Manolis Markianos

Plasma testosterone in male patients with Huntington's disease: Relations to severity of illness and dementia

Huntingtons disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms and by a progressive loss among other, of dopaminergic receptors in striatum, cortex, and hypothalamus. Central dopaminergic activity has been implicated in the regulation of sex hormones. Several features of testosterone deficiency, such as reduced muscle mass, depressive mood, and cognitive impairment, are often present in HD patients, but data on their testosterone levels are lacking. We assessed plasma levels of testosterone, LH, and FSH in 42 male patients with HD, confirmed by molecular genetic analysis, and searched for differences from age‐matched healthy male subjects and for relations to CAG repeat number, age, age range, 26 to 76 (mean, 50.7 ± 12.3) years; duration of illness range, 1 to 23 (mean, 6.7 ± 6.3) years; and CAG repeat numbers from 40 to 65 (45.1 ± 3.8). Disease symptomatology was assessed using the Unified Huntingtons Disease Rating Scale. Testosterone and LH levels of the patients were significantly lower compared to the levels of 44 age‐matched (mean age, 48.9 ± 13.0, range, 26–76 years) healthy men. Severity of illness was negatively related to plasma testosterone levels. Further, low testosterone levels were associated with dementia but not with depression or psychotic features. Clinical studies with selected HD patients are needed to evaluate possible beneficial effects of androgen substitution therapy on cognitive functions, depression, muscle mass and strength, general well‐being, and, eventually, neuroprotective effects. Ann Neurol 2005;57:520–525

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

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.

Central Serotonergic Responsiveness in Neurocardiogenic Syncope A Clomipramine Test Challenge

BACKGROUND Central serotonergic mechanisms appear to participate in the pathogenesis of recurrent neurally mediated syncope. The aim of the study was to investigate the responsiveness of the central serotonergic system by measuring the prolactin and cortisol responses to intravenous administration of the serotonin reuptake inhibitor clomipramine. METHODS AND RESULTS Twenty subjects free of any medical treatment were tested. Twelve had a history of recurrent syncopal attacks and positive tilt test (patient group, mean age 47+/-18 years, 8 men); 8 subjects without syncope and a negative tilt test result served as control subjects (mean age 49+/-10 years, 5 men). Twenty-five milligrams of clomipramine was administered intravenously within 15 minutes, and blood samples were taken at 0, 15, 30, 45, and 60 minutes. Two days later, a tilt test was performed at 60 degrees for 30 minutes and blood samples were taken at 0, 10, 20, and 30 minutes. During the clomipramine challenge, plasma prolactin levels increased in both groups. The levels at 30 minutes were higher in the patient group compared with the control group (17.3+/-7.2 vs 9.3+/-7.6 ng/mL, P=0.05). Similar results were observed for cortisol at 30 minutes (172+/-15 vs 118+/-21 ng/mL P=0. 04) and at 45 minutes (189+/-20 vs 116+/-23 ng/mL, P=0.03). The tilt test was positive in 8 (67%) out of 12 of the patient group and negative in all control subjects. In the samples taken during the tilt test, significant increases in prolactin and cortisol were observed only in the subjects with positive tilt test results. CONCLUSIONS Patients with a history of neurocardiogenic syncope show a higher responsiveness of the central serotonergic system to clomipramine challenge. The results support the view that central serotonergic mechanisms are involved in the pathophysiology of the syndrome.

Gonadal axis hormones in psychiatric male patients after a suicide attempt

Epidemiological and clinical studies support the view that aggressive acts like suicidal and violent behaviors share a common substrate. Certain aspects of violence in males have been related to high testosterone levels, but the relation of testosterone to attempted suicide has not been studied until now. We estimated plasma levels of testosterone (T), LH, and FSH in 80 male subjects after a suicide attempt and in whom a psychiatric assessment was done during their hospitalization. Suicide intent was evaluated in 72 subjects. A group of 56 healthy males in the same age range served as control. As a group, attempters showed significantly lower T levels, marginally higher LH, and normal FSH compared to controls. The attempters who used violent methods (26 subjects) had T levels even lower than the non-violent (drug overdose) subgroup. Comparisons of T levels of subgroups according to the (main) drug ingested (analgesics, benzodiazepines, antidepressants, neuroleptics, or other drugs) did not reveal any significant drug effect. In relation to diagnosis, the lowest T levels were found in the subgroup with schizophrenia (29 subjects). The T levels of this subgroup were also significantly lower compared to those of a group of 31 male schizophrenic patients, hospitalized and treated with neuroleptics. If the influence of post-attempt stress and medical condition on plasma T could be ruled out, low plasma T may prove to be a biological predictor of attempt, at least in male schizophrenic patients. Nevertheless, the findings differentiate suicidal behavior from other aggressive/violent behaviors and do not support the notion that suicidal and aggressive behaviors are manifestations of the same impulse.

Aggression, Impulsivity, Plasma Sex Hormones, and Biogenic Amine Turnover in a Forensic Population of Rapists

The aim of the present study was to assess androgen plasma levels and biogenic amine metabolites in a sex-offender group as well as to investigate the relationship between the biological findings and the impulsive, aggressive, and suicidal profile of the offenders. Fiftyseven males convicted for rape and 25 normal males comprised the study sample. We found that although both testosterone levels and aggression-impulsivity scores were higher in the group of rapists, testosterone levels were not associated with the aggression and impulsivity scores. Nevertheless, aggression-impulsivity scores were clearly associated with luteinizing hormone levels. This association may indicate a hyperactive hypothalamic-pituitary-gonadal axis, possibly the result of a reduced serotonergic activity.

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.

Suicide attempt by jumping: a study of gonadal axis hormones in male suicide attempters versus men who fell by accident.

Low plasma total testosterone (T) levels may influence the sense of well-being and produce depressive symptomatology, increasing the risk of suicide. In a previous study, we reported reduced serum T levels in male psychiatric patients after a suicide attempt. The reduction was more pronounced in subjects who used violent attempt methods, and we discussed the possible influence of stress of hospitalization, serious medical condition and treatment. In order to minimize the influence of such factors, we compared in this study the levels of plasma sex hormones of 15 psychiatric patients (10 suffering from schizophrenia and 5 from depression) who had attempted suicide by jumping with those of a group of 18 male subjects who were hospitalized after accidentally falling from a high height. Compared with a healthy control group of 40 males, both accident and attempt groups had lower T levels. The attempt group showed a trend toward lower T levels compared with levels in the accident group. In the accident group, luteinizing hormone (LH) levels were elevated compared with levels in healthy controls, indicating a normal function of the hypothalamic-pituitary-gonadal (HPG) axis. This was not the case for the attempt group, where low T levels were not accompanied by increases in LH. Cortisol and prolactin were similarly elevated in both patient groups, but were not related to the low T levels. The results indicate that male psychiatric patients who attempt suicide by violent methods may have low total plasma T levels, possibly due to a dysfunction of the HPG axis at the hypothalamic-pituitary level. Monitoring HPG axis function in future studies could prove to be a predictor of suicide at least for male psychiatric attempters, and could lead to preventive strategies.