Problems in evaluating new antipsychotic drugs

A number of novel antipsychotics were registered and introduced into clinical practice in the last decade. These include olanzapine, quetiapine, risperidone, sertindole and zotepine as well as ziprasidone, which is still in the registration process. It quickly became apparent, that it is not always easy to translate results from phase II and III clinical trials into everyday clinical practice. In this context, we discuss methodological aspects that mainly deal with selection of patients for clinical trials and clinical trial methodology. Next to that, an overview of the current knowledge concerning novel antipsychotics is given. There is no doubt that these drugs broaden the therapeutic spectrum made available to patients suffering from schizophrenia. On the other hand, it is evident that there is still a need for a critical evaluation of the risk-benefit-ratio of novel antipsychotics. Clinical psychiatrists also face the challenge to modify some of the traditional treatment approaches. These prerequisites will allow the embedding of novel antipsychotics into modern integrative treatment concepts of schizophrenia.     

Quetiapine: a new atypical antipsychotic

Quetiapine has recently been approved for treatment of psychotic disorders. In short term (6 weeks) trials this atypical antipsychotic was shown to be as efficacious as the standard antipsychotics for the treatment of the positive symptoms of schizophrenia without causing any extrapyramidal symptoms or increase in the prolactin levels. Its efficacy for treating the negative symptoms was variable. Preliminary observations suggest its potential to improve the cognitive deficits of schizophrenia. It is metabolized by the p450 CYP 3A4 system with an estimated elimination half life of 6 hours. The optimal treatment is 300 mg to 400 mg/day in two to three divided oral doses. The most common side effects include dizziness, hypotension, somnolence and weight gain. Changes in the ECG, the thyroid hormone and hepatic enzymes levels appear to be clinically insignificant. Quetiapine interacts with phenytoin, carbamazepine, barbiturates, rifampin and glucocorticoids; and coadministration with these drugs may require dosage adjustment. Doses need not be adjusted when fluoxetine, imipramine, haloperidol and resperidone are coadministered. Quetiapine may enhance the effects of antihypertensive agents and may antagonize those of levodopa and dopamine. Long term efficacy of quetiapine has not been determined. Also undetermined are its effectiveness for treating the first episode and treatment-refractory schizophrenia. Data suggest that quetiapine may be used for the management of psychotic disorders in patients who may not tolerate the side effects of the typical antipsychotics and clozapine. It may also be helpful in patients whose psychotic manifestations did not adequately respond to risperidone and olanzapine.     

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Protecting the Environment

Survey of new technology now on the job     

Sertindole, a new atypical antipsychotic for the treatment of schizophrenia

Recent studies have shown that at least some of the functional effects of serotonin (5-HT) on motoneuron excitability are direct and are mediated via postsynaptic 5-HT receptors on motoneurons. To determine the spatial distribution of direct inputs from the serotonin system on the proximal and distal dendrites of individual motoneurons, we examined identified motoneurons in vivo with a combination of immunohistochemical localization of 5-HT-immunoreactive boutons and intracellular staining with horseradish peroxidase. Seventeen intracellularly stained motoneurons from 12 adult cats were analyzed with light microscopy. Quantitative analysis of 5-HT boutons apposed to dendrites of five representative motoneurons that were entirely reconstructed in three dimensions (each from the lumbosacral spinal cord of a different animal) revealed a total of 7,848 contacts (1,570+/-487 contacts/postsynaptic neuron; mean +/- SD) over the dendrites of these cells. Analysis of contacts on the soma of two of these cells, and on the somas of an additional 12 intracellularly stained motoneurons, revealed a wide range of somatic contacts (11-211 contacts/cell) on motoneuron cell bodies, with an average of 52 contacts/cell. These results indicate that the vast majority of 5-HT-immunoreactive boutons are apposed to dendritic branches rather than to the somatic surface of motoneurons. The spatial distribution of contacts essentially matched the distribution of surface membrane area of the postsynaptic neuron, resulting in a relatively uniform density of contacts (<1/100 microm2) on proximal and distal dendrites. Consequently, the frequency of contacts was higher on the proximal dendritic compartments where available membrane area is greater. There was no preferential distribution of contacts to particular dendrites. Light/electron microscopic correlations were performed on 21 boutons that contacted dendrites (n = 7) of three motoneurons from different animals. At the electron microscope level, most appositions (18/21; 85.7%) selected by our light microscopic criteria were confirmed as direct contacts when the 5-HT boutons were examined through serial sections. Synaptic junctions, generally small and symmetric, were positively identified in only a subset of these cases (n = 6; 28.6%), in part due to the obscuring effects of the peroxidase histochemical precipitate present in both pre- and postsynaptic profiles. A few 5-HT boutons (3/21; 14.3%) selected as contacts by our light microscopic criteria were in fact separated from the adjacent labeled dendrites; in two of these three cases, the separation was due to intrusion of very thin glial lamellae (<0.3 microm in cross section). These results indicate that the bulbospinal serotonergic system(s) provide a significant, direct synaptic input to spinal motoneurons that innervate hindlimb muscles. The nature of the modulatory actions exerted by such widespread synaptic inputs will affect all regions of the somatodendritic membrane and will ultimately depend on the nature of the 5-HT receptors present over different parts of the postsynaptic neuron's dendritic tree.     

Quetiapine: a new atypical antipsychotic for the treatment of schizophrenia

In the first of a new series of updates on recent advances in medication, RICHARD GRAY outlines the dibenzothiazepine quetiapine, which offers an alternative to conventional antipsychotics for the treatment of schizophrenia, with fewer side effects.     

Survey of new technology — Now on line

Translated from Metallurg, No. 4, pp. 28–30, April, 1993.     

Survey of new technology — Now on line

Survey of new technology — Now on line     

Survey of new technology — Now on line

Survey of new technology — Now on line     

Survey of new technology — Now on line

Survey of new technology — Now on line     

Survey of new technology — Now on line

Survey of new technology — Now on line     

Survey of new technology — Now on line

Survey of new technology — Now on line