Schizophrenia is a mental disorder affecting about 1% of the population. Traditionally, the so-called “typical” antipsychotic drugs have been employed in the treatment. These include the phenothiazines such as chlorpromazine; butyrophenones such as haloperidol; diphenyl butylpiperidines (fluspiriline and pimozide); substituted benzamides (sulpiride); oxypertine; and loxapine. Antipsychotic medications can control symptoms such as delusions, hallucinations and disorganised communication, and maintenance treatment reduces the risk of relapse. However, the typical antipsychotics have limitations, including resistance to treatment in up to one third of patients; a limited effect on negative symptoms such as restricted emotional experience and low social drive; and drug-related adverse effects. Adverse effects are related to the many actions of these drugs - antidopaminergic, anticholinergic, antiadrenergic, antihistamine and antiserotonergic mechanisms. In view of these disadvantages, typical anti-psychotics are not considered to be satisfactory treatments for schizophrenia. Considerable effort has gone into the search for more effective and better-tolerated compounds. Extrapyramidal side effects are particularly important as the greatest cause of non-compliance resulting in treatment failure.
Some of the relatively newer antipsychotics are associated with a lower incidence of extrapyramidal side effects, and are called “atypical” agents. A model atypical agent is clozapine which has a higher affinity for D1- rather than D2-dopaminergic receptors, and also for 5HT 2A-serotonergic and D4-dopaminergic receptors. Its has similar efficacy to the typical antipsychotics on the positive symptoms of schizophrenia and may also be effective in patients who are resistant to these drugs. Some studies have shown benefit on negative symptoms. It produces less extrapyramidal adverse effects and does not appear to cause hyperprolactinaemia. However, it causes antiadrenergic and anticholinergic side effects. An important limitation is agranulocytosis, which occurs in 0.05-2% of patients - ten times more than the phenothiazines.
Newer atypical antipsychotics, such as olanzapine, quetiapine, risperidone and ziprasidone are also effective in treating schizophrenia with fewer extrapyramidal side effects, and are generally better tolerated than clozapine. These drugs are not associated with agranulocytosis. Quetiapine produces D2- and 5-HT2 receptor antagonism, but its receptor blockade is less than that of risperidone. Muscarinic blockade and extrapyramidal side effects are minimal. Quetiapine does not cause a sustained increase in levels of prolactin, but olanzapine and ziprasidone probably do. Risperidone is effective in some ‘treatment-resistant’ patients and can reduce the negative symptoms of schizophrenia. However, extrapyramidal side effects occur at higher doses and serum prolactin levels are raised. Olanzapine is an atypical antipsychotic which produces D2-receptor blockade and 5-HT2-receptor blockade similar to risperidone. Like risperidone, it improves the negative symptoms of schizophrenia. Muscarinic blockade is similar to that with clozapine. It has a lower incidence of extrapyramidal side effects than risperidone.
Another drug with effective antipsychotic activity is sertindole, which also has less extrapyramidal adverse effects compared to traditional antipsychotic drugs. It does not cause marked sedation. However, QTc interval prolongation and cardiac arrhythmias are an important limitation, and sertindole’s marketing authorisation has been suspended in the first country of its launch, the U.K. Sertindole should not be used in combination with medications known to prolong the QTc interval and is contraindicated in patients with clinically significant cardiovascular disease.
From time to time, other drugs also evoke interest. Interest has been shown in eicosapentaenoic acid (EPA), which could be an effective treatment for some patients. Sedation, extrapyramidal side effects and weight gain are avoided. Another interesting possibility is that some of the older antipsychotics could show atypical properties. Most of these typical antipsychotics were evaluated at the time of their introduction several years ago, when the criteria for defining schizophrenia and for drug evaluation were considerably different from what they are today. Thus a relook could provide fresh insights. For example, recent studies have shown that loxapine, a typical antipsychotic, behaves atypically when employed in lower doses, with relative freedom from extrapyramidal side effects. Loxapine also improves the negative symptoms of schizophrenia. This could mean that an important source of “new” drugs could be the old agents themselves. And since atypical antipsychotics seem to be a buzzword today, what’s required is an answer to this incompletely-answered question: What really makes an antipsychotic atypical?
October 2000 Pharma Marketing Page. http://pharmapage.tripod.com/1.html
This article appeared in Pharma Business, November 24, 2000.
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