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
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
Determining the second half of the equation, they said, could lead to
advances in efforts to develop new antipsychotic medications with enhanced
The study, "Equivalent Occupancy of Dopamine
D1and 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