A PET study of D2 and 5-HT2 receptor occupancy induced by risperidone in poor metabolizers of debrisoquin and risperidone

The hydroxylation of the new antipsychotic drug risperidone to its main, active metabolite 9-hydroxyrisperidone is catalyzed by the hepatic cytochrome P450 enzyme CYP2D6, and cosegregates with the polymorphic hydroxylation of debrisoquin. We have previously examined central D₂ dopamine and 5-HT₂ receptor occupancy after 1 mg risperidone orally in three healthy subjects who were extensive metabolizers (EM) of debrisoquin, using positron emission tomography and the radioligands [¹¹C]raclopride and [¹¹C]NMSP. In this study, the same experimental design was repeated in two healthy poor metabolizers (PM) of debrisoquin to compare the D₂ and 5-HT₂ receptor occupancy induced by risperidone in EM and PM. The two PM had much higher plasma concentrations and longer elimination half-lives of risperidone than the three EM. Plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone partly overlapped among the EM and PM. D₂ receptor occupancy was 50% and 54% in the two PM, as compared to 40%, 43% and 55% in the EM. 5-HT₂ receptor occupancy was 63% and 73%, as compared to 45%, 56% and 68% in the EM. These findings support the view that the active 9-hydroxyl metabolite of risperidone contributes to the in vivo effects of risperidone in humans, and thus partly counterbalances the marked variability in the disposition of risperidone.     

Central 5-HT2A and D2 dopamine receptor occupancy after sublingual administration of ORG 5222 in healthy men

It has been suggested that a combined blockade of 5-HT_2A and D₂-dopamine receptors improves efficacy and reduces the risk for extrapyramidal symptoms when treating schizophrenic patients with antipsychotic drugs. ORG 5222 is a new potential anti-psychotic drug which has high affinity for 5-HT_2A, D₂-dopamine and α₁ adrenergic receptors in vitro. The objective of this study was to examine if ORG 5222 occupies 5-HT_2A and D₂-dopamine receptors in human subjects in vivo. Central receptor occupancy was measured by positron emission tomography (PET) in three healthy subjects after sublingual administration of 100 μg ORG 5222. [¹¹C]N-methylspiperone ([¹¹C] NMSP) was the radioligand used to measure 5-HT_2A receptor binding in the neocortex and [¹¹C]raclopride to measure D₂-dopamine receptor binding in the striatum. The 5-HT_2A occupancy was 15–30% and the D₂-dopamine receptor occupancy was 12–23%. The study confirms that ORG 5222 binds to 5-HT_2A and D₂-dopamine receptors in human brain. Since receptor occupancy of ORG 5222 is rather low, doses higher than 100 μg are suggested in future clinical trials to evaluate the antipsychotic drug effect of ORG 5222. Received: 9 September 1996 / Final version: 2 January 1997     

High 5-HT2 receptor occupancy in clozapine treated patients demonstrated by PET

The clinical benefit of the atypical antipsychotic drug clozapine may be related to a combined effect on D₂ and 5-HT₂ receptors. To examine the basis for this hypothesis, positron emission tomography (PET) and the radioligand [¹¹C]N-methylspiperone were used to determine cortical 5-HT₂ receptor occupancy in three psychotic patients treated with 125 mg, 175 mg and 200 mg clozapine daily. The uptake of [¹¹C]N-methylspiperone in the frontal cortex was very low compared to that in neuroleptic naive schizophrenic patients. 5-HT₂ receptor occupancy calculated in the clozapine treated patients was 84%, 87% and 90%. The results show that clinical treatment with clozapine induces a high 5-HT₂ receptor occupancy in psychotic patients at a low dose level.     

Survey on the pharmacodynamics of the new antipsychotic risperidone

This review reports on the pharmacodynamics of the new antipsychotic risperidone. The primary action of risperidone is serotonin 5-HT₂ receptor blockade as shown by displacement of radioligand binding (K_i: 0.16 nM), activity on isolated tissues (EC₅₀:0.5 nM), and antagonism of peripherally (ED₅₀: 0.0011 mg/kg) and centrally (ED₅₀:0.014 mg/kg) acting 5-HT₂ receptor agonists in rats. Risperidone is at least as potent as the specific 5-HT₂ receptor antagonist ritanserin in these tests. Risperidone is also a potent dopamine D₂ receptor antagonist as indicated by displacement of radioligand binding (K_i: 1.4 nM), activity in isolated striatal slices (IC₅₀: 0.89 nM), and antagonism of peripherally (ED₅₀: 0.0057 mg/kg in dogs) and centrally acting D₂ receptor agonists (ED₅₀: 0.056–0.15 mg/kg in rats). Risperidone shows all effects common to D₂ antagonists, including enhancement of prolactin release. However, some central effects such as catalepsy and blockade of motor activity occur at high doses only. Risperidone is 4–10 times less potent than haloperidol as a central D₂ antagonist in rats and it differs from haloperidol by the following characteristics: predominant 5-HT₂ antagonism; LSD antagonism; effects on sleep; smooth dose-response curves for D₂ antagonism; synergism of combined 5-HT₂/D₂ antagonism; pronounced effects on amphetamine-induced oxygen consumption; increased social interaction; and pronounced effects on dopamine (DA) turnover. Risperidone displays similar activity at pre- and postsynaptic D₂ receptors and at D₂ receptors from various rat brain regions. The binding affinity for D₄ and D₃ receptors is 5 and 9 times weaker, respectively, than for D₂ receptors; interaction with D₁ receptors occurs only at very high concentrations. The pharmacological profile of risperidone includes interaction with histamine H₁ and -adrenergic receptors but the compound is devoid of significant interaction with cholinergic and a variety of other types of receptors. Risperidone has excellent oral activity, a rapid onset, and a 24-h duration of action. Its major metabolite, 9-hydroxyrisperidone, closely mimics risperidone in pharmacodynamics. Risperidone can be characterized as a potent D₂ antagonist with predominant 5HT₂ antagonistic activity and optimal pharmacokinetic properties.Unpublished research reports are available from Documentation Service, Janssen Pharmaceutica, B-2340 Beerse, Belgium     

Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study

Rationale The D₁-like dopamine receptors have been suggested to play a role in the pathophysiology and treatment of schizophrenia. Previous positron emission tomography studies have demonstrated that the atypical antipsychotic clozapine occupies D₁-like dopamine receptors in the striatum in clozapine-treated patients. Objectives The aim of the present study was to compare striatal and cortical D₁-like dopamine receptor occupancy by clozapine in the primate brain. Methods Three monkeys were each examined three times at the same day with the radioligand (+)−[¹¹C]NNC 112. The first measurement was at baseline conditions, the second after 1.5 mg/kg and the third after 6 mg/kg clozapine IV. To compare regional levels of nonspecific binding in brain regions, an additional monkey was examined using the inactive enantiomer (−)−[¹¹C]NNC 112. Receptor occupancy was calculated using both the equilibrium–ratio analysis and the simplified reference tissue model. Results After 1.5 mg/kg the D₁-like dopamine receptor occupancy ranged from 30 to 38% in the striatum, whereas the range was 51 to 57% in the frontal cortex. After 6.0 mg/kg the occupancy was 53 to 64% in the striatum and 63 to 83% in the frontal cortex. The differences between striatal and cortical D₁-like receptors occupancy were between 12 and 25%. The study with (−)−[¹¹C]NNC 112 did not show regional differences in nonspecific binding that might explain the regional differences in occupancy. Conclusions The higher D₁-like dopamine receptor occupancy in the frontal cortex may reflect a different distribution of the D₁ and D₅ dopamine receptor subtypes among brain regions and different affinity of clozapine for the two subtypes. The finding supports the suggestion that binding to D₁-like dopamine receptors may explain clozapine’s atypical drug actions.     

Evaluation of dopamine D2/D3 and serotonin 5-HT2A receptor occupancy for a novel antipsychotic, lurasidone, in conscious common marmosets using small-animal positron emission tomography

Rationale

Lurasidone is a novel antipsychotic drug with potent binding affinity for dopamine D₂ and serotonin (5-hydroxytryptamine, 5-HT)_2A, 5-HT₇, and 5-HT_1A receptors. Previous pharmacological studies have revealed that lurasidone exhibits a preferable profile (potent antipsychotic activity and lower incidence of catalepsy) to other antipsychotic drugs, although the contribution of receptor subtypes to this profile remains unclear.

Objectives

To compare target engagements of lurasidone with those of an atypical antipsychotic, olanzapine, we performed evaluation of dopamine D₂/D₃ and serotonin 5-HT_2A receptor occupancy in vivo by positron emission tomography (PET) with conscious common marmosets.

Methods

We measured brain receptor occupancies in conscious common marmosets after oral administrations of lurasidone or olanzapine by PET with [¹¹C]raclopride and [¹¹C]R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907) for D₂/D₃ and 5-HT_2A receptors, respectively.

Results

Increases in brain D₂/D₃ receptor occupancies of both lurasidone and olanzapine, which reached >80 % at maximum, were observed in the striatum with significant correlations to plasma drug levels. However, lurasidone showed lower 5-HT_2A receptor occupancy in the frontal cortex within the same dose range, while olanzapine showed broadly comparable 5-HT_2A and D₂/D₃ receptor occupancies.

Conclusions

Compared with olanzapine, lurasidone preferentially binds to D₂/D₃ receptors rather than 5-HT_2A receptors in common marmosets. These results suggest that the contribution of in vivo 5-HT_2A receptor blocking activity to the pharmacological profile of lurasidone might differ from olanzapine in terms of the low risk of extrapyramidal syndrome and efficacy against negative symptoms.     

In vivo occupancy of dopamine D2 receptors by antipsychotic drugs and novel compounds in the mouse striatum and olfactory tubercles

Interaction with dopamine D₂-like receptors plays a major role in the therapeutic effects of antipsychotic drugs. We examined in vivo dopamine D₂ receptor occupancy of various established and potential antipsychotics in mouse striatum and olfactory tubercles 1 h after administration of the compound, using [³H]nemonapride as a ligand. All the compounds reduced in vivo binding of [³H]nemonapride in the striatum. When administered systemically, conventional antipsychotics, D₂ antagonists, nemonapride (ID₅₀: 0.034 mg/kg), eticlopride (0.047), haloperidol (0.11) and raclopride (0.11) potently inhibited [³H]nemonapride binding. The ‘atypical’ antipsychotics, risperidone (0.18), ziprasidone (0.38), aripiprazole (1.6), olanzapine (0.99), and clozapine (11.1) were less potent for occupying D₂-like receptors. New compounds, displaying marked agonism at 5-HT_1A receptors in addition to D₂ receptor affinity, exhibited varying D₂ receptor occupancy: bifeprunox (0.25), SLV313 (0.78), SSR181507 (1.6) and sarizotan (6.7). ID₅₀ values for inhibition of [³H]nemonapride binding in the striatum correlated with those in the olfactory tubercles (r=0.95, P<0.0001). These values also correlated with previously-reported in vitro affinity of the compounds at rat D₂ receptors (r=0.85, P=0.0001) and with inhibition of apomorphine-induced climbing in mice (r=0.79 P=0.0005). In contrast, there was no significant correlation between ID₅₀ values herein and previously-reported ED₅₀ values for catalepsy in mice. These data indicate that: (1) there is no difference in D₂ receptor occupancy in limbic versus striatal regions between most classical and atypical or potential antipsychotics; and (2) high occupancy of D₂ receptors can be dissociated from catalepsy, if the drugs also activate 5-HT_1A receptors. Taken together, these data support the strategy of simultaneously targeting D₂ receptor blockade and 5-HT_1A receptor activation for new antipsychotics.     

Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography

Rationale

Cariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D₃ and D₂ receptors and moderate affinity to serotonin 5-HT_1A receptors. Targeting receptors other than D₂ may provide a therapeutic benefit for both positive and negative symptoms associated with schizophrenia. Positron emission tomography (PET) can be used as a tool in drug development to assess the in vivo distribution and pharmacological properties of a drug.

Objectives

The objective of this study was to determine dopamine D₂/D₃ and serotonin 5-HT_1A receptor occupancy in monkey brain after the administration of cariprazine.

Methods

We examined three monkeys using the following PET radioligands: [¹¹C]MNPA (an agonist at D₂ and D₃ receptors), [¹¹C]raclopride (an antagonist at D₂ and D₃ receptors), and [¹¹C]WAY-100635 (an antagonist at 5-HT_1A receptors). During each experimental day, the first PET measurement was a baseline study, the second after a low dose of cariprazine, and the third after the administration of a high dose.

Results

We found that cariprazine occupied D₂/D₃ receptors in a dose-dependent and saturable manner, with the lowest dose occupying ~5% of receptors and the highest dose showing more than 90% occupancy. 5-HT_1A receptor occupancy was considerably lower compared with D₂/D₃ occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei.

Conclusions

We conclude that cariprazine binds preferentially to dopamine D₂/D₃ rather than to serotonin 5-HT_1A receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans.     

Occupancy of dopamine D2 receptors by antipsychotic drugs is related to nicotine addiction in young patients with schizophrenia

Rationale Occupancy of dopamine D₂ receptors by antipsychotic drugs depends on the individual availability of D₂ receptors and on the dose and type of antipsychotic medication. It has been suggested that a low availability of these receptors may increase the risk for addictive behavior. Objective This study aims to show that patients with relatively high occupancy of D₂ receptors by antipsychotic drugs are more prone to nicotine consumption. Methods Striatal D₂ receptor occupancy by equivalent doses of olanzapine or risperidone was assessed with [¹²³I]iodobenzamide single-photon emission computed tomography (SPECT) in 36 patients with schizophrenia. Smoking status at the time of SPECT imaging was assessed. The number of cigarettes used in the following three consecutive years was estimated with the Life Chart Schedule (LCS). Results There was a positive and significant relation between D₂ receptor occupancy following treatment with olanzapine (n=19) or risperidone (n=12) and the number of cigarettes smoked in three consecutive years (r=0.60, p<0.001) in patients who smoked. There was a significant difference in the percentage of D₂ occupancy for smokers (mean 74.3%, SD 12.8, n=31) and nonsmokers (mean 49.8%, SD 9.1, n=5). Conclusion Frequency of cigarette smoking in schizophrenic patients treated with antipsychotic medication is significantly and negatively related to the availability of striatal D₂ receptors.     

Targeting the dopamine D2 receptor in schizophrenia

After a 12-year search for the antipsychotic receptor, the binding site was discovered and labelled by [³H]haloperidol in 1975. Of the various neurotransmitters, dopamine was the most potent in inhibiting the binding of [³H]haloperidol, indicating that the antipsychotic receptor was a dopamine receptor, now named the dopamine D₂ receptor, a major targeting site in schizophrenia. All antipsychotic drugs, including traditional and newer antipsychotics, either bind to D₂ in direct relation to their clinical potencies or hinder normal dopamine neurotransmission, as in the case of partial dopamine agonists. In fact, the antipsychotic concentrations found in the plasma water of treated patients closely match the predicted therapeutic absolute concentrations, adjusted for the 60 – 75% D₂ occupancy needed for clinical efficacy. Antipsychotics that elicit low or no Parkinsonism or prolactinaemia are loosely attached to D₂ and rapidly dissociate from D₂, whereas those eliciting Parkinsonism stay tightly attached to D₂ for many hours. Because animal models of psychosis (amfetamine sensitisation, brain lesions) all show a marked elevation in the number of high-affinity states of D₂, the antipsychotics are thought to specifically target these D₂^High states in psychosis in general and schizophrenia in particular.     

Evaluation of SCH 39166 as PET ligand for central D1 dopamine receptor binding and occupancy in man

SCH 39166 is the first selective D₁-dopamine receptor antagonist developed for clinical trials in schizophrenia. SCH 39166 was evaluated as a radioligand for PET, labeled with¹¹C, and as a D₁-dopamine receptor antagonist after single oral doses in healthy men. After intravenous injection of [¹¹C]SCH 39166 distribution of radioactivity in brain grossly reflected D₁-dopamine receptor density. The putamen to cerebellum ratio at equilibrium was low (1.54±0.18 SD), which makes [¹¹C]SCH 39166 less suitable as a radioligand for applied PET studies. Saturability of specific binding was demonstrated after IV injection of [¹¹C]SCH 39166 with low specific radioactivity. Stereospecificity of binding was examined using the stereoisomer [¹¹C]SCH 39165. D₁-Receptor occupancy was demonstrated with [¹¹C]SCH 39166 2 h after administration of single oral doses of unlabeled SCH 39166 to each of three healthy subjects (25, 100 and 400 mg). There was a substantial reduction of specific [¹¹C]SCH 39166 uptake in the putamen after all doses. Single oral doses of 100 mg induced approximately 70% D₁-dopamine receptor occupancy in the basal ganglia, which should be sufficient to investigate the antipsychotic potential of D₁-dopamine receptor antagonism in clinical studies.     

Neuroleptic Malignant Syndrome with Risperidone

Neuroleptic malignant syndrome is thought to be a result of dopamine D₂ receptor blockade in the striatum of the basal ganglia. Risperidone, a benzisoxazole derivative antipsychotic, has high serotonin 5-HT₂ receptor blockade and dose-related D₂ receptor blockade. The high ratio is believed to impart the low frequency of extrapyramidal symptoms with risperidone at low dosages. With this low frequency of extrapyramidal symptoms, it was thought the frequency of neuroleptic malignant syndrome might also be lowered. A 73-year-old woman developed neuroleptic malignant syndrome after monotherapy with risperidone. The syndrome reversed after discontinuing risperidone and starting treatment with dantrolene and bromocriptine. It appears that the protection from extrapyramidal side effects observed with risperidone does not ensure protection from neuroleptic malignant syndrome.     

Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications

Rationale To examine the D₂ occupancy of two commonly used antipsychotic medications and relate this to the D₂ occupancy by endogenous dopamine in schizophrenia.Objectives The aim of this study is to compare the occupancy of striatal D₂ receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D₂ occupancy by dopamine as a result of these treatments.Methods Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [¹²³I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V₃) after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]–1. D₂ receptor occupancy was calculated by comparing V₃ measured in treated patients to an age-corrected V₃ value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1–(V₃ treated/V₃ drug free).Results V₃ was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23±0.06 versus 0.34±0.08, P=0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69±8% versus 55±11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D₂ receptors by antipsychotic medications required to reduce the occupancy of these receptors by endogenous dopamine to control values. In medication-free patients with schizophrenia, the occupancy of striatal D₂ receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D₂ receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D₂ receptors in patients with schizophrenia to control values, 48% receptor occupancy by antipsychotic medications is required.Conclusions These data indicate that the dosage of these medications, found to be effective in the treatment of schizophrenia, reduces DA stimulation of D₂ receptors to levels slightly lower than those found in unmedicated healthy subjects.     

Pharmacokinetic-Pharmacodynamic Modeling of the D2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats

Purpose

A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D₂ and serotonin 5-HT_2A receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats.

Methods

A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D₂ and 5-HT_2A RO data. A previously published physiology- and mechanism-based (PBPKPD) model describing brain concentrations and D₂ receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT_2A receptors in the frontal cortex.

Results

A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D₂ and 5-HT_2A RO well. Inclusion of binding to 5-HT_2A receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern.

Conclusion

Binding to both D₂ and 5-HT_2A receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D₂ and 5-HT_2A receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.     

Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors

The serotonin 5-HT_2A receptor (5-HT_2AR) and dopamine D₂ receptor (D₂R) are high-affinity G protein-coupled receptor targets for two different classes of antipsychotic drugs used to treat schizophrenia. Interestingly, the antipsychotic effects are not based on the regulation of same signaling mediators since activation of the 5-HT_2AR and of the D₂R regulate G_q/11 protein and G_i/o protein, respectively. Here we use radioligand binding and second messenger production assays to provide evidence for a functional crosstalk between 5-HT_2AR and D₂R in brain and in HEK293 cells. D₂R activation increases the hallucinogenic agonist affinity for 5-HT_2AR and decreases the 5-HT_2AR induced inositol phosphate production. In vivo, 5-HT_2AR expression is necessary for the full effects of D₂R antagonist on MK-801-induced locomotor activity. Co-immunoprecipitation studies show that the two receptors can physically interact in HEK293 cells and raise the possibility that a receptor heterocomplex mediates the crosstalk observed. The existence of this 5-HT_2AR-D₂R heteromer and crosstalk may have implications for diseases involving alterations of serotonin and dopamine systems and for the development of new classes of therapeutic drugs.     

A positron emission tomography (PET) study of cerebral dopamine D<Subscript>2</Subscript> and serotonine 5-HT<Subscript>2A</Subscript> receptor occupancy in patients treated with cyamemazine (Tercian)

Rationale Cyamemazine (Tercian) is an antipsychotic drug with anxiolytic properties. Recently, an in vitro study showed that cyamemazine possesses high affinity for serotonin 5-HT_2A receptors, which was fourfold higher than its affinity for dopamine D₂ receptors (Hameg et al. 2003).Objectives The aim of this study is to confirm these previous data in vivo in patients treated with clinically relevant doses of Tercian.Methods Eight patients received 37.5, 75, 150 or 300 mg/day of Tercian depending on their symptomatology. Dopamine D₂ and serotonin 5-HT_2A receptor occupancies (RO) were assessed at steady-state plasma levels of cyamemazine with positron emission tomography (PET), using [¹¹C]raclopride and [¹¹C]N-methyl-spiperone, respectively. The effective plasma level of the drug leading to 50% of receptor occupancy was estimated by fitting RO with plasma levels of cyamemazine at the time of the PET scan.Results Cyamemazine induced near saturation of 5-HT_2A receptors (RO=62.1–98.2%) in the frontal cortex even at low plasma levels of the drug. On the contrary, occupancy of striatal D₂ receptors increased with plasma levels, and no saturation was obtained even at high plasma levels (RO=25.2–74.9%). The effective plasma level of cyamemazine leading to 50% of D₂ receptor occupancy was fourfold higher than that for 5-HT_2A receptors. Accordingly, individual 5-HT_2A/D₂ RO ratios ranged from 1.26 to 2.68. No patients presented relevant increased prolactin levels, and only mild extrapyramidal side effects were noticed on Simpson and Angus Scale.Conclusion This in vivo binding study conducted in patients confirms previous in vitro findings indicating that cyamemazine has a higher affinity for serotonin 5-HT_2A receptors compared to dopamine D₂ receptors. In the dose range 37.5–300 mg, levels of dopamine D₂ occupancy remained below the level for motor side effects observed with typical antipsychotics and is likely to explain the low propensity of the drug to induce extrapyramidal side effects.     

Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine — a123 IBZM single photon emission tomography (SPET) study

We have studied striatal D₂ dopamine binding in schizophrenic patients treated with the novel atypical antipsychotic drug, olanzapine.¹²³I iodobenzamide (IBZM) single photon emission tomography (SPET) was used to estimate striatal dopamine D₂ receptor binding in vivo. Patients were recruited from a prospective, double blind controlled trial of olanzapine versus haloperidol treatment. In vivo striatal D₂ binding data from olanzapine treated patients (n=6) were compared with previously reported data from typical antipsychotic responsive (n=10); clozapine (n=10); and risperidone (n=6) treated patient groups. Mean % Brief Psychiatric Rating Scale score (BPRS) improvement following olanzapine treatment was 49% (SD 44). The hypothesis that clinical improvement in olanzapine treated patients would be associated with higher mean striatal D₂ binding of¹²³I IBZM (reflecting lower levels of D₂ occupancy) than typical antipsychotic (1.25±0.05) or risperidone (1.24±0.04) treatment was confirmed. Olanzapine treated patients had similar levels of striatal D₂ binding in vivo (1.41±0.06) as those treated with clozapine (1.49±0.04). This preliminary evidence suggests olanzapine is another atypical antipsychotic drug in which therapeutic response is not associated with a high degree of striatal D₂ receptor occupancy in vivo.     

Antipsychotics possessing antidepressive efficacy increase G<Subscript>olf</Subscript> protein in rat striatum

Rationale Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects. Objectives In this study, we measured striatal and extrastriatal dopamine D₂ receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose. Materials and methods Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [¹¹C]raclopride and one with [¹¹C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D₂ receptor occupancy was calculated. Results The dopamine D₂ receptor occupancies in the striatum measured with [¹¹C]raclopride and the temporal cortex measured with [¹¹C]FLB 457 were 54.2–85.5% and 34.5–87.3%, respectively. ED₅₀ values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D₂ receptor occupancy between the striatum and the temporal cortex. Conclusions The data from this study suggest that paliperidone ER at 6–9 mg provides an estimated level of dopamine D₂ receptor occupancy between 70–80% and that the magnitude of dopamine D₂ receptor occupancy is similar between the striatum and temporal cortex.     

Dopamine D2 receptor blockade in vivo with the novel antipsychotics risperidone and remoxipride — an123I-IBZM single photon emission tomography (SPET) study

Risperidone and remoxipride are recently introduced atypical antipsychotics, with clinical efficacy comparable to that of classical antipsychotics but lower propensity to induce extrapyramidal side effects (EPS). It is unclear whether these properties relate to weak dopamine D₂ receptor blockade in vivo, as has been suggested for the archetypal atypical antipsychotic clozapine. We have used¹²³I-IBZM single photon emission tomography (SPET) to characterize the patterns of striatal D₂ receptor binding in vivo in DSMIII-R-diagnosed schizophrenic and schizo-affective patients treated with either risperidone (n=6) or remoxipride (n=4) but predominantly EPS free. These groups were compared to age- and BPRS- matched subjects from a previously reported D₂ receptor binding database of patients treated with clozapine (n=10) and classical antipsychotics (n=10). Patients on risperidone and remoxipride had high levels of D₂ receptor blockade, comparable to those of patients on classical antipsychotics, and significantly greater than those obtained with clozapine-treated patients (risperidone versus clozapine,P<0.005; remoxipride versus clozapine,P<0.025). These results suggest high levels of striatal D₂ receptor occupancy in association with remoxipride and risperidone treatment and argue against modest D₂ antagonism as the explanation for the low incidence of EPS associated with these drugs.     

Serotonin 2A receptor antagonists for treatment of schizophrenia

Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D₂) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia.

Areas covered: Preclinical, clinical and post-mortem studies of the serotonin 5-HT_2A system in schizophrenia are reviewed. The implications of a combined D₂ and 5-HT_2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT_2A receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT_2A receptor antagonists for the treatment of schizophrenia.

Expert opinion: 5-HT_2A receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT_2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT_2A receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia.