[Clinical evaluation in geriatric psychopharmacology. The point of view of the pharmaceutical industry]. / L'évaluation clinique en psychopharmacologie gériatrique. Le point de vue de l'industrie pharmaceutique.

In order to promote optimal characterization of new drugs for the psychogeriatric patient, a clear delineation of both patients and therapies is needed. Diagnostic evaluation of the patient includes a careful differential diagnosis, a definition of target symptoms and an evaluation of severity and stage of disease. Criteria for assessment of drug efficacy must take into account the pharmacological effects of the drug, the hypothesis to be investigated and the target population. Drug assessment should include indicators of drug activity such as physiological, biochemical or psychometric measurements. In order to facilitate progress in geriatric psychopharmacology, full use should be made of the various hypothesis for drug treatment originating from the rapid advancement in our understanding of the biological basis of senile mental incapacitation.

Hydergine in senile mental impairment.

Among gerontopsychiatric drugs, Hydergine is pharmacologically characterized by agonist action at central dopamine and serotonin receptors. This review presents a summary of the results obtained with Hydergine in numerous controlled trials in patients with senile mental impairment. Assessment was carried out by means of a rating scale (mainly the Sandoz Clinical Assessment Geriatric, or SCAG, scale), psychometric tests (e.g. the Nuremberg Geriatric Inventory, or NGI), and the EEG. Hydergine also lowers serum prolactin, though a correlation with clinical improvement has not been established as yet. In the discussion, the need for objective, measurable and precise indicators in gerontopsychiatry is stressed.

Inhibition of reserpine-induced PGO waves in the cat by ergot derivatives.

The number of reserpine-induced PGO waves in the cat is decreased by administration of ergot derivatives. The inhibition is dose-dependent and the various ergot derivatives show differing potencies. The action of the ergot derivatives may result from stimulation of central serotonin receptors. In addition, possible involvement of dopaminergic systems is discussed.

Changes in the rat electrocorticogram following administration of two dihydrogenated ergot derivatives.

Dihydroergotoxine mesylate (DHET; active substance of Hydergine) and dihydro-beta-ergosine altered the sleep-wakefulness cycle of the rat by increasing wakefulness and decreasing slow wave and rapid eye movement sleep. In addition, power spectrum analysis indicated that, in comparison with placebo, DHET increased total power. Dihydro-beta-ergosine increased relative power in the theta-(4--8 Hz) and in the fast beta-(30--40 Hz) bands of ther electrocorticogram. The alterations in the sleep-wakefulness cycle and in the distribution of power in the rat electrocorticogram are discussed as possible indices of changes in alertness and attention.

Neurochemical and neuropharmacological investigations with four ergot derivatives: bromocriptine, dihydroergotoxine, CF 25-397 and CM 29-712.

Neurochemical and neuropharmacological investigations with four ergot derivatives reveal differential pharmacodynamic effects of these compounds. Bromocriptine and CM 29-712 showed actions typical of postsynaptic dopamine receptor stimulants, in particular in the extrapyramidal system. CM 29-712 proved to be more potent than bromocriptine, with an early onset of action. CF 25-397 and dihydroergotoxine, while not showing all actions typical of central dopamine agonists, appeared to exert some of their effects by means of a stimulation of central serotoninergic sites. In the rat sleep-wakefulness cycles and in reserpine-induced ponto-geniculooccipital waves in the cat, they mimicked the effects of 5-hydroxytryptophan. In the latter test, CF 25-397 proved to be particularly potent. In addition, bromocriptine, dihydroergotoxine and CM 29-712 showed neurochemical effects consistent with central alpha-adrenergic blockade or an enhanced impulse flow in central noradrenergic neurons.

Polygraphic sleep studies in rats and humans: their use in psychopharmacological research.

The effects of selected centrally acting drugs on sleep after single administration to rats and humans were studied using polygraphic sleep recording techniques. D-Amphetamine, a stimulant, had similar effects in both species: reduction of total sleep time, of N(non-)REM- and particularly REM (rapid eye movement)-sleep, increased restlessness during sleep. The psychodepressants mesoridazine and, in particular, nitrazepam had relatively little effects on sleep stages. In doses which did not cause side effects they reduced restlessness during sleep. The most typical effect of the antidepressant imipramine was a dose dependent reduction of REM-sleep duration in both species, without impairment of NREM-sleep. The central dopamine agonist, bromocriptin, had little effect on sleep and did not reduce total sleep and REM-sleep. These examples suggest that polygraphic sleep studies are a sensitive and stable method for the study of centrally acting drugs. The specificity of the model is illustrated by its ability to differentiate chemically and pharmacologically different drug classes. The validity of the model, i.e., its ability to allow predictions from the laboratory conditions to the therapeutic situation, varies in different drug classes. Investigations in normal subjects and animals appear to be relevant for the study of CNS-stimulants, whereas for CNS-depressants studies in sleep-disturbed subjects or animals are more likely to provide dependable results.

Effects of dihydrogenated ergot alkaloids on the sleep-wakefulness cycle and on brain biogenic amines in the rat.

Investigations with four dihydrogenated ergot alkaloids, dihydroergotoxine, dihydroergonine, dihydroergostine and dihydro-beta-ergosine indicate that they exert similar dose dependent effects on the sleep-wakefulness cycle of the rat. The duration of wakefulness was increased, non-rapid eye movement (NREM) and, in particular, rapid eye movement (REM) sleep were shortened. 5-Hydroxytryptophan, but not apomorphine, induced similar changes of the rat sleep-wakefulness cycle. Neurochemical studies on rat brain biogenic amines indicate that dihydroergotoxine lowers homovanillic acid (HVA) levels and reduces HVA elevations after morphine or haloperidol in the striatum. In addition, the turnover of serotonin was slowed down and 5-hydroxyindoleacetic acid (5-HIAA) content in the whole brain was reduced. 5-HIAA elevation induced by clozapine was inhibited. These results suggest that the electroencephalographic changes in the rat produced by treatment with dihydrogenated ergot alkaloids reflect an enhanced level of vigilance and could be related to changes of brain biogenic amine metabolism.

Stimulant properties of bromocriptine on central dopamine receptors in comparison to apomorphine, (+)-amphetamine and L-DOPA.

1. The activity of bromocriptine has been investigated in tests for the stimulation of central dopaminergic mechanisms. The results obtained have been compared with those of apomorphine, (+)-amphetamine and L-DOPA. 2. Bromocriptine (2.5 to 10 mg/kg) induced stereotyped sniffing and licking in rats. The stereotypy was more intense than that induced by L-DOPA and less intense than that of apomorphine and (+)-amphetamine over the dose ranges studied. 3. In rats lesioned unilaterally in the substantia nigra by local injection of 6-hydroxydopamine, bromocriptine, like apomorphine and L-DOPA, induced turning contralateral to the side of the lesion. The smallest dose of bromocriptine to induce turning was 0.5 mg/kg. 4. Reserpine-induced catalepsy in mice was antagonized by bromocriptine, with an ED50 of 1.8 mg/kg. It was intermediate in potency to apomorphine and L-DOPA. 5. Spontaneous locomotor activity in mice was stimulated by bromocriptine in a dose-dependent manner from 2.5 to 10 mg/kg after an initial suppression of activity. 6. In all experiments, bromocriptine was characterized by a prolonged duration of activity after a delay in the onset of effect. 7. The stereotyped behaviour induced by bromocriptine was inhibited by prior administration of pimozide, reserpine or alpha-methyl-p-tyrosine. 8. Bromocriptine-induced turning behaviour was abolished by pretreatment with pimozide, and reduced after alpha-methyl-p-tyrosine treatment. 9. The results obtained support the conclusion that bromocriptine acts by stimulating dopamine receptors in the central nervous system and that intact catecholamine synthesis and granular amine storage mechanisms are necessary for it to bring about its effects.

Inter-group aggression in mice: a new method for testing the effects of centrally active drugs.

A new method is described with which the effects of drugs on aggressive behaviour can be compared with their effects on general activity. Two groups of 3 male mice are housed in either half of a macrolon living cage which is divided down the middle by a non-transparent barrier. After 21 days the cage is placed on an activity meter and the dividing wall is removed. The ensuing fighting is scored by an observer and at the same time activity is measured using the activity meter. It was shown that aggression occurred mainly between groups with the dominant members doing most of the fighting. It appeared further that the two parameters measured--aggression and motor activity--respond differentially to the effects of standard psychotropic drugs. By this means it was possible to distinguish between the effects of chlorpromazine, pentobarbitone, chlordiazepoxide and d-amphetamine. In addition it was possible to confirm that an experimental compound, YG 19-256, which in other tests has been shown to inhibit aggressive behaviour without causing general sedation, also has selective anti-aggressive effects in this test. From these results it seems that the intergroup aggression test could well be useful in identifying different classes of psychotropic agents.