Søren Korsgaard

Behavioral aspects of serotonin-dopamine interaction in the monkey

The effects of serotonin (5-hydroxytryptamine; 5-HT) antagonists and 5-HT uptake inhibitors on the behavioral response to amphetamine and haloperidol in monkeys (cercopithecus aethiops) were investigated. Amphetamine increased locomotor activity and reactivity and induced repetitive movements of head, limbs and trunk, but no oral hyperkinesia. Haloperidol induced dystonia and parkinsonism. Pretreatment with the 5-HT antagonists cyproheptadine and mianserin increased amphetamine-induced locomotor activity, reactivity and repetitive movements and decreased haloperidol-induced dystonia and parkinsonism. Conversely the 5-HT uptake inhibitors paroxetine and CGP 6085 A decreased amphetamine-induced repetitive movements and aggravated haloperidol-induced dystonia and parkinsonism. The 5-HT uptake inhibitors produced oral hyperkinesia resembling human tardive dyskinesia, which was intensified by amphetamine and blocked by haloperidol. These findings support the suggestion that 5-HT inhibits dopamine functions and may imply that 5-HT antagonists could have a beneficial effect against acute extrapyramidal side-effects of neuroleptic treatment. 5-HT uptake inhibitors in the monkey may serve as a model for tardive dyskinesia.

Effects of serotonergic and anticholinergic drugs in haloperidol-induced dystonia in cebus monkeys

In rodents, serotonin (5-HT) antagonists counteract behavioral and biochemical effects of neuroleptic drugs. Therefore, we have studied the effect of different 5-HT drugs and one anticholinergic drug in acute dystonia in five cebus monkeys chronically treated with haloperidol. Acute dystonia induced by subcutaneous injections of haloperidol was slightly reduced by the 5-HT antagonist methysergide (4.0 mg/kg), while mianserin, ketanserin, and ritanserin (R 55 667; a new selective and potent 5-HT receptor blocker) had no effect. This was contrasted by the marked antidystonic effect of the anticholinergic drug biperiden (0.05-1.0 mg/kg). The 5-HT agonist citalopram, a specific 5-HT uptake inhibitor, had no significant effect. It is concluded that 5-HT antagonists have no useful effect in neuroleptic-induced dystonia.

Effect of gamma-vinyl GABA in tardive dyskinesia

gamma-Vinyl GABA (gamma-aminobutyric acid), a drug that increases brain GABA via GABA transaminase inhibition, was evaluated in a blind, placebo-controlled trial in 10 patients with stable tardive dyskinesia. Drug effects during active treatment (2 to 6 g/day) and during pre- and posttreatment placebo periods were determined by scoring randomly sequenced videotapes of tardive dyskinesia and parkinsonian symptoms recorded weekly during standardized examinations. Tardive dyskinesia was significantly reduced, and correlated to increased parkinsonism. Eye blinking rates decreased, but psychiatric symptoms were unchanged during treatment.

Effects of citalopram, a specific serotonin uptake inhibitor, in tardive dyskinesia and parkinsonism

Serotonin (5-HT) has been proposed to exert an inhibitory effect on central dopamine activity, so increased brain 5-HT would be expected to reduce tardive dyskinesia (TD). Therefore a new antidepressant, a selective 5-HT uptake inhibitor, citalopram, was evaluated in 13 psychiatric patients with TD, 11 of whom also had neuroleptic-induced parkinsonism. Drug effects during active treatment (20-40 mg/day for 3 weeks) and pre- and posttreatment placebo periods were scored blindly from videotapes recorded weekly. TD, parkinsonism, and eyeblinking rates were unchanged. Psychiatric symptoms showed no significant changes, and no side effects were reported. The data suggest that increasing 5-HT activity by 5-HT uptake inhibitors has no significant beneficial effect in TD, but citalopram may be advantageous in the treatment of depressed patients who also have TD, as this drug does not aggravate TD as do tricyclic antidepressants.

Effects of mianserin in neuroleptic-induced parkinsonism

It has been proposed that serotonin (5-HT) antagonists counteract neuroleptic-induced extrapyramidal symptoms by disinhibition of dopamine activity. The effects of the 5-HT antagonist mianserin, the anticholinergic drug procyclidine and placebo were evaluated in 16 psychiatric patients with chronic neuroleptic-induced parkinsonism in a double-blind cross-over trial. The patients received each drug in random order in 3-week periods separated by washout periods of 2 weeks. The effect of mianserin did not significantly differ from that of placebo, while parkinsonian symptoms were significantly reduced during treatment with procyclidine (P<0.05). Although mianserin was ineffective in chronic neuroleptic-induced parkinsonism, it cannot be excluded that 5-HT antagonists may be effective in the treatment of acute extrapyramidal side effects.

High-dose destyrosine-γ-endorphin in tardive dyskinesia

Destyrosine-γ-endorphin (DTGE) has purported neuroleptic properties, although the findings have been conflicting. Four chronic psychotic inpatients with neuroleptic-induced dyskinesias were treated with single injections of placebo and DTGE in high doses (20–120 mg). No consistent differences were found in tardive dyskinesia, parkinsonism, eye-blindking rates, or mental status. Laboratory tests were unchanged. It is concluded that acute DTGE treatment has no beneficial effect in drug-induced dyskinesia.

Effects of apomorphine and haloperidol on “spontaneous” stereotyped licking behaviour in the Cebus monkey

Three recently arrived drug naive Cebus apella monkeys with “spontaneous” stereotyped oral movements were treated with apomorphine and haloperidol using a wide dose range. Low doses of apomorphine (0.05–0.1 mg/kg) suppressed the oral stereotypies without affecting normal behaviour such as grooming and scratching. Higher doses of apomorphine (0.25–1.0 mg/kg) and haloperidol (0.01–0.1 mg/kg) also decreased or abolished the oral stereotypies, but induced generalized stereotypies (apomorphine) or dystonia/parkinsonism (haloperidol), suppressing normal behaviour. The findings indicate that dopamine is involved in these presumably stress-induced (not drug-induced) stereotypies.

Klassifikation OG Prævalens Af Ekstrapyramidale Syndromer Hos Psykiatriske Patienter I Neuroleptisk Langtidsbehandling

Neuroleptic-induced neurological side effects have usually been classified as acute dystonia, Parkinsonism, akathisia and tardive dyskinesia (TD). Recent observations in monkeys and man have revealed that classification in this way is over-simplified because nearly identical extrapyramidal syndromes may appear as a result of 1) neuroleptic treatment, 2) withdrawal of neuroleptic treatment and initiation of anticholinergic treatment, or 3) age and/or the psychotic process. The aim of the present study was to determine the prevalence of the these first two syndromes.Two hundred and two long-term neuroleptically treated psychiatric inpatients were evaluated 1) during treatment with their usual neuroleptic medication, but without anticholinergics for 2 days, and 2) after treatment with anticholinergics for 14 days, the last two of which the neuroleptic treatment was stopped. Patients with extrapyramidal symptoms were divided into subgroups depending on response to this pharmacological manipulation: those who ...

Enkephalin, Naloxone, and [Des-Tyr1]-γ-Endorphin in Tardive Dyskinesia

Tardive dyskinesia (TD) is a potentially irreversible hyperkinetic syndrome primarily localized in the muscles of the oral and facial regions, and it may also occur in the limbs and trunk. It develops during or following long-term neuroleptic treatment, especially in elderly patients (Crane, 1973; Tarsy and Baldessarini, 1976; Gerlach, 1979). The pathophysiological mechanisms underlying the syndrome are only partly clarified. Reversible TD appears to depend on reduced dopaminergic neurotransmission during neuroleptic treatment, followed by adaptive phenomena such as postsynaptic dopamine receptor hypersensitivity and cholinergic hypofunction (Tarsy and Baldessarini, 1976). In irreversible TD, these adaptive phenomena may be persistent, and “degenerative” processes may lead to a decreased threshold for spontaneous TD-like dyskinesias (Gerlach, 1979). γ-Aminobutyric acid (GABA) may also be involved in some movement disorders, but the anatomical and functional complexity of GABA influences make it difficult to evaluate their clinical significance. GABA agonists have shown some beneficial effect in the treatment of TD, preferentially in patients concurrently receiving neuroleptics in relatively high doses (Tamminga et al., 1979; Casey et al., 1980; Nair et al., 1980).