Neuroendocrine evidence of normal hypothalamus-pituitary dopaminergic function in Huntington's disease.

OBJECTIVES: In addition to neuronal loss in striatum and cerebral cortex that characterizes Huntington's disease (HD), hypothalamic atrophy has also been found only in certain areas, probably not including dopaminergic functions. METHODS: We assessed the reactivity of the hypothalamus-pituitary dopaminergic system by measuring the acute prolactin (PRL) responses to 5 mg i.m. haloperidol in male and female HD patients and in female subjects with expanded CAG repeats in the Huntington gene before disease onset, as well as in a group of healthy males. RESULTS: The responses of the male patients were similar to those of a group of male healthy volunteers. Females gave higher PRL responses, with no differences in the response patterns of female patients and females at risk for HD. PRL elevations were not related to severity of illness, or to presence of dementia, depression, or psychotic features. CONCLUSIONS: The results implicate a normal dopaminergic input from hypothalamus to pituitary and preserved pituitary dopamine receptors, indicating that hypothalamic atrophy in HD does not affect mechanisms involved in PRL secretion by haloperidol.

Larger variability of saccadic reaction times in schizophrenia patients.

Slower mean reaction time (RT), known as psychomotor slowing, is well documented in patients with schizophrenia. Fewer studies have shown increased variability of RT in these patients suggesting a basic difference in the distribution of RT. In this study median RT and its variability were measured for visually guided saccades performed by 53 patients and 1089 control subjects. Then average cumulative RT distributions were derived for each group and the RT distribution for each group was modeled using a decision signal rising linearly to a threshold signaling the beginning of the visually guided saccade. There was a small increase in the median RT for patients while their RTs were much more variable from trial to trial leading to a difference in the average RT distribution of the patient group. The model application led to the conclusion that this difference in the distribution of RT for patients could be attributed to a basic difference in information processing leading to the decision to move the eyes to the visually presented target. This information-processing difference could be the result of a difference in the build-up of neuronal activity involved in the generation of visually guided saccades in the frontal cortex.

Plasma testosterone and dehydroepiandrosterone sulfate in male and female patients with dysthymic disorder.

BACKGROUND: Depressive symptomatology has been connected with an activation of the hypothalamus-pituitary-adrenal axis and, in several studies, with reduced androgen levels, while administration of androgens, usually in older subjects, may have positive effects on mood, both in males and females. Regarding dysthymic disorder (DD), low serum testosterone levels have been reported in older males, while information on younger male or on female patients is lacking. METHODS: We assessed the serum levels of testosterone (T), dehydroepiandrosterone sulfate (DHEAS) and cortisol in male and female patients with DD, and compared them to the levels of sex and age matched controls. Eighteen male and 43 female patients in the age range of 22 to 71 years were studied and diagnosed according to the Scheduled Diagnostic Interview for DSM-IV axis I disorders (SCID). Depressive symptomatology was assessed using the Hamilton Depression Rating Scale. Subgroups with subjects below or over 50 years of age were also built and compared. RESULTS: Serum T levels were lower than controls mainly in the subjects aged below 50 years, in both genders. More pronounced were reductions in DHEAS levels both in male and female patients, while cortisol levels were normal or reduced. T levels were positively correlated to both DHEAS and cortisol. The negative correlations of DHEAS and T to age were significant for all groups and subgroups, except in the group of male patients. Four male patients (22%) had T levels below 2.0 ng/ml. CONCLUSIONS: Male and female patients with DD aged below 50 years show reduced gonadal and adrenal androgen levels, and normal to low cortisol levels. These neuroendocrine characteristics differentiate DD from depression, and place this diagnostic group closer to posttraumatic stress disorder.

Adjunctive topiramate in the maintenance treatment of bipolar disorders: an open-label study.

OBJECTIVE: A considerable number of patients with bipolar disorder fail to respond completely to mood stabilizers. The anti-epileptic topiramate shares some pharmacological actions with carbamazepine and valproate. We therefore explored the efficacy and tolerability of topiramate in the prophylaxis of bipolar disorder. METHODS: Fifty-six patients receiving outpatient treatment for bipolar affective disorder who had been on mood stabilizers, and had relapsed at least once in the past 12 months, were treated with topiramate in an add-on design and were evaluated for 1 year. Patients were assessed biweekly for the first 3 months and every month thereafter. RESULTS: Fifty out of 56 patients completed the 1-year study, which indicated that adjunctive topiramate was associated with a significant reduction of new manic and depressive episodes compared to the past 12 months. The most common adverse effects were reduced appetite, fatigue and somnolence. CONCLUSIONS: This was an open-label, uncontrolled study involving retrospective evaluation of episodes prior to the initiation of treatment, and the use of more than one mood stabilizer in a few patients. However, these preliminary observations of adjunctive topiramate as a maintenance treatment encourage further investigations, especially with controlled trials, for its long-term effect.

Manic symptoms associated with quetiapine treatment.

This case illustrates the induction of manic-like symptoms in a 26-year-old male patient with DSM-IV paranoid schizophrenia following treatment with quetiapine. The only drug he had received prior to quetiapine was risperidone which was occasionally taken in the previous 3 years. The manic symptoms remitted after quetiapine withdrawal.

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.

Serotonergic and dopaminergic neuroendocrine responses of male depressive patients before and after a therapeutic ECT course.

BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for major depressive illness, even for patients who do not respond to antidepressant drugs. According to the prevailing neurophysiological hypotheses for depression, it can be expected that an ECT therapeutic course modulates the responsivity of central neurotransmitter systems, but the results up to now have been inconclusive. To test such hypotheses, we studied possible changes in the serotonergic and in dopaminergic systems' responsivity in 11 male patients with major depression by performing neuroendocrine challenge tests before and after a therapeutic ECT course. METHODS: Serotonergic responsivity was assessed by measuring the prolactin and cortisol responses to i. v. administration of the serotonin uptake inhibitor clomipramine (CMI test), and dopaminergic responsivity by measuring the prolactin responses to the dopamine receptor blocker haloperidol (HAL test), administered intramuscularly. The prolactin and cortisol responses during the first and the last ECT of the course (8 to 13 sessions) were also assessed. The CMI and HAL tests were also performed in 13 male healthy subjects. RESULTS: The prolactin responses to CMI were significantly blunted in the patient group compared to the control group, and remained unaltered at the end of the ECT course, although the depressive symptomatology was substantially reduced from 27.8 +/- 7.1 to 4.8 +/- 2.3 points in the Hamilton Depression Rating Scale. The cortisol responses to CMI were blunted before the ECT course compared to controls, but not after the course: there was a moderate increase of cortisol at + 30 min in the CMI test after the ECT course compared to that before ECT (p = 0.05). The prolactin and cortisol responses to the electrical stimulus during the first and the last ECT were identical. CONCLUSIONS: The strong therapeutic effect of ECT in depression, observed already at the end of the course, is not a result of considerable modifications in central serotonergic or dopaminergic responsivity, as revealed by the neuroendocrine challenge tests and the hormone responses to the electrical stimulus. The enhancement of the cortisol responses to CMI after the course may indicate a moderate increase in 5-HT1A receptor responsivity.

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

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 patient's 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.

Biogenic Amine Metabolites During Electroconvulsive Therapy of Melancholic Patients.

We assayed the urinary neurotransmitter metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxy-indoleacetic acid (5-HIAA) in unipolar depressed patients before and after a simulated electroconvulsive therapy ECT (SECT), and during course of 10 ECT sessions. A repeated measures analysis of variance (ANOVA) showed no significant changes in the three-metabolite excretion during the course of ECT. Planned comparisons performed after ANOVA revealed a trend for HVA and 5-HIAA levels to increase after SECT and a significantly higher MHPG excretion after the 10th ECT session. Seven depressed patients who responded favorably to ECT (reduction in Hamilton Rating Scale for Depression score of 50% or more) but not the seven nonresponders had significantly higher MHPG excretion after the final ECT compared to baseline levels. A significant relationship was found between low pretreatment MHPG excretion and therapeutic response.