Propranolol in schizophrenia. Clinical, metabolic, and pharmacological findings.

Six schizophrenic patients received propranolol hydrochloride to evaluate pharmacological, endocrinological, and antipsychotic properties of the drug. They had previously been unsuccessfully treated with phenothiazines. After a drug-free period of two weeks, propranolol was administered in gradually increasing doses. After two to four weeks, a low dose of phenothiazines was added. The clinical effect was evaluated using the Comprehensive Psychopathological Rating Scale. Three of the six patients showed a definite improvement with propranolol therapy given as a sole treatment. Propranolol in plasma was positively correlated to dosage. The proportion of its major metabolite, 4-hydroxy-propranolol, decreased with increasing drug dose. Melatonin and prolactin levels in serum decreased noticeably with propranolol treatment. When phenothiazines were added, prolactin increased above drug-free levels. These results support the view that propranolol has an antipsychotic potential that needs further evaluation in clinical trials.

Clinical experiences and biochemical findings with tacrine (THA).

A clinical comparison of tacrine (THA) and placebo was performed in 15 Alzheimer patients using a double blind crossover technique over 4 plus 4 weeks with one drug-free week in between. Treatment results, as evaluated by clinical rating scales and neuropsychological tests, were mostly negative. Side effects were few, except for elevation liver enzymes which occurred in one third of the patients. CSF levels of the monoamine metabolites HVA and 5-HIAA increased on tacrine as evidence for activation of dopamine and serotonin pathways through cholinergic receptors. Pharmacokinetic investigations showed that the oral bioavailability of tacrine was low and greatly varying between subjects. Patients with high bioavailability of the drug tended to improve more, and also to have more liver enzyme elevations, than those with low bioavailability. A gel preparation for rectal administration was manufactured for comparison of plasma levels attained during one week's treatment with levels attained with oral capsules. Preliminary results indicate that the dose of tacrine can be reduced to 50 per cent when administered rectally, probably as by this route the rapid first-pass metabolism of the drug in the liver is diminished. A clinical trial of tacrine via the rectal route would be justified as this could decrease the number of patients with liver side effects and increase the number of patients improving on the treatment.

Relationships in healthy volunteers between secretion of monoamine metabolites in urine, and family history of psychiatric morbidity.

In 66 physically and mentally healthy human subjects the total concentrations of 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), 5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and dihydroxyphenyl acetic acid (DOPAC) in urine collected between midnight and 8 AM were analyzed by mass fragmentography. In the volunteers reporting the occurrence of psychiatric morbidity among relatives an increased variance in their MOPEG levels was found as compared to the volunteers without such a family history. In the male subjects with no family history of psychiatric disease there was a positive correlation between urine and cerebrospinal fluid levels of MOPEG. The urine levels of 5-HIAA, HVA, and DOPAC did not demonstrate any changes that could be related to psychopathology within the family. Changes in urine secretion of MOPEG indicate an altered metabolism of norepinephrine/MOPEG in some subjects with the occurrence of severe psychiatric disease within the family. MOPEG levels in urine may be a predictor of a family vulnerability for psychiatric morbidity in healthy subjects.

Effects of piracetam on brain monoamine metabolism and serum prolactin levels in the rat.

Levels of monoamine metabolites in three different regions of the rat brain were determined following treatment with piracetam (0.5 and 5 g/kg, i.p.). The concentration of prolactin in serum was also measured. Piracetam, at 5 g/kg, increased the levels of dihydroxyphenylacetic acid, homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, whereas 5-hydroxyindoleacetic acid was unaffected. The drug also increased prolactin concentrations in serum. The level of dopamine was unchanged in the olfactory tubercle and the striatum. These effects are different from those obtained with amphetamine-like drugs. The results would seem to indicate that piracetam accelerates brain catecholamine (CA) turnover via a blockade of CA receptors, as suggested for neuroleptic drugs. This effect could be responsible for the therapeutic action of piracetam on psychotic symptoms in psycho-organic disorders of old age. A blockade of brain CA receptors by piracetam is not compatible with facilitated learning, which seems to be mediated via other neuron systems than CA pathways.

PET studies of the uptake of (S)- and (R)-[11C]nicotine in the human brain: difficulties in visualizing specific receptor binding in vivo.

(S)- and (R)-[11C]nicotine were synthesized by methylation of (S)- and (R)-nornicotine using [11C]methyl iodide. Following their intravenous injection in tracer doses to smoking and nonsmoking healthy males the radioactivity in arterial blood showed a sharp peak at about 1 min followed by a plateau level for the remaining 50 min of recording. Uptake in the brain, as measured by positron emission tomography (PET), was rapid with a peak at 5 min followed by a steady decline towards the end of the measurement. The regional distribution of radioactivity followed essentially the distribution of gray matter with high uptake in the cortex, the thalamus and the basal ganglia and low uptake in the pons, cerebellum and white matter. Levels of the labelled natural enantiomer, (S)-[11C]nicotine, were higher than those of the synthetic enantiomer, (R)-[11C]nicotine, particularly in the smokers. The time-activity curves of (S)-[11C]nicotine uptake were not changed by co-administration of 1.0 mg of unlabelled nicotine with the labelled nicotine. Similarly administration of unlabelled nicotine at the peak of radioactivity, 6 min following (S)-[11C]nicotine, had no effect on the time-activity curves. Thus essential criteria for visualizing receptor binding with the PET technique could not be fulfilled. Calculation of kinetic constants using a two-compartment model gave values indicating that the brain uptake of [11C]nicotine is mainly determined by the cerebral blood flow, extraction of the tracer over the blood-brain barrier and unspecific binding. Thus 11C-labelled nicotine does not seem to be a suitable tracer for PET studies of nicotinic cholinergic receptors in the human brain.

Tricyclic antidepressants: effects on the firing rate of brain noradrenergic neurons.

The spontaneous activity of the norepinephrine-containing cells of the locus coeruleus was recorded in chloral hydrate-anesthetized rats. The effect of seven tricyclic antidepressants on the firing rate of single cells in the locus coeruleus was studied. All the drugs tested, except iprindole markedly decreased the rate of firing of the noradrenergic cells. Antidepressants having a secondary amine in the side chain, desipramine, nortriptyline and chlordesipramine, were more potent than their respective tertiary amine analogues, imipramine, amitriptyline and chlorimipramine. Alteration of the rate of drug metabolism by pretreatment with SKF-525A or phenobarbital did not change the doses of tertiary antidepressnats required to decrease norepinephrine cell firing. Depletion of the norepinephrine stores by pretreatment with alpha-methyl-p-tyrosine and reserpine markedly increased the dose of desipramine required to depress the norepinephrine cells. The results are in good agreement with previous studies showing that secondary amine antidepressants are more potent than their tertiary amine homologues in blocking the uptake of norepinephrine into brain and peripheral tissues. Despite their lower potency it is concluded that tertiary antidepressants act on noradrenergic neurons in their unchanged form and not via secondary amine metabolites formed during the recording experiments since alterations in liver metabolism did not influence the response. The findings are consistent with the suggestion made from studies on transmitter turnover that antidepressants by inhibiting reuptake of norepinephrine cause a stimulation of postsynaptic receptors which decreases the activity of the presynaptic neurons by a feed-back mechanism. This view is further supported by the finding of an inverse relation between the norepinephrine content of the brain and the dose of desipramine required to decrease the firing rate of the noradrenergic neurons.

Levels of cerebrospinal fluid apolipoprotein E in patients with Alzheimer's disease and healthy controls.

One isoform of apolipoprotein E (apoE), a protein primarily involved in transport of lipids, is associated with an increased risk for Alzheimer's disease. Moreover, fragments of apoE are deposited in the amyloid that invariantly are found in brain tissue of disease victims. An intriguing possibility is therefore that increased levels of apoE are involved in the pathogenesis of the disease. Levels of full-length apoE in cerebrospinal fluid from 13 Alzheimer patients and 12 healthy controls were determined using Western blotting technique. Levels of the protein were essentially identical to previously reported findings and no difference between patients and healthy controls was found. Hence, it is concluded that increases in cerebrospinal fluid (CSF) levels of apoE are not involved in the pathogenesis of Alzheimer's disease and that measurement of CSF apoE levels does not seem to be useful as a diagnostic procedure.

Neurotransmitter receptor imaging in Alzheimer's disease.

Recent developments in positron emission tomography and ligand binding techniques have allowed the visualization of regional metabolism and neuroreceptor distributions in the living human brain. For dopamine-D 2 and benzodiazepine receptors it has also been possible to determine neuroreceptor characteristics such as Bmax and Kd by performing in vivo saturation analysis of ligand binding to the receptors. Using 11-C raclopride and 11-C-Ro 15-1788 as ligands for dopamine-D 2 and benzodiazepine receptors respectively we have determined Bmax and Kd-values in healthy volunteers and patients with various types of neuropsychiatric disorders. These ligands were also used in order to determine the degree of receptor occupancy in psychiatric patients treated with different types of drugs interfering with these neuroreceptors. We have administered 11-C-deoxy-glucose, 11-C-raclopride and 11-C-Ro 15-1788 to patients with Alzheimer's disease in order to examine possible alterations of glucose utilization and neuroreceptor distribution and quantities in these patients. The preliminary results indicate that this approach may be useful for the analysis of degenerative alterations of neuron populations and neuroreceptor systems in Alzheimer's disease.

Tacrine in Alzheimer's disease: pharmacokinetic and clinical comparison of oral and rectal administration.

In a previous pharmacokinetic study in Alzheimer patients great inter-individual variation and low oral bioavailability of the cholinesterase inhibitor tacrine (tetrahydroaminoacridine, THA) were found. In the present investigation oral and rectal administration of tacrine were compared with the aim to find a route for improved bioavailability through diminished first-pass metabolism in the liver. Eight patients suffering from Alzheimer's dementia were given tacrine by oral (25 and 50 mg b.i.d.) and rectal (12.5 and 25 mg b.i.d.) routes for 1 week with 4-6 weeks washout in between. Drug hydroxylation capacity in the patients was determined using the debrisoquine test. Levels of tacrine in plasma and cerebrospinal fluid (CSF) were determined and the cognitive performance was examined by the Mini-Mental State Examination (MMSE) and the Alzheimer Deficit Assessment Scale (ADAS). Tacrine was well tolerated in all but one patient, a slow hydroxylator, who developed an aplastic anemia. MMSE and ADAS scores did not significantly change, except for word recall which was improved on tacrine when given by the rectal route. Pharmacokinetic analysis of the two administration routes revealed that the drug dose may be reduced by almost 50% when given rectally compared to orally. Concentrations of tacrine in the CSF were significantly lower and correlated linearly with the concentrations in plasma.

Pharmacokinetics of tetrahydroaminoacridine: relations to clinical and biochemical effects in Alzheimer patients.

The pharmacokinetics of tetrahydroaminoacridine (THA) was studied in patients suffering from Alzheimer's dementia. Single doses of the drug were administered by intravenous (15 mg), oral (50 mg) and rectal routes (25 mg). Pharmacokinetic parameters were related to clinical and biochemical effects in patients who, in a separate study, participated in a clinical trial of oral THA. The bioavailability of THA was low and varied considerably between subjects. Clinical improvement and occurrence of elevated liver enzymes correlated positively with drug bioavailability. Acetyl and butyryl cholinesterase activities in the plasma did not change following THA administration. Rectally administered THA had a higher bioavailability than orally administered THA in three subjects who were given the drug by both routes. These results indicate that a clinical trial of rectal THA would be justified as this administration route may improve resorption and diminish first-pass metabolism of the drug in the liver compared with oral administration.

Smooth pursuit eye tracking, neuropsychological test performance, and computed tomography in schizophrenia.

Smooth pursuit eye movements (SPEM) were measured in 18 patients who met Research Diagnostic Criteria for schizophrenia. Some degree of SPEM impairment was present in most patients. Deviant eye tracking was not related to ratings of severity of illness, but was related to recurrent episodes of hospitalization, antipsychotic medication, and lower ratings in anxiety and delusions. Worse SPEM tended to be associated with larger lateral ventricles as assessed on computed tomography. Three patients with reversed occipital asymmetry had more deviant eye tracking than the remaining patients. Eye movement impairment was related to worse performance in Finger Tapping and in the Trail-Making Test, and to fewer perceived alternations of a Necker cube, suggesting that frontoparietal disturbances are related to poor pursuit eye tracking in schizophrenia.

Cerebroventricular size and cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy volunteers.

Computed tomography (CT) measures and cerebrospinal fluid (CSF) levels of the monoamine metabolites homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were determined in 43 healthy volunteers and in 26 patients with an acute psychosis of the schizophrenic type. There were no differences in the mean CSF levels of monoamine metabolites between the two groups. However, the patients had significantly wider lateral and third ventricles as compared to the volunteers. In the volunteers there were no significant correlations between ventricular sizes and monoamine metabolite levels, whereas in the patients a significant negative correlation was obtained between the size of the lateral ventricles and the levels of HVA and 5-HIAA in the CSF. These results may indicate that the enlargements of the brain ventricles found in a subgroup of schizophrenic patients may be associated with deficiencies in central monoamine transmission mechanisms.

Increased frequency of aberrant CSF circulation in schizophrenic patients compared to healthy volunteers.

In a previous cisternographic study of the cerebrospinal fluid (CSF) circulation in schizophrenic patients, indications for disturbed flow dynamics were found in 10 of 30 subjects. In order to replicate and investigate the clinical and pathophysiological significance of this finding, 39 schizophrenic patients and 42 healthy subjects were examined with an improved method for measurement of CSF circulation. (99m)Tc-DTPA was injected intrathecally and the gamma cisternograms were evaluated blindly. Correlations between cisternography findings and age, duration of disease, previous hospitalizations, positive or negative symptomatology, exposure to neuroleptics, psychiatric family history, CT findings and CSF levels of protein, tryptophan and monoamine metabolites, were calculated. Seven of the patients showed abnormalities in the cisternograms with a slow or obstructed flow of CSF over the convexities (P < 0.01) whereas none of the healthy volunteers showed abnormalities. There were no correlations between disturbed CSF circulation in the patients and the clinical and biochemical parameters, thus the significance of the deviations, similar to other biological aberrations found in schizophrenic patients, is not known. Recent developments in magnetic resonance imaging offer new possibilities to further examine CSF circulation abnormalities in schizophrenia.