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Clozapine Study Zeroes In On Dopamine Receptors

Many researchers have searched for the answer to a long-pondered question in antipsychotic pharmacology: just what makes clozapine unique?

Clozapine (Clozaril) stands alone in its effectiveness in the treatment of patients with refractory schizophrenia. As new antipsychotic medications have come (and some gone), researchers have continued their attempts to discover the molecular secrets of the drug, hoping to tease out and exploit those properties that contribute to its effectiveness, while discarding those properties responsible for significant adverse effects.

In a new study using positron emission tomography (PET), researchers have determined that clozapine alone among the newer generation antipsychotics has a relatively balanced affinity for dopamine type 1 (D₁) receptors and dopamine type 2 (D₂) receptors. This balanced D₁/D₂ ratio, they noted, may be the answer to the question. The research, led by Johannes Tauscher, M.D., a professor of psychiatry at the Medical University of Vienna, Austria, along with a group of researchers at the University of Toronto, appears in the September issue of the American Journal of Psychiatry. The work was funded by Eli Lilly Canada.

Many have put forth theories for clozapine's relative superiority in treating schizophrenia patients who have not responded to other medications. It has been noted, for example, that the medication's low propensity to induce extrapyramidal symptoms (EPS) is explained by its combined antagonism of both 5HT-_2A and D₂ receptors, and possibly also its relatively quick dissociation from the D₂ receptor after binding. But while these pharmacologic factors could explain its low EPS profile, researchers believe they do not contribute to an explanation of the drug's greater efficacy in certain patient populations.

Other theories have been put forward, including clozapine's affinity to bind to the D₄ receptor; however, to date, Tauscher and his colleagues stressed, "none of these theories has held so far." The team set out to determine whether the medication's affinity for the D₁ receptor—previously documented in animal studies—could play a role.

Tauscher's team studied 25 patients with schizophrenia or schizoaffective disorder who were receiving ongoing antipsychotic therapy either as inpatients or outpatients. Patients had been on stable doses of second-generation antipsychotics for at least 14 days prior to PET scanning. Seven patients were on clozapine, six on olanzapine (Zyprexa), five on quetiapine (Seroquel), and seven on risperidone (Risperdal). Using two radioligands—specific for either D₁ receptors or D₂ receptors—each patient was scanned using standard PET protocols to determine receptor binding, specifically to dopamine receptors in the striatum.

The affinities for the four antipsychotic medications varied greatly. Clozapine was found to bind the strongest to D₁ receptors (55 percent of D₁ receptors bound), followed in decreasing order by olanzapine (43 percent), risperidone (25 percent), and quetiapine (12 percent). In contrast, risperidone bound most tightly to D₂ (81 percent of receptors bound), followed by olanzapine (79 percent), clozapine (61 percent), and quetiapine (30 percent).

Significantly, Tauscher and his colleagues noted, clozapine is the only one of the four medications to even come close to a ratio of 1. Clozapine's D₁/D₂ binding ratio specifically was 0.88, while olanzapine exhibited a binding ratio of 0.54, quetiapine a ratio of 0.41, and risperidone a ratio of 0.31.

Tausher and his colleagues suggested that their pilot study provides "a strong impetus for prospective clinical studies focusing on the role of dopamine D₁ receptors," while they cautioned that "it is still unclear whether agonistic or antagonistic properties are desirable."

Determining the second half of the equation, they said, could lead to advances in efforts to develop new antipsychotic medications with enhanced therapeutic efficacy.

The study, "Equivalent Occupancy of Dopamine D₁ and D₂ Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics," is posted online at <http://ajp.psychiatryonline.org/cgi/content/full/161/9/1620>.

Am J Psychiatry 2004 161 1620[Abstract/Free Full Text]

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