Association study of schizophrenia and the dopamine D3 receptor gene locus in two independent samples.

Using a case-control design, an association of schizophrenia with the dopamine D3 receptor gene (D3RG) locus was investigated. Initial analysis of pooled results from published studies revealed a significant excess of individuals homozygous for either allele among the patients. The association was next tested in two cohorts ascertained independently at Pittsburgh, Pennsylvania and at Houston, Texas. The Pittsburgh sample was comprised of patients with schizophrenia (DSM-III-R) (n = 130). The controls belonged to two groups: adults screened for the absence of substance abuse or major psychiatric illness (n = 128), and neonates (n = 160). Multivariate analysis suggested an association with allele 1 of the biallelic D3RG polymorphism in comparison with the adult, but not the neonatal, controls. The association was most marked among Caucasian patients with a family history of schizophrenia (odds ratio 13.69, confidence intervals 1.80, 104.30). Survival analysis suggested an earlier age of onset among male patients homozygous for allele 2. The Houston cohort included Caucasian patients with schizophrenia or schizoaffective disorder (DSM-III-R criteria, n = 50), and normal controls matched for gender (n = 51). In this group, no significant associations were noted among all the patients or among subgroups of patients based on family history or age of onset. Possible reasons for the discordant results are discussed.

Association between genetic variation at the porphobilinogen deaminase gene and schizophrenia.

There is growing evidence that some genetic predisposition is important in the etiology of schizophrenia. We have sought to implicate a major gene by performing a candidate gene association study comparing the allele frequencies of seven restriction fragment length polymorphisms (RFLPs) at six loci in both a psychiatrically normal control group (N = 51) and an affected (schizophrenia or schizoaffective disorder) group (N = 55). Each group comprised Caucasians of northern European origin. The candidate areas (D5S39, D5S78, dopamine receptor D2 (DRD2), D11S29, porphobilinogen deaminase (PBGD), and D11S84) were selected on the basis of prior cytogenetic findings in schizophrenics, linkage studies, and/or implicated gene products. The presence of a polymorphic ApaLI site within the PBGD gene showed a significant association with the presence of illness (P = 0.02). The relative risk of possessing the allele with the ApaLI site was 2.10. No significant association was found with any of the six other RFLPs. Our data suggests that either the PBGD gene itself or an unknown gene linked to and/or in linkage disequilibrium with the PBGD locus predisposes some individuals to schizophrenia. Independent replication of these findings will be required to determine their relevance to schizophrenia.

Three-dimensional mapping of local cerebral perfusion in alcoholic encephalopathy with and without Wernicke-Korsakoff syndrome.

Seventeen severe chronic alcoholic patients with and without Wernicke-Korsakoff syndrome (WKS) were examined prospectively after being treated by withdrawal from alcohol. The WKS patients also received thiamine supplements. Three-dimensional measurements of local cerebral blood flow (LCBF) and local partition coefficients (L lambda) were made utilizing xenon contrast computed tomography (Xe CT-CBF). Results were displayed as color-coded brain maps before and after treatment and these were correlated with neurological and cognitive examinations. Before treatment chronic alcoholics without WKS (n = 10) showed diffuse reductions of LCBF values throughout all gray matter including hypothalamus, vicinity of nucleus basalis of Meynert, thalamus, and basal ganglia. Similar, but more severe, reductions were seen in patients with WKS (n = 7), however, white matter perfusion was also reduced. In WKS, most prominent reductions of LCBF were also seen in hypothalamus and basal forebrain nuclei but thalamus, basal ganglia, and limbic systems were severely reduced. After treatment, both groups with alcoholic encephalopathy showed marked clinical improvement and cerebral perfusion was restored toward normal. Chronic alcohol abuse, in the absence of thiamine deficiency, reduces CBF by direct neurotoxic effects. If thiamine deficiency is also present, more severe and localized hemodynamic reductions are superimposed.

Abstinence improves cerebral perfusion and brain volume in alcoholic neurotoxicity without Wernicke-Korsakoff syndrome.

Twenty severe chronic alcoholic patients with signs of neurotoxicity but without Wernicke-Korsakoff syndrome were treated by abstinence from alcohol and examined prospectively at intervals thereafter. Serial examinations included detailed medical histories, neurological examinations, cognitive capacity screening examinations, computed tomography scans with measurements of sulcal and ventricular volume, and measurements of regional CBF. All sedatives were withdrawn before CBF measurements were made. Before treatment, gray matter blood flow values were significantly reduced compared with those of age-matched normal volunteers, but white matter blood flow values were normal and the ventricles were enlarged. After abstinence from alcohol, mean gray matter blood flow values and brain volume both increased significantly.

Noradrenergic and cholinergic agents in Korsakoff's syndrome.

Subjects suffering from memory disorders associated with Korsakoff's syndrome were treated with noradrenergic and cholinergic drugs in two phases. In the acute phase, tests of short- and long-term memory were conducted shortly after the administration of methylphenidate, physostigmine, an oral placebo, and an intramuscular placebo. In the chronic phase, the memory tests were given after the subjects had been administered each of the following for 1-week periods: methylphenidate, choline chloride, methylphenidate plus choline chloride, and an oral placebo. Significant improvements were seen in long-term memory scores of patients receiving chronic methylphenidate treatment. Significant improvement was not found in short-term memory measures with any of the drug treatments.

Cerebral atrophy and hypoperfusion improve during treatment of Wernicke-Korsakoff syndrome.

Nineteen patients with sudden onset of impaired recent memory, cerebellar ataxia, peripheral neuropathy, and other signs of Wernicke-Korsakoff syndrome (WKS) were treated and examined prospectively for 3 months. Serial studies included histories, neurological examinations, cognitive capacity screening examinations (CCSE), computed tomography (CT) scans, and measurements of regional CBF. Patients were detoxified and withdrawn from sedatives before CBF measurements were examined. Treatment included alcohol withdrawal, nutritious diet, and 300 mg thiamine daily. Before treatment CCSE scores and blood flow values of both white and gray matter were reduced, particularly within both temporoparietal regions. After treatment of compliant patients (n = 10), white and gray matter blood flow increased concurrently with improved CCSE scores. Abnormal eye signs, ataxia, peripheral neuropathy, and performance of activities of daily living also improved. Cerebral atrophy and ventricular enlargement measured by CT decreased. Early recognition and treatment of WKS in compliant patients permit rapid reversals of cognitive and neurological impairments associated with increased blood flow of gray and white matter and improvements of brain atrophy measured by CT scanning.

Neuroleptic bioequivalency: tablet versus concentrate.

Two forms of the antipsychotic neuroleptic molindone were administered to newly admitted psychotic patients. A coated tablet was administered for ten days, followed by administration of liquid concentrate in equivalent doses for four days. Plasma was analyzed by gas chromatography with electron capture for the parent compound following each dosing phase. Our data suggest that oral doses of the tablet and concentrate forms of this neuroleptic are equivalent in clinical bioavailability.

Nomifensine vs. imipramine in depressed inpatients.

In a double-blind random assignment study, nomifensine was compared to imipramine in a population of depressed male inpatients (N = 36; ages 22-56 years). Nomifensine and imipramine in doses of 100-150 mg/day were found to be comparable over the 4-week treatment period on the Hamilton Depression Rating Scale and Clinical Global Impressions. The Self-Rating Symptom Scale showed differences favoring nomifensine for the Depression factor at Days 3, 7, and 10. In extensive laboratory analyses, no clinically important changes were seen within or between groups. Although differences were not significant, more discomforting side effects--specifically, anticholinergic, nervousness/restlessness, and sedation--were seen in the imipramine than the nomifensine group. These results indicate that nomifensine compares favorably with imipramine in the treatment of depressed inpatients.

Multiple-dose doxepin kinetics in depressed patients.

Doxepin (DOX) and desmethyldoxepin (DMD) kinetics were examined in seven depressed patients receiving single daily doses of 150 mg DOX for 1 to 3 wk. Blood samples were collected at 0, 4, 12, 15, 18, and 24 hr after the first dose, at bedtime before doses 7, 14, and 21, and at 4, 12, 15, 18, and 24 hr after the last dose. Plasma concentrations of DOX and DMD were analyzed by high-pressure liquid chromatography. Clinical response to DOX treatment was evaluated by the Zung self-rating depression scale and the Hamilton rating scale for depression. Mean DOX t1/2 after the first dose was 17.7 hr, and it rose to 21.8 hr after the last dose. Mean DMD t1/2 was not significantly affected by multiple dosing (34.2 hr after first dose and 37.1 hr after last dose). Mean values for plasma clearance, volume of distribution, and first-pass metabolism were 0.87 l/hr/kg, 23.8 l/kg, and 69.5%. In depressed patients kinetics were in the normal range. Steady-state concentrations of DOX and DMD were reached within 2 wk of beginning DOX dosing. The concentration-response curve indicated strong correlation between total DOX concentration (DOX + DMD) and antidepressant effect (r2 = 0.76).

Alprazolam in older depressed inpatients.

Alprazolam, a triazolobenzodiazepine first developed as an anxiolytic, has been shown to be effective in the treatment of depression in several comparison studies with tricyclic antidepressants. This open label study examined the efficacy and safety of alprazolam in patients aged 56-78. Of 18 patients with evaluable data, 12 were responders (improvement greater than or equal to 50% on the Hamilton Depression Rating Scale); 4 patients were partial responders (HAM-D improvement of 25%-49%); and 2 patients were nonresponders. Initial drowsiness was the only side effect observed.

Bupropion in depression: a tri-center placebo-controlled study.

In a double-blind, placebo-controlled, variable-dose study of 59 hospitalized nonpsychotic depressed patients, bupropion was significantly (p less than .05 to less than .001) more effective than placebo on measures of depression, anxiety, and global improvement. Statistically significant drug-placebo differences appeared as early as day 5 of treatment and increased on subsequent assessments. In an evaluation of Baseline X Treatment interactions, bupropion was particularly more effective than placebo in those patients with more severe depression. Placebo and bupropion groups had similar frequencies and severity of side effects. Laboratory data showed minimal differences between the two treatments. The most common adverse experience was mild dry mouth (20% of patients). Compared to placebo, bupropion was found to be effective in the treatment of depression and to have a favorable safety profile.

High-dose benzodiazepine therapy in hospitalized anxious patients.

Severely anxious hospitalized patients were treated with rapidly increasing doses of two benzodiazepine compounds to test the feasibility of rapid pharmacotherapy of the condition. Twenty-one subjects completing the study all obtained substantial relief from symptoms; in only three subjects were symptoms completely eliminated. No serious side effects were encountered.

Pharmacology, efficacy, and adverse effects of halazepam, a new benzodiazepine.

Halazepam is a new benzodiazepine derivative that is molecularly similar to chlordiazepoxide and diazepam. Animal studies indicated that halazepam produces sedative and antianxiety effects with less toxicity than chlordiazepoxide or diazepam. Computer EEG and somatosensory evoked potential studies demonstrated that halazepam has a significant effect on the EEG, characteristic of changes that occur with benzodiazepines. In initial clinical studies, halazepam exhibited not only anxiolytic properties but also reduced symptoms of depression and had a therapeutic effect on epilepsy. In preliminary, uncontrolled clinical trials, halazepam was effective in ameliorating anxiety and tension in alcoholic and acute schizophrenic patients, with few adverse effects. Later double-blind studies generally demonstrated that halazepam is significantly superior to placebo in alleviating symptoms of anxiety and tension. Most comparative studies indicate that halazepam is equal to or more effective than diazepam with a lower frequency of side effects. Halazepam does not increase hostility and aggression, as chlordiazepoxide and diazepam have been shown to do, and it is effective in both situational and characterologic anxiety. Drowsiness and slight dry mouth are the only side effects reported in more than isolated instances, although geriatric patients may frequently become ataxic with higher doses.

A method for the determination of amitriptyline and its metabolites nortriptyline, 10-hydroxyamitriptyline, and 10-hydroxynortriptyline in human plasma using stable isotope dilution and gas chromatography-chemical ionization mass spectrometry (GC-CIMS).

A gas chromatography--mass spectrometry (GC-MS) method has been developed to measure amitriptyline and its metabolites nortriptyline, 10-hydroxyamitriptyline, and 10-hydroxynortriptyline in human plasma. Deuterated analogs of each compound were synthesized as internal standards. Isobutane was used as both gas chromatography (GC) carrier gas and chemical ionization (CI) reagent gas. In order to obtain compounds with satisfactory GC and mass spectrometry (MS) properties, the two alcohol metabolites were dehydrated without loss of label during sample preparation. Selective ion monitoring of the MH+ ions of the protio- and deuterio- compounds gave ion ratios which were converted to plasma concentrations using standard curves. For amitriptyline and nortriptyline, which are assayed using multiple deuterated analogs as internal standards, the curves are straight lines. For 10-hydroxyamitriptyline and 10-hydroxynortriptyline, which are assayed using monodeuterated analogs as internal standards, the curves are nonlinear and are analyzed using an iterative computer procedure. Assay sensitivity is 0.5 ng/ml for amitriptyline, nortriptyline, and 10-hydroxyamitriptyline and 1 ng/ml for 10-hydroxynortriptyline. Assay precision and accuracy in terms of percent error are both less than 5%. Following oral administration of a single 75-mg dose of amitriptyline to two subjects, the mean plasma levels of amitriptyline, nortriptyline, 10-hydroxyamitriptyline, conjugated 10-hydroxyamitriptyline, 10-hydroxynortriptyline, and conjugated 10-hydroxynortriptyline were 36, 8, 10, 66, 16, and 46 ng/ml, respectively, at 2 hr after dosing and 3, 4, 0.5, 1, 6, and 17 ng/ml, respectively, at 72 hr after dosing. Analyses of plasma samples from 12 subjects who had been receiving 50 mg amitriptyline therapy three times a day for an average +/- SD of 32 +/- 5 days gave a mean concentration of 81 +/- 40 ng/ml for amitriptyline, 71 +/- 57 ng/ml for nortriptyline, 12 +/- 5 ng/ml for 10-hydroxyamitriptyline, 91 +/- 30 ng/ml for conjugated 10-hydroxyamitriptyline, 82 +/- 27 ng/ml for 10-hydroxynortriptyline, and 176 +/- 64 ng/ml for conjugated 10-hydroxynortriptyline.