Metyrapone and cocaine: a double-blind, placebo-controlled drug interaction study.

Pre-clinical research suggests that suppression of adrenocorticosteroid synthesis might decrease susceptibility to stress-induced relapse. Metyrapone effectively suppresses cortisol synthesis and thus might have promise as a cocaine dependence treatment. The present inpatient study evaluated the interaction of metyrapone and cocaine to assess the safety of conducting an outpatient trial. Twelve nontreatment-seeking cocaine-dependent individuals completed this double-blind, placebo-controlled, crossover study with two factors: medication (750 mg of metyrapone vs. placebo) and infusion (40 mg of cocaine vs. saline). Safety measures included vital signs, adverse events, and electrocardiogram. Efficacy measures included visual analog scale (VAS) ratings of craving and drug effect. Neuroendocrine measures included cortisol and ACTH. As predicted, metyrapone was well tolerated and did not exacerbate cocaine's physiological effects. Also as predicted, metyrapone did not significantly alter cocaine's subjective effects. The results of the present study suggest that metyrapone at the dose studied can likely be used safely in an outpatient study with active cocaine users.

Evidence that L-deprenyl treatment for one week does not inhibit MAO A or the dopamine transporter in the human brain.

In this study, we investigated whether treatment with L-deprenyl, a selective monoamine oxidase B (MAO B) inhibitor, also inhibits MAO A or the dopamine transporter in the human brain. Six normal volunteers (age 46+/-6 yrs) had two PET sessions, one at baseline and one following L-deprenyl (10 mg/day) for 1 week. Each session included one scan with [11C]clorgyline (to assess MAO A) and one scan 2 hours later with [11C]cocaine (to assess dopamine transporter availability). A 3-compartment model was used to compare the plasma-to-brain transfer constant, K1 (a function of blood flow) and lambdak3 (a kinetic term proportional to brain MAO A) before and after treatment. Dopamine transporter availability was measured as the ratio of distribution volumes of the striatum to cerebellum (DVR) which is equal to Bmax/KD +1. L-Deprenyl treatment for 1 week did not affect either brain MAO A activity or dopamine transporter availability. There was a non-significant trend for an increase in K1 after L-deprenyl. These results confirm that L-deprenyl after one week of treatment at doses typically used clinically is selective for MAO B and that it does not produce a measurable affect on the dopamine transporter, suggesting that MAO A inhibition and dopamine transporter blockade do not contribute to its pharmacological effects.

6-(18)F-DOPA PET study in patients with schizophrenia. Positron emission tomography.

Presynaptic dopamine metabolism was studied in a group of patients with schizophrenia and in an age- and gender-matched normal control group using 6-[(18)F]fluoro-L-DOPA ((18)F-DOPA) and positron emission tomography (PET). Nineteen patients, nine drug-free, 10 on neuroleptics, and 13 normal control subjects underwent PET scans using (18)F-DOPA. The neuroleptic-treated patients were taking typical neuroleptics (N=4) or the atypical neuroleptic, clozapine (N=6). The ratio of specific/non-specific activity was calculated for eight cortical and subcortical regions of interest. Medication-free patients had a significant reduction in (18)F-DOPA uptake in the ventral striatum (P=0.04) and significantly increased uptake in the posterior cingulate (P=0.02) compared with normal control subjects. The 18F-DOPA PET technique proved to be useful and sensitive in detecting changes in dopamine metabolism in patients with schizophrenia in vivo. The results of this study provide evidence of an aberrant dopamine system in schizophrenia.

MRI changes during water loading in patients with polydipsia and intermittent hyponatremia.

OBJECTIVE: Patients with polydipsia and intermittent hyponatremia have greater ventricle-brain ratios (VBRs) than matched patients without polydipsia and intermittent hyponatremia and normal subjects. Unlike previous studies, this study controlled for the impact of water loading when examining the volume of intracranial structures. METHOD: Under controlled conditions, eight male schizophrenic patients with polydipsia and intermittent hyponatremia were first assigned to either normal fluid intake or oral water loading and then the alternative condition the following day. Magnetic resonance imaging (MRI) volumetric measurements were made with the use of a standardized protocol. RESULTS: During water loading, total VBR and lateral ventricle volume significantly decreased by 13.1% and 12.6%, respectively. A strong association between change in serum sodium concentration and change in VBR was noted across conditions. CONCLUSIONS: These findings indicate that 1) water loading does not account for the diminished brain volume observed in patients with polydipsia and intermittent hyponatremia in previous studies, and 2) hyponatremia can significantly alter brain morphology on MRI.

Tardive dyskinesia: possible involvement of free radicals and treatment with vitamin E.

A decade ago a hypothesis introduced to explain tardive dyskinesia (TD) implicated free radicals generated secondary to neuroleptic treatment. Since then many preclinical and clinical studies have investigated this possibility. These studies suggest that free radicals are probably involved in the pathogenesis of TD and that vitamin E could be efficacious in its treatment.

Clonidine does not potentiate the antipsychotic effects of neuroleptics in chronically ill patients.

Clonidine is a centrally acting antihypertensive and has been prescribed widely for more than 20 years. Because it decreases central norepinephrine activity, clonidine has been investigated as an antipsychotic. In most of the preliminary studies, clonidine was tested as the sole antipsychotic agent. We performed a double-blind, placebo-controlled, crossover study to compare a placebo plus a neuroleptic to clonidine plus a neuroleptic in a group of 16 chronically psychotic patients. Of these 16, 3 dropped out secondary to side effects of the clonidine and 1 withdrew from the study. The clonidine dosage varied from 0.2 to 0.6 mg per day. The concurrent neuroleptic (one of the following: haloperidol, thiothixene, thioridazine, mesoridazine, or fluphenazine) averaged 34 mg per day of haloperidol equivalents. Symptoms were monitored using the Psychiatric Symptoms Assessment Scale. The data provided evidence that a clonidine/neuroleptic combination was not more effective than a neuroleptic alone in this group of patients. These data suggest that the central antinorepinephrine activity of a neuroleptic is not potentiated further by clonidine.

The relationship between urine excretion and biogenic amines and their metabolites in cerebrospinal fluid of schizophrenic patients.

Concentrations of norepinephrine and metabolites of biogenic amines were measured in lumbar cerebrospinal fluid of 30 patients with chronic schizophrenia, nine of whom were polyuric. The mean level of norepinephrine was two-fold higher (p < or = 0.025) in polyuric patients than in patients whose excretion of urine was within the normal range. CSF levels of histamine's primary metabolite, tele-methylhistamine, an index of brain histaminergic activity, were positively correlated (p < 0.005) with daily urine volume. These results are consistent with the known influence of norepinephrine and histamine on fluid regulation and suggest that norepinephrine and histamine may be involved in psychogenic polydipsia-polyuria in schizophrenic patients.

Coadministration of fluvoxamine increases serum concentrations of haloperidol.

Four patients with chronic schizophrenia were treated with a combination of fluvoxamine, haloperidol, and benztropine. The combination significantly impaired performance on tests of delayed recall memory and attentional function. Haloperidol concentrations in serum were monitored in three patients and were robustly elevated by fluvoxamine.

Effects of water loading in schizophrenic patients with polydipsia-hyponatremia: an MRI pilot study.

We conducted an MRI pilot study of three schizophrenic patients with the syndrome of polydipsia-hyponatremia. Paired MRI scans were obtained at baseline and in the water-loaded state to study the acute effects of water loading and accompanying changes in serum sodium and osmolality on brain structures. We report the pilot data on the observed individual MRI changes of reduced volume of the lateral ventricles in all three patients, and the third ventricles in two patients, in the water-loaded state. These changes were not statistically significant possibly because of small sample size.

Basal ganglia pathology in schizophrenia and tardive dyskinesia: an MRI quantitative study.

Magnetic resonance imaging was used to measure the volumes of the caudate, putamen, and globus pallidus of 25 schizophrenic patients (17 men and eight women) and 26 age- and sex-matched comparison subjects (18 men and eight women). Schizophrenic patients had significantly larger right and left globus pallidus and right putamen volumes than comparison subjects. There were no significant differences between schizophrenic patients with and without persistent tardive dyskinesia in the volume of any of the three structures.

Basal ganglia iron in tardive dyskinesia: an MRI study.

Alterations in brain iron could play an important role in the development of tardive dyskinesia in patients receiving neuroleptic medication. To test this hypothesis, magnetic resonance imaging scans of the brain were performed on 21 chronic schizophrenic patients. Ten patients met research diagnostic criteria for persistent tardive dyskinesia, and 11 were free of tardive dyskinesia. All patients had received long-term neuroleptic treatment and were on a stable neuroleptic dose for at least 3 months before scanning. The signal intensity of basal ganglia structures was obtained as a quantitative estimate of brain iron content. No difference was found in the signal intensity ratios between the two groups. This suggests that iron deposition in the basal ganglia, at least as assessed by this measure, does not play a role in the pathophysiology of tardive dyskinesia.

Structural abnormalities in deficit and nondeficit schizophrenia.

OBJECTIVE: Previous studies have suggested the involvement of the frontal and parietal cortices and thalamus in a neural circuit underlying the production of primary enduring negative or deficit symptoms of schizophrenia. The purpose of this study was to examine whether structural changes in the proposed circuit are associated with the production of deficit symptoms. METHOD: Magnetic resonance imaging was used to measure the volume of selected circuit brain regions (i.e., the prefrontal region and caudate) and noncircuit brain regions (i.e., the amygdala/hippocampus complex) in 17 deficit and 24 nondeficit schizophrenic outpatients and 30 normal comparison subjects. RESULTS: Right and left total prefrontal volumes discriminated deficit from nondeficit patients, with prefrontal volumes being smaller in nondeficit patients. There were no differences between the two schizophrenic subgroups in left caudate or right and left amygdala/hippocampus complex volumes. The right caudate was larger in deficit patients, but the difference between the two schizophrenic subgroups was not significant. There were no differences between deficit and normal subjects on any prefrontal region measure. Nondeficit patients had smaller total right and left prefrontal volumes than normal subjects. Both schizophrenic subgroups had larger left caudate volumes and smaller right and left amygdala/hippocampus complex volumes than the normal subjects. There was a trend for deficit patients to have larger right caudate volumes. CONCLUSIONS: These results suggest that structural changes in the prefrontal region are not responsible for deficit symptoms. The caudate, particularly the right caudate, may be associated with the production of these symptoms.

Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures.

We used magnetic resonance imaging to examine the morphologic characteristics of the amygdala/hippocampus, prefrontal cortex, and caudate nucleus in 29 healthy volunteers matched for age, gender, and head of household socioeconomic status and 44 patients with chronic schizophrenia. Total volumes of these structures were determined from 3-mm contiguous coronal sections. Schizophrenic patients, compared with healthy controls, had significantly smaller right and left amygdala/hippocampal complex volumes, smaller right and left prefrontal volumes, and larger left caudate volumes. A secondary analysis revealed reductions in the right and left amygdala and the left hippocampus. In addition, prefrontal white matter, but not gray matter, was reduced in the schizophrenic patients. Moreover, the right white matter volume in schizophrenic patients was significantly related to right amygdala/hippocampal volume (r = .39), data that provide preliminary support for a hypothesis of abnormal limbic-cortical connection in schizophrenia. We studied the implications of these data for the pathophysiology of schizophrenia.

Treatment of tardive dyskinesia with vitamin E.

OBJECTIVE: Vitamin E (alpha-tocopherol), a free-radical scavenger, has been reported to improve symptoms of tardive dyskinesia. The authors attempted to replicate this finding under more controlled conditions in a larger study group. METHOD: Fifteen inpatients and six outpatients with tardive dyskinesia received up to 1600 IU/day of vitamin E for 6 weeks in a double-blind, placebo-controlled crossover study. Abnormal Involuntary Movement Scale (AIMS) examinations of these patients were videotaped and rated independently by two trained raters. Levels of neuroleptic medication and vitamin E were measured during both treatment periods. Eighteen patients who demonstrated high blood levels of vitamin E were included in the data analysis. RESULTS: Vitamin E levels were significantly higher while the patients were receiving vitamin E than while they were receiving placebo. For all 18 patients, there were no significant differences between AIMS scores after receiving vitamin E and AIMS scores after receiving placebo. In agreement with previous studies, however, the nine patients who had had tardive dyskinesia for 5 years or less had significantly lower AIMS scores after receiving vitamin E than after receiving placebo. There were no changes in neuroleptic levels during vitamin E treatment. CONCLUSIONS: Vitamin E had a minor beneficial effect on tardive dyskinesia ratings in a selected group of patients who had had tardive dyskinesia for 5 years or less. This effect was not due to an increase in blood levels of neuroleptic medications.

Vitamin E in the treatment of tardive dyskinesia.

Eight subjects with persistent tardive dyskinesia were treated with vitamin E and placebo in a randomized, double-blind crossover study. Their mean score on the Abnormal Involuntary Movement Scale (AIMS) was significantly lower after treatment with vitamin E than after placebo administration.