Why Are Low Doses of Clozapine or Remoxipride Effective in Treating lDOPA Psychosis

The psychosis caused by l-DOPA or bromocriptine in Parkinson's Disease can be readily treated by low doses of either clozapine68-72 or remoxipride.73 The average dose for clozapine is 55 mg/day, while that for remoxipride is 150 mg/day, much lower than that used in schizophrenia for either drug (Figure 1).

These lower doses follow directly from the well-known fact that 90 to 99% of brain dopamine has been depleted in Parkinson's disease. Hence, there is virtually no endogenous dopamine to compete against clozapine or remoxipride. The low dose of clozapine corresponds to a low spinal fluid concentration of clozapine and norclozapine, estimated to be of the order of 60 nM (given that the unbound clozapine is 20% of the total plasma clozapine11). Under these conditions, the fraction of D2 receptors occupied would be about 60%.* This D2 occupancy by clozapine may be even lower, possibly 20%, if the estimated free concentration of clozapine in plasma (~10 nM) is used from four Parkinson patients who developed psychosis.74 Because the D2 occupancy by

* Where C/(C + K) is 60 nM/(60 + 44 nM) = 60% of D2.

FIGURE 10 Possible resolution of the findings that ["Cjmethylspiperone, but not ["Cjraclopride reveals elevated densities of D2 in schizophrenia. [3H]Spiperone (S) preferentially labels D2 monomers, while [3H]nemonapride labels D2 monomers and dimers. If radioraclopride (R) behaves as [3H]nemonapride, then one may not expect a change in the density of the total population of D2 receptors in schizophrenia, but the density of D2 monomers may rise as a result of high release of dopamine.84

FIGURE 10 Possible resolution of the findings that ["Cjmethylspiperone, but not ["Cjraclopride reveals elevated densities of D2 in schizophrenia. [3H]Spiperone (S) preferentially labels D2 monomers, while [3H]nemonapride labels D2 monomers and dimers. If radioraclopride (R) behaves as [3H]nemonapride, then one may not expect a change in the density of the total population of D2 receptors in schizophrenia, but the density of D2 monomers may rise as a result of high release of dopamine.84

clozapine in Parkinson patients has not been directly examined, however, the D2 occupancy by clozapine in such patients remains uncertain.

The treatment of l-DOPA psychosis by 150 mg/day of remoxipride would be expected to be associated with about 73%* occupancy of dopamine D2 receptors, in accord with the general rule of 60 to 80% of D2 block for antipsychotic action.

0 0

Post a comment