alcohol for more than 6 months, and ten had relapsed within 6 months. Comparison of the clinical and neuroendocrine data for the two subgroups revealed no significant differences in age, amount of alcohol consumed during alcohol abuse, score in the Beck Depression Inventory, score in the Brief Michigan Alcoholism Screening Test, or prolactin responses to haloperidol before detoxification. In patients who relapsed, the duration of alcoholism was marginally shorter (P=0.055). Patients who did not relapse had significantly higher (P=0.003) prolactin responses to haloperidol in the test performed after detoxification as compared with patients who did relapse, and their responses were similar to those of a group of healthy male subjects. The results show that the increase in dopamine receptor responsivity that occurs after detoxification is a favourable factor for non-relapse; it may reflect recovery from down-regulation of the dopaminergic reward system caused by alcohol consumption.

A psychoendocrine study in male paranoid schizophrenics with delusional ideas of homosexual content.

ABSTRACT– The serum prolactin (PRL), luteinizing hormone (LH), testosterone (T) and estradiol (E) levels were investigated in a group of male paranoid schizophrenics with delusional ideas of homosexual content, in a group of male paranoid schizophrenics without delusional ideas of homosexual content, and in a group of healthy, male heterosexual subjects. Only male paranoid schizophrenics with delusional ideas of homosexual content had significantly lower serum PRL values and significantly higher serum E levels than those of the age‐matched group of normal, male heterosexual controls; also, these patients tended to have higher (though not to a statistically significant degree) serum LH and T levels than those of normal controls. Findings of this study are discussed within the framework of the possible involvement of endocrine factors in the occurrence of delusional ideas of homosexual content in male patients with paranoid schizophrenia.

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.

Relationship between prolactin responses to ECT and dopaminergic and serotonergic responsivity in depressed patients

Abstract The prolactin (PRL) increases in plasma, induced by the electrical stimulus during electroconvulsive therapy (ECT), is a consistent finding that can be studied in order to obtain information about its actions on the brain neurotransmitter systems, the most probable candidates being the serotonergic and the dopaminergic system. Central serotonergic and dopaminergic responsivity may also be assessed using neuroendocrine challenge tests. In this study, we measured the PRL responses during the first ECT of a therapeutic course in 15 male depressive patients, of mean age 49.2 ± 14.5 (range 22 to 68 years), and score in the HDRS of 29 ± 8 (range 18 to 43 points). Before the ECT course, we assessed the central serotonergic and dopaminergic responsivities, by measuring the PRL responses to the administration of the serotonin uptake inhibitor clomipramine (CMI) intravenously, and, two days later, the PRL responses dopamine receptor blocker haloperidol (HAL), administered intramuscularly. The CMI and HAL tests were also performed in 15 healthy male subjects. The PRL responses to CMI of the patients were blunted compared to healthy controls, while the PRL responses to HAL were not significantly different from controls. Searching for correlations among the maximal PRL responses to the three stimuli in the patients group, we found that the PRL responses to ECT were significantly correlated to the PRL responses to i. m. HAL (r = 0.8205, N = 15, p < 0.001) and not to the PRL responses to i. v. CMI (r = 0.1713, n. s.). It is suggested that the rises in PRL during ECT reflect the responsivity of the hypothalamus-pituitary dopaminergic system, and seem to be the result of a transient decrease in the inhibitory dopaminergic input of the hypothalamus to the pituitary lactotrophs, caused by the electrical stimulus and the subsequent seizure.