The pharmacological and biochemical basis of neuroleptic treatment in schizophrenia

Abstract

In a short review some historical data are presented that underline the importance of the dopamine hypothesis in schizophrenia and the mechanism of action of neuroleptics. The assumption that neuroleptics are postsynaptic dopamine receptor blockers in certain areas of the brain is based on pharmacological, biochemical and clinical findings. New pharmacological data are presented which show that apomorphine, amphetamine, cocaine and caffeine in different ways and at different levels may exert agonist activity on the dopaminergic system in the brain. The agonist activity of these compounds, which is expressed by an increase in motility of the injected animals, can be antagonized by neuroleptics such as haloperidol. However, the higher the dose levels of the agonists, thus the higher the dopaminergic overstimulation, the higher the dose of haloperidol needed to normalize the motility.

These data tend to confirm the dopamine hypothesis and may give some support for the use of individually adapted doses in the treatment of schizophrenia and mania,i.e. doses that match the dopaminergic overstimulation. Thus patients with high dopaminergic overstimulation need higher doses of neuroleptics than patients with low dopaminergic overstimulation. This could explain why some so-called ‘therapy-resistant’ patients, not responding to conventional doses, respond to high doses of neuroleptics. Adapted individualized dose levels, however, also mean low doses of neuroleptics in patients with a low dopaminergic overstimulation. It should be mentioned in this respect that chronic overblockade of the dopaminergic system (overdoses of neuroleptics) may be masked by the concomitant administration of antiparkinson agents and that chronic overblockade may induce dopaminergic hypersensitivity and lead to tardive dyskinesia. Also high doses of neuroleptics therefore should never be given to non-responders over long periods of time.

Although dopamine seems to be a very important neurotransmitter involved in the mechanism of action of neuroleptics, it should be remembered that other neurotransmitters may also be of importance, since the activity of neuroleptics is not necessarily limited to dopamine receptor blockade and schizophrenia is such a complicated disease that its manifestations can hardly be explained by merely the overstimulation of postsynaptic dopamine receptors.