Tung Ping Su

Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach.

Agents that antagonize the glutamatergic N‐methyl‐d‐aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia. A dysfunction in NMDA–dopaminergic interactions has been proposed as a mechanism for these behavioral effects. In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel 11C‐raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct‐acting dopamine agonist amphetamine. We found that the percent decreases (mean ± SD) in specific 11C‐raclopride binding from baseline for ketamine (11.2 ± 8.9) was greater than for saline (1.9 ± 3.7) (t = 2.4, df = 13, P = 0.003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations. Ketamine‐related binding changes were not significantly different than the decreases in percent change (mean ± SD) in specific 11C‐raclopride binding caused by amphetamine (15.5 ± 6.2) (t = 1.3, df = 19, P = 0.21). Ketamine‐induced changes in 11C‐raclopride‐specific binding were significantly correlated with induction of schizophrenia‐like symptoms. The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed. Synapse 29:142–147, 1998. Published 1998 Wiley‐Liss, Inc.

Fluoxetine in the Treatment of Premenstrual Dysphoria

We performed a double-blind, placebo-controlled, crossover trial of fluoxetine in 17 women with prospectively confirmed PMS who also met criteria for premenstrual dysphoric disorder (PMDD). A subset of 10 women with PMDD and an additional 10 controls participated in a single-dose m-chlorophenylpiperazine (m-CPP) challenge during the follicular and luteal phases of the menstrual cycle. We evaluated the ability of the acute behavioral response to luteal phase m-CPP administration to predict therapeutic response to fluoxetine. Compared with baseline, fluoxetine, but not placebo, treatment significantly improved both emotional and physical symptoms. We identified 11 (65%) fluoxetine responders who no longer met diagnostic criteria for PMDD during fluoxetine but remained symptomatic during placebo treatment. In addition, acute symptomatic improvement also occurred following m-CPP administration in 7 of 10 women with PMDD. The small number of m-CPP nonresponders did not respond to fluoxetine either. Our findings confirm that fluoxetine is an effective treatment of PMDD.

Neuroendocrine and behavioral effects of high-dose anabolic steroid administration in male normal volunteers

OBJECTIVE Despite widespread abuse of anabolic-androgenic steroids (AAS), the endocrine effects of supraphysiologic doses of these compounds remain unclear. We administered the AAS methyltestosterone (MT) to 20 normal volunteers in an in-patient setting, examined its effects on levels of pituitary-gonadal, -thyroid, and -adrenal hormones, and examined potential relationships between endocrine changes and MT-induced psychological symptoms. METHOD Subjects received MT (three days of 40 mg/day, then three days of 240 mg/day) or placebo in a fixed sequence with neither subjects nor raters aware of order. Samples were obtained at the ends of the baseline, high-dose MT and withdrawal phases. Potential relationships between hormonal changes and visual analog scale measured mood changes were examined. RESULTS Significant decreases in plasma levels of gonadotropins, gonadal steroids, sex hormone binding globulin, free T3 and T4, and thyroid binding globulin (Bonferroni t, p<0.01 for each) were seen during high-dose MT; free thyroxine and TSH increased during high-dose MT, with TSH increases reaching significance during withdrawal. No significant changes in pituitary-adrenal hormones were observed. Changes in free thyroxine significantly correlated with changes in aggressiveness (anger, violent feelings, irritability) (r=0.5,p=0.02) and changes in total testosterone correlated significantly with changes in cognitive cluster symptoms (forgetfulness, distractibility) (r=0.52,p=0.02). Hormonal changes did not correlate with plasma MT levels. CONCLUSIONS Acute high-dose MT administration acutely suppresses the reproductive axis and significantly impacts thyroid axis balance without a consistent effect on pituitary-adrenal hormones. Mood and behavioral effects observed during AAS use may in part reflect secondary hormonal changes.

Effects of Atypical Antipsychotic Drug Treatment on Amphetamine-Induced Striatal Dopamine Release in Patients with Psychotic Disorders

Clozapine, risperidone, and other new “atypical” antipsychotic agents are distinguished from traditional neuroleptic drugs by having clinical efficacy with either no or low levels of extrapyramidal symptoms (EPS). Preclinical models have focused on striatal dopamine systems to account for their atypical profile. In this study, we examined the effects of clozapine and risperidone on amphetamine-induced striatal dopamine release in patients with psychotic disorders. A novel 11C-raclopride/PET paradigm was used to derive estimates of amphetamine-induced changes in striatal synaptic dopamine concentrations and patients were scanned while antipsychotic drug-free and during chronic treatment with either clozapine or risperidone. We found that amphetamine produced significant reductions in striatal 11C-raclopride binding during the drug-free and antipsychotic drug treatment phases of the study which reflects enhanced dopamine release in both conditions. There were no significant differences in % 11C-raclopride changes between the two conditions indicating that these atypical agents do not effect amphetamine-related striatal dopamine release. The implications for these data for antipsychotic drug action are discussed.

Cerebrospinal fluid somatostatin, mood, and cognition in multiple sclerosis

BACKGROUND Cerebrospinal fluid (CSF) somatostatin (SS) levels have been shown to be decreased in multiple sclerosis (MS) during relapse as well as in disorders characterized by depression or cognitive impairment. Since MS is often associated with depression and cognitive impairment, we examined both the effect of course of illness on CSF SS as well as the variance in SS attributable to associated features (e.g., depression or cognitive impairment). METHODS Fifteen patients with chronic progressive MS participating in a 2-year cyclosporine trial underwent lumbar punctures for CSF SS at baseline and at 12 and 24 months. Additionally, patients were evaluated by neuropsychological testing, and physical disability and mood ratings. Baseline CSF SS levels were also obtained in a group of control subjects (n = 10). RESULTS At baseline, CSF SS levels were lower in MS patients than control subjects (p < .001). Decreased CSF SS at 24 months was correlated with decreased cognitive performance on several measures and was best and significantly predicted by cognitive deterioration at 24 months. CONCLUSIONS Our data support those from previous studies that found lower levels of CSF SS in MS during relapse and suggest that changes in CSF SS are related to the process responsible for diminished cognitive function in MS.

Gonadotropin-releasing hormone-stimulated gonadotropin levels in women with premenstrual dysphoria

Despite consistent evidence that premenstrual dysphoria (PMD) is not characterized by abnormalities in basal ovarian hormone secretion, the possibility remains that PMD is associated with an abnormality in the regulation of the hypothalamic-pituitary-ovarian (HPO) axis. We studied HPO axis regulation in 11 women with prospectively confirmed PMD and 20 asymptomatic controls, during both the follicular and luteal phases of the menstrual cycle. Plasma levels of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), were obtained before and after stimulation with gonadotropin-releasing hormone (GnRH) (100 μg intravenously). Potential diagnostic- and menstrual cycle phase-related differences in basal and plasma hormone levels were analyzed by repeated-measures analysis of variance. No significant differences were observed between women with PMD and controls in either basal or stimulated levels of FSH and LH. Stimulated FSH was significantly increased and stimulated LH was significantly decreased during the follicular compared with the luteal phase in both women with PMD and controls. These data are consistent with prior findings of normal basal reproductive hormone levels in women with PMD. Our data suggest the absence in women with PMD of an abnormality of dynamic ovarian function as measured by GnRH stimulation.

Neuroanatomical localization of ketamine-induced psychosis in schizophrenic patients and controls

A. Breier, A.K. Malhotra, T.P. Su, D. Ho, J.K. Hsiao, & D. Pickax trois, there was a significant relationship between the decrement of hippocampai volume and the duration of illness (but not age) in schizophrenia. It could be speculated that this may be a neurotoxic effect of repeated psychotic episodes or its treatment (or inadequate treatment?) There are some studies that show gliosis in the hippocampus on postmortem histopathology which would be consistent with our findings, which suggest progressive atrophy rather than static hypoplasia in schizophrenia.