Atypical Antipsychotics
Atypical antipsychotics, also known as serotonin-dopamine antagonists, have reduced extrapyramidal symptoms (EPS) compared with conventional antipsychotics. They are also believed to reduce the negative, cognitive, and affective symptoms of schizophrenia more effectively. All atypical antipsychotics are potent antagonists of serotonin 5-HT2A and dopamine D2 receptors; however, they also act on many other receptors, including multiple serotonin receptors. The challenge remains to determine which of these secondary pharmacological properties may lead to improved efficacy and which are undesired and account for the side effects.
Clozapine, the first atypical antipsychotic, was developed in 1959 by the small Swiss company Wander AG (which also invented Ovaltine). During the clinical trials, clozapine showed strong sedating effects and proved to be efficacious for schizophrenia, but it also showed some liver toxicity. Wander planned to withdraw the drug because of difficulty in receiving regulatory approval. But the clinicians who participated in clinical trials urged Wander to provide more samples, because their patients fared better on clozapine than on typical antipsychotics. For a population of patients who responded poorly to standard therapy, clozapine was especially effective. Wander AG reluctantly proceeded with more trials and received approval to market clozapine in a few European countries in 1971, although liver toxicity limited its widespread use. Unfortunately, clozapine was removed from the market in 1975 due to rare but potentially fatal drug-associated agranulocytosis, a blood disorder that resulted in lowered white-cell counts. In Finland, eight patients died from subsequent infections. Additional side effects of clozapine therapy include sedation, weight gain, and orthostatic hypotension. Clozapine was reintroduced in 1990 by Sandoz, and it is now used as a second-line treatment that requires extensive monitoring of the patient’s blood cell count. Over the years it has demonstrated efficacy against treatment-resistant schizophrenia, and some still consider it the gold standard for treatment-refractory patients despite the inconvenience of a weekly check of white blood cell counts.
The second atypical antipsychotic was risperidone (trade name Risperdal), introduced by Janssen Pharmaceuticals in Belgium in 1993. «With haloperidol successfully on the market, Janssen systematically explored its clinical utilities. In one trial, they found that a combination therapy of haloperidol and the serotonin antagonist ritanserin improved negative symptoms, depression, and anxiety in patients with schizophrenia. Intrigued, Janssen initiated a medicinal chemistry program led by chemist Anton Megens. Based on the neuroleptics lenprone and benperi-dol, they ultimately discovered risperidone. Within a series of benzisoxa-zole derivatives, risperidone showed a desired combination of very potent serotonin and potent dopamine antagonism. In essence, risperidone possessed the attributes of both ritanserin and haloperidol, a typical antipsychotic. In patients with schizophrenia, risperidone is effective against both positive and negative symptoms with reduced EPS liability and has become a first-line therapy.
The third atypical antipsychotic was Eli Lilly’s olanzapine (Zyprexa), launched in 1996, which brought in $4.28 billion in 2004 (about a third of Lilly’s total sales). Zyprexa, an antagonist against several receptors, including dopamine, serotonin, histamine, adrenergic, and muscarinic receptors, was selected from a large series of chemical analogs based on behavioral tests. Like many atypical antipsychotics, one of the side effects of Zyprexa is weight gain. Ironically, the weight-gain side effects of some atypical antipsychotics may be used as an advantage when they are prescribed off-label to patients with anorexia. Because those patients normally would not eat enough food, the side effect of inducing hunger actually helps them to start eating.
Additional atypical antipsychotics are AstraZeneca’s Seroquel (quetiap-ine; 1997), Pfrzer’s Geodon (ziprasidone; 2001), and Bristol-Myers Squibb/ Otsuka’s Abilify. One of the great advantages of Geodon and Abilify is that they do not have the weight-gain side effect.
