Effects of raclopride treatment on plasma and CSF HVA: relationships with clinical improvement in male schizophrenics.

Thirty-two acutely psychotic, male schizophrenic patients received raclopride, at 2, 6, or 12 mg/day, or haloperidol, 15 mg/day for 4 weeks after randomized, double-blind assignment. Twenty-six patients, including 19 who had been assigned one of the three doses of raclopride, completed the study. Raclopride, particularly at 12 mg/day, increased CSF homovanillic acid (HVA) at 4 weeks, and plasma HVA at 2 days, of treatment. The clinical response to raclopride was significantly correlated with plasma raclopride concentrations and baseline plasma HVA concentrations. Although raclopride is a substituted benzamide with atypical properties in animals, these results suggest that the doses of raclopride required for clinical efficacy and elevation of clinical indices of brain dopamine turnover are similar.

A microassay for measuring synaptosomal 3H-dopamine and 3H-metabolite release.

A modified synaptosomal superfusion apparatus is described which uses less than 10 micrograms of tissue per replicate sample and facilitates the routine separation of 3H-DA, 3H-DOPAC, and 3H-HVA. A flow rate of 1.5 ml/min allows superfusion without the use of reuptake or monoamine oxidase inhibitors. Superfusate samples are collected directly onto alumina columns for the separation of 3H-DA and its acid metabolites. Total recovery of authentic 3H-DA applied via superfusion was 87.63(1.10) percent [Mean(SEM)]. Contamination of the acetic acid eluate fraction, containing 80.98(1.15)% of the total DA, by DOPAC and HVA was less than 0.1%. To illustrate the utility of this technique, the relative proportions of 3H-DA and 3H-metabolites released from synaptosomes by 6 mM potassium and 1 microM reserpine were compared.

Correlates of rapid neuroleptic response in male patients with schizophrenia.

Correlates of neuroleptic response latency were assessed in 16 male schizophrenic inpatients during 4 weeks of fixed dose (20 mg/day) haloperidol treatment. Rapid responders showed a mean 40% reduction in Brief Psychiatric Rating Scale (BPRS) positive symptom scores by day 10 of treatment. Rapid responders had significantly lower plasma homovanillic acid (pHVA) concentrations compared to non-rapid responders during week 4 of haloperidol treatment. However, rapid versus non-rapid responders did not differ with respect to demographics, baseline positive or negative BPRS symptom scores, performance on tests of neuropsychological function, or mean plasma haloperidol concentrations.

Sensitization versus tolerance to the dopamine turnover-elevating effects of haloperidol: the effect of regular/intermittent dosing.

Recent clinical research suggests that particular patterns of changes in presynaptic dopamine (DA) turnover accompany the therapeutic response to neuroleptics. We sought to determine whether daily versus weekly dosing of haloperidol for 3 weeks produced distinct effects on DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) concentrations in multiple brain areas. Daily dosing favored the development of tolerance to the DA-turnover elevating effects of haloperidol in the striatum and nucleus accumbens. Weekly dosing favored the development of sensitization in the striatum, posterior olfactory tubercle, and ventral tegmental area. These results suggest that dosing schedules may determine, at least in part, the effects of chronic neuroleptic administration on presynaptic DA function.

Interrelationships between plasma homovanillic acid and indices of dopamine turnover in multiple brain areas during haloperidol and saline administration.

Haloperidol or saline was administered to rats daily for 1, 8, 15 or 22 days. During haloperidol, but not saline administration, changes in plasma homovanillic acid (HVA) concentrations were correlated with changes in nucleus accumbens HVA. Haloperidol administration also had a significant effect on the intercorrelation of dopamine (DA) concentrations and indices of DA turnover across multiple brain areas. In particular, intercorrelations of HVA concentrations among DA terminal brain areas (i.e. striatum, nucleus accumbens, and olfactory tubercle) occurred only during haloperidol treatment.

Double-blind comparison of alprazolam, diazepam, and placebo for the treatment of negative schizophrenic symptoms.

Fifty-five schizophrenic outpatients with negative symptoms were treated for up to six weeks by the addition of alprazolam (mean dose, 4.2 mg/d), diazepam (mean dose, 40.4 mg/d), or placebo to their ongoing neuroleptic treatment. A repeated-measures analysis of variance with baseline measurements entered as covariates indicated the presence of a significant time X drug interaction effect for the weekly Brief Psychiatric Rating Scale (BPRS) withdrawal/retardation subfactor scores. During the initial weeks of the study, the alprazolam-treated group had lower scores, while the diazepam-treated group had higher scores than the placebo-treated group. However, an end point analysis performed on the final BPRS withdrawal/retardation subfactor scores showed no significant differences among the three groups, nor were beneficial effects observed on any of the BPRS subfactor scores that assess positive symptoms. Plasma alprazolam levels were maintained throughout the study and ranged from 20 to 100 ng/mL. These results suggest that alprazolam had no sustained significant effect on negative schizophrenic symptoms.

Mesolimbic dopaminergic supersensitivity following electrical kindling of the amygdala.

Limbic seizures developed in rats following daily electrical stimulation of the basolateral nucleus of the amygdala. Animals were designated as "kindled" after five complete (stage 5) behavioral seizures were observed. A subgroup, designated as "superkindled," received three additional weeks of electrical stimulations. Kindled rats were significantly subsensitive to the stereotypy-inducing effects of apomorphine, a direct dopamine agonist, compared to controls. Superkindled rats were supersensitive to the effects of apomorphine. However, both kindled and superkindled rats demonstrated an increase in 3H-spiperone Bmax values, reflecting dopamine D2-receptor densities, in the nucleus accumbens ipsilateral to the stimulating electrode. The number of interictal spikes recorded from the stimulating amygdaloid electrode during the last week of kindling was correlated with changes in apomorphine sensitivity in individual animals.

Plasma concentrations of thiothixene and clinical response in treatment-resistant schizophrenics.

Plasma concentrations of thiothixene were measured during treatment of 42 treatment-resistant schizophrenic patients. Inter-individual variability was marked even when patients were treated with the same dose or dose regimen. Intra-individual variability was less but still considerable. A highly significant correlation was found between dose and plasma concentration, but this relationship was unpredictable for individual patients. A median plasma concentration of 12 to 15 ng/ml might be expected with daily doses of 60 mg. No definite range of therapeutic plasma concentrations could be determined. Patients who attained moderate degrees of improvement did so at a median dose of 26 ng/ml, which is within the range of therapeutic plasma concentrations previously reported for thiothixene in similar patients.

Mood alteration following oral and intravenous haloperidol and relationship to drug concentration in normal subjects.

Haloperidol was administered to 12 subjects intravenously (0.125 mg/kg) and to nine subjects orally (0.5 mg/kg). These doses produced sedation in most subjects. A minimal decrease in orthostatic blood pressure was observed. Administration of the Profile of Mood States to these subjects revealed effects on factor 4, vigor-activity, and factor 6, confusion-bewilderment, but many subjects could not complete testing due to excessive sedation. Haloperidol concentrations were obtained during testing and correlated moderately with scores of these subscales. Correlation was also noted between haloperidol concentration and chlorpromazine effect as measured by the Addiction Research Center Inventory. Extrapyramidal reactions, mainly acute dystonic reactions and akathisia, were common. Dystonia occurred in four subjects after intravenous, and three subjects, after oral administration. Akathisia occurred in eight subjects after intravenous, and three subjects after oral administration. Extrapyramidal reactions tended to occur relatively early or relatively late, at times when drug concentrations were far less than peak values.

Treatment of negative schizophrenic symptoms with alprazolam: a preliminary open-label study.

Eight schizophrenic patients received alprazolam in an open-label protocol. A partial reversal of negative symptoms was noted in six of the eight patients. Also, all eight experienced a decrease in anxiety. Alprazolam in doses of 5 to 7 mg/day yielded steady state plasma levels of 6 to 64 ng/ml. As the drug was well tolerated at these doses and as negative symptoms of schizophrenia are difficult to treat, a double-blind, controlled trial of alprazolam is underway to test more rigorously these preliminary results.

Circadian variations of lorazepam-induced neurologic deficits.

Circadian variations of lorazepam-induced neurologic deficits were tested in mice. The duration of the impairment after administration of 3 mg/kg lorazepam was considerably shorter at 2100 h compared to other times of the day. No significant variations could be found for brain concentrations of drug at recovery and 15 or 30 min after drug administration. Food intake did not seem to account for the circadian pattern observed. It was therefore concluded that chronergy of lorazepam is a result of altered sensitivity of the animal over time rather than to altered pharmacokinetics.

Functional tolerance to alprazolam-induced neurologic deficits in mice.

Tolerance to alprazolam-induced neurologic deficits was assessed in mice by a rotarod test. Tolerance was found following a second administration of 2 mg/kg alprazolam 24 h after the first dose and it decayed gradually over a period of several weeks. Brain and plasma concentrations of alprazolam indicated that this tolerance was functional.

Haloperidol kinetics after oral and intravenous doses.

Haloperidol kinetics were determined after oral and intravenous drug doses in 15 men. Mean elimination t1/2 for the subjects was 17.9 +/- 6.4 (SD) hr. After 0.125 mg/kg IV, mean distribution t1/2s in six subjects were 0.19 +/- 0.07 and 2 +/- 1 hr, and in 12 subjects mean clearance was 11.8 +/- 2.9 ml/kg/min and mean steady-state volume of distribution was 17.8 +/- 6.5 l/kg. After 0.50-mg/kg oral doses in eight subjects, mean lag time before drug absorption was 0.82 +/- 0.25 hr. Mean absorption t1/2 was 0.37 +/- 0.18 hr and mean distribution t1/2 was 0.96 +/- 0.20 hr. Bioavailability was 0.65 +/- 0.14 after oral doses. In 14 kinetic studies in nine subjects, data was analyzed by both model-dependent (open two- and three-compartment models using nonlinear regression) and model-independent (AUC and first moment curve) approaches. Results of the two were found to be in close agreement. The long elimination t1/2 of haloperidol is explained by the drug's extensive tissue distribution.

Correlation of initial thiothixene serum levels and clinical response. Comparison of fluorometric, gas chromatographic, and RBC assays.

A series of three experiments addressed major problems concerning the use of serum levels as predictors of clinical response to thiothixene (Navane) hydrochloride in schizophrenia: correlation of initial test doses with clinical response; comparison of fluorescence spectrophotometry with gas chromatography in relation to clinical response; and comparison of serum levels with RBC levels in relation to clinical response. All assays correlated (near r = .5) with Brief Psychiatric Rating Scale improvement during hospitalization, except RBC levels seemed to have superior correlations (.64) in patients with lower serum levels. These correlations are similar to those obtained with steady state levels. The different methods of determining thiothixene concentrations were highly intercorrelated as well. Thus, single-dose serum levels give important clinical correlations regardless of which assay is used for thiothixene determination.

Modification of assays for the routine analysis of 3-methoxy-4-hydroxyphenylglycol in urine by electron-capture gas chromatography.

Urinary 3-methoxy-4-hydroxyphenylglycol has been reliably assayed on a routine basis using an electron-capture detector method. Modifications of previous procedures include simplifcation of extraction and derivatization of urine, inclusion of an internal standard, prevention of losses during concentration, use of each urine as its own standard, and better chromatographic resolution by lengthening of columns and programming temperature. The assay shows a coefficient of variation of 3.1%.

VI. Separation of cannabinoids by sequential thin layer chromatography.

Using a series of solvent systems, one neutral and non-polar, another basic and a third acidic, in a sequential thin layer chromatography (TLC) scheme we developed, cannabinoids can be resolved by their major functional groups into natural neutral, hydroxylated or alcoholic neutrals and acidics.