Mechanism of action of clozapine in the context of dopamine D1-D2 receptor hetero-dimerization--a working hypothesis (original) (raw)
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American Journal of Psychiatry, 2004
Objective: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D 4 receptors, serotonin 5-HT 2A receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D 2 receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D 1 and D 2 receptor profile of clozapine compared with other atypical antipsychotics. Method: Positron emission tomography with the radioligands [ 11 C]SCH23390 and [ 11 C]raclopride was used to investigate D 1 and D 2 receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone. Results: Mean striatal D 1 occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D 2 occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D 1 /D 2 occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31).
Journal of Pharmacology and Experimental Therapeutics, 2005
Drugs that antagonize D 2 -like receptors are effective antipsychotics, but the debilitating movement disorder side effects associated with these drugs cannot be dissociated from dopamine receptor blockade. The "atypical" antipsychotics have a lower propensity to cause extrapyramidal symptoms (EPS), but the molecular basis for this is not fully understood nor is the impact of inverse agonism upon their clinical properties. Using a cell-based functional assay, we demonstrate that overexpression of G␣ o induces constitutive activity in the human D 2 -like receptors (D 2 , D 3 , and D 4 ). A large collection of typical and atypical antipsychotics was profiled for activity at these receptors. Virtually all were D 2 and D 3 inverse agonists, whereas none was D 4 inverse agonist, although many were potent D 4 antagonists. The inverse agonist activity of haloperidol at D 2 Article, publication date, and citation information can be found at
Neuropsychopharmacology, 2006
Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D 2 /D 3 dopamine receptors in human striatum. Here, the occupancy of D 2 /D 3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [ 18 F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D 2 /D 3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, po0.005). While the maximum attainable receptor occupancy E max approached 100% both in the striatum and cortex, the plasma concentration at 50% of E max (ED 50 ) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D 2 /D 3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350-400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.
Progress in Neuro Psychopharmacology Biological Psychiatry, 1998
In vitro receptor autoradiography was used to examine the long-term effects of a typical (fluphenazine), atypical (clozapine), or potential atypical antipsychotic (S[+]-N-npropylnorapomorphine; [+I-NPA) on different dopamine (DA) receptor subtypes. Dt-Like and & receptor levels were not changed with any treatment in any brain region examined. D2 Receptors in caudate-putamen (CPU), nucleus accumbens (NAc) and olfactory tubercle (OT) were significantly increased by long-term treatment with fluphenazine, but not with clozapine or S[+]-NPA. D2 Receptor levels in medial prefrontal cortex (MPC), but not dorsolateral frontal cortex (DFC), were elevated after repeated daily administration of fluphenazine, clozapine, and S[+]-NPA. D4-Like receptors, assayed under D4-selective conditions, were increased by fluphenazine, clozapine and S(+)-NPA in both NAc and CPU, but by none of these treatments in OT, DFC or MPC. These results support a common role for medial prefrontal cortical D2 and striatolimbic D4 receptors in mediating the clinical actions of typical and atypical antipsychotic drugs.
Clozapine can induce high dopamine D 2 receptor occupancy in vivo
Psychopharmacology, 2002
Rationale: Clozapine is a unique antipsychotic with very low propensity to cause motor side effects. In contrast to most other antipsychotics that block more than 70% of dopamine D 2 receptors at therapeutic doses, clozapine occupies less than 70%. Furthermore, even at maximum occupancy, 70% is not exceeded. Several mechanisms have been proposed as explanations for this low D 2 receptor occupancy, but clear evidence is limited. Objectives: In patient studies the data are limited by the dose-range that can be safely used; therefore, the aims of this study were to examine the maximum occupancy of dopamine D 2 receptors with up to 5.0 mg/kg of bolus injection of clozapine to non-human primates and to measure the time course of occupancy. Methods: PET examination with [ 11 C]raclopride was performed to measure the dopamine D 2 receptor occupancy in the striatum of two monkeys after the bolus injection of 0.2-5.0 mg/kg clozapine. [ 11 C]raclopride was injected sequentially to follow the time course of occupancy up to 7 h after the clozapine injection. Results: Dopamine D 2 receptor occupancy reached up to 83% after 5.0 mg/kg clozapine injection. Occupancy decreased with a half-life of 7.22 h after 5.0 mg/kg clozapine and 5.25 h after 1.0 and 2.0 mg/kg clozapine. Conclusions: Clozapine could occupy a high proportion of dopamine D 2 receptors. The time course of occupancy was relatively fast, with a half-life of several hours.
The role of D1–D2 receptor hetero-dimerization in the mechanism of action of clozapine
European Neuropsychopharmacology, 2008
Clozapine is effective although still not perfect drug used to treat schizophrenia. The precise mechanism of its action is not known. Here we show that there are two binding sites for clozapine at the dopamine D 1 and D 2 receptors, and the affinity of D 1 R strongly depended on whether the receptor was present alone or together with D 2 R (or its genetic variant D 2 Ser311Cys) in the cell membrane, pointing to the role of receptor hetero-dimerization in the observed phenomenon. The use of fluorescence resonance energy transfer (FRET) technology, observed via fluorescence lifetime microscopy of the single cell, indicated that low concentration of clozapine (10 − 9 M), sufficient to saturate the high affinity site, uncoupled the D 1 R-D 2 R hetero-dimers. Therefore it has been concluded that clozapine might antagonize the effect of concomitant stimulation of both dopamine receptors, which has been shown previously to enhance the formation of heterodimers and to stimulate the calcium signaling pathway.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2006
Most antipsychotics were thought to induce antipsychotic action at an excess of 70% striatal dopamine D 2 receptor occupancy, while the clinical dose of clozapine was reported to show less than 60% occupancy. High-dose clozapine could occupy as high as 80% of striatal dopamine D 2 receptor in monkey PET studies. Although the time course of dopamine D 2 receptor occupancy is an important property of antipsychotics, that by clozapine has not been investigated in a clinical setting. We measured the time course of extrastriatal dopamine D 2 receptor occupancy with different doses of clozapine and evaluated whether the measured occupancies fitted the binding theory. Three consecutive PET scans with [ 11 C]FLB 457 were performed for two patients with schizophrenia, chronically taking 600 mg/day and 200 mg/ day of clozapine, respectively. Series of occupancies were also measured in combination with fluvoxamine or paroxetine in one patient. Dopamine D 2 receptor occupancies were also simulated using individual clozapine plasma data and previously determined in vivo ED 50 value. The occupancy of one patient with high plasma concentration (1207 ng/ml at peak time) was around 75% at peak and around 60% after 26 h. Another patient with medium plasma concentration (649 ng/ml at peak time) showed less than 50% occupancy at peak, decreasing to 15% after 25 h. The measured occupancy values fitted well with the simulated occupancy values. At high plasma concentration, clozapine can induce high extrastriatal dopamine D 2 receptor occupancy in the human brain, and this finding fitted well with the theoretical estimation. D Abbreviations: PET, positron emission tomography; SSRI, selective serotonin reuptake inhibitor.
New Insights into the Biology of Schizophrenia through the Mechanism of Action of Clozapine
Neuropsychopharmacology, 1995
Many studies have detected in the brain of schizophrenic patients various morphological and structural abnormalities in various regions and in particular in the cortical and limbic areas. These abnormalities might in part result from neurodevelopmental disturbances suggesting that schizophrenia might have organic causes. These abnormalities may be the primary event in schizophrenia and be responsible for altered dopaminergic, but not only dopaminergic, neurotransmission in these regions. If schizophrenia is in some way strictly related to brain morphological abnormalities it becomes hard to believe that a curative treatment will ever be possible. Considering this scenario, treatment of schizophrenia will be restricted to symptomatic and preventive therapy and therefore, more effective and better tolerated antipsychotics are necessary. The widely used classical antipsychotic drugs present some disadvantages. They do not improve all symptoms of schizophrenia, are not effective in all patients, produce a number of unpleasant and serious, and partly irreversible, motor side effects. The atypical antipsychotic clozapine constitutes a major advance in particular for patients not responding to conventional neuroleptics. To explain the unique therapeutic effect of clozapine many hypotheses have been proposed. Most of the explanations given so far assume that the D2 blockade is the basis for the antipsychotic activity of clozapine and that the difference in respect to other antipsychotics is due to the contribution of other
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2001
Conditioned avoidance response (CAR) behavior and catalepsy (CAT) are the standard preclinical tests used to predict antipsychotic activity and motor side-effect liability, respectively. Recent data in patients show that striatal dopamine D(2) occupancy predicts antipsychotic response (at 65% D(2) occupancy) and motor side-effects (at greater than 80%). To relate preclinical and clinical findings, this study examined the relationship between striatal D(2) occupancy, CAT and CAR in rats receiving typical and atypical antipsychotics. CAT was observed in animals receiving haloperidol, risperidone and olanzapine, but only at doses that produced a D(2) receptor occupancy > or =85%. The D(2) occupancy of quetiapine did not cross the 85% threshold (up to 100 mg/kg) and it did not show catalepsy. All drugs were effective in the CAR model at a lower level of D(2) occupancy than was required for catalepsy. We suggest that the CAR and CAT models may have displayed high predictive accuracy b...
Molecular Psychiatry, 1998
This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.