In vivo determination of striatal dopamine D2 receptor occupancy in patients treated with olanzapine.

In vivo studies of dopamine D2 receptor occupancy with atypical antipsychotics have suggested good clinical efficacy at occupancy rates less than those observed with typical neuroleptics, and few extrapyramidal side effects (EPS), possibly even at high levels of D2 occupancy. We used [123I]IBZM-SPECT to investigate striatal D2 receptor occupancy in 10 schizophrenic patients who were treated with both a low (5 mg) and a high dose (20 mg) of the novel antipsychotic olanzapine without concomitant medications. The mean D2 occupancy at 5 mg was 59.8% (range 33-81%); the mean D2 occupancy at 20 mg was 82.8% (range 56-97%). Although the D2 occupancy rates on 5 and 20 mg olanzapine were significantly different (P < 0.001), there were no significant differences in clinical ratings for psychiatric symptoms or extrapyramidal side effects between the two doses of olanzapine. These data suggest that: (1) olanzapine doses below those used routinely occupy D2 receptors at levels approaching those associated with therapeutic response; (2) higher doses produce relatively high levels of D2 occupancy rates; and (3) EPS are mild even at relatively high levels of D2 occupancy.     

Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography

Risperidone (Risperdal) is a novel antipsychotic drug, with beneficial effects on both positive and negative symptoms of schizophrenia, and with a low incidence of extrapyramidal side effects (EPS). These particular properties have been attributed to the predominant and very potent serotonin 5-HT₂ receptor antagonism of the drug combined with less potent dopamine D₂ antagonism. In order to provide data on the degree to which various central neurotransmitter receptors are occupied in vivo, we performed ex vivo receptor occupancy studies with risperidone in comparison with clozapine and haloperidol in rats and guinea pigs. Various types of receptors, to which the compounds were known to bind to in vitro, were investigated precisely using receptor autoradiography in sections of the same rat brain except for histamine H₁ receptors that were measured in the guinea-pig cerebellum. Risperidone (2 h after s.c. treatment) occupied 5-HT₂ receptors at very low doses (ED₅₀ = 0.067mg/kg). Nearly full occupancy (80%) was achieved before H₁, D₂, α₁ andα₂ receptors became occupied (ED₅₀ = 0.45, 0.66, 0.75and3.7mg/kg, respectively). Clozapine displayed occupancy of H₁ andα₁ receptors at low doses (ED₅₀ = 0.15and0.58mg/kg, respectively) and of 5-HT₂, 5-HT_1C, D₂, α₂, cholinergic muscarinic and 5-HT_1A receptors at higher dosesED₅₀ = 1.3, 1.8, 9.0, 9.5, 11and15mg/kg, respectively). Haloperidol occupied D₂ andα₁ receptors at low doses (ED₅₀ = 0.13and0.42mg/kg, respectively) and 5-HT₂ receptors at a higher dose (ED₅₀ = 2.6mg/kg). Occupancy of receptor types occurred with similar ED₅₀-values in various brain areas, e.g. D₂ receptors in striatum and mesolimbic areas. The ED₅₀-values for the ex vivo measured occupancy of 5-HT₂ and D₂ receptors were in good agreement with ED₅₀-values for functional effects putatively mediated by these central receptors. The dose-dependent occupancy of D₂ receptors proceeded more gradually with risperidone (slope in the caudate-putamen: 0.85) than with clozapine (slope: 1.44) or haloperidol (slope: 1.51). It has previously been suggested that partial D₂ receptor occupancy may suffice to control the positive symptoms of schizophrenia, whereas higher D₂ receptor occupancy would induce extrapyramidal symptoms (EPS). The dose ratio for high (75%) vs. low (25%) D₂ receptor occupancy in the caudate-putamen, was 37.3 for risperidone, 8.4 for clozapine, and 7.9 for haloperidol. It was also suggested that a strong 5-HT₂ receptor blockade preceding a low occupancy of D₂ receptors underlies the beneficial effects on the negative symptoms of schizophrenia and reduces incidence of EPS. At dosages inducing 25% D₂ receptor occupancy in the caudate-putamen, risperidone (0.11 mg/kg) showed 60% occupancy of 5-HT₂ receptors and less than 25% occupancy of the other receptors including H₁ receptors. At 25% D₂ receptor occupancy, clozapine (3.1 mg/kg) resulted in 65% occupancy of 5-HT₂ receptors, but also in more than 80% occupancy ofα₁ receptors and full occupancy of H₁ receptors. At 25% D₂ receptor occupancy, haloperidol (0.048 mg/kg) virtually did not interfere with other receptors. Our study provides evidence that risperidone shows an in vivo receptor occupancy profile in the rat brain that is compatible with the one that is apparently required for beneficial clinical effects, i.e. predominant 5-HT₂ receptor occupancy concomitant with low D₂ receptor occupancy; the gradual increase in D₂ receptor occupancy with increasing dosages provides a wider therapeutic window before EPS-inducing high D₂ receptor occupancy is reached.     

Extrastriatal dopamine D2 receptor occupancy in olanzapine-treated patients with schizophrenia

Olanzapine is described as a multi-acting receptor-targeted antipsychotic agent. Although regional differences of dopamine D₂ receptor occupancy, i.e., limbic selectivity, were reported for olanzapine, contradictory results were also reported. We measured dopamine D₂ receptor occupancy of olanzapine in extrastriatal regions in patients with schizophrenia using positron-emission tomography with [¹¹C]FLB457 and the plasma concentrations of olanzapine. Ten patients with schizophrenia taking 5–20 mg/day of olanzapine participated. Dopamine D₂ receptor occupancy in the temporal cortex ranged from 61.1 to 85.8%, and plasma concentration was from 12.7 to 115.4 ng/ml. The ED₅₀ value was 3.4 mg/day for dose and 10.5 ng/ml for plasma concentration. The ED₅₀ values obtained in this study were quite similar to those previously reported in the striatum. In conclusion, although the subjects and methods were different from previous striatal occupancy studies, these results suggest that limbic occupancy by olanzapine may not be so different from that in the striatum.     

Dopamine- and serotonin-receptors in schizophrenia: results of imaging-studies and implications for pharmacotherapy in schizophrenia

Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. Since psychopharmacological treatment is thought to act on the underlying biological basis of the disease, brain imaging techniques enable us to understand the mechanism of action of such compounds. Positron emission tomography (PET) as well as single photon emission computerized tomography (SPECT) are important tools used to determine patterns of brain dysfunction and to uncover the mechanism of action for antipsychotic compounds. These techniques allow us to determine striatal D₂ receptor as well as cortical 5-HT_2A receptor occupancy rates which are linked, at least partly, to clinical efficacy as well as side effect rates. In general it has been shown that atypical antipsychotics have a lower striatal D₂ receptor occupancy rate than typical antipsychotics, parallelling the more favorable extrapyramidal side effects of atypical antipsychotics, and as a group effect they have a high 5-HT_2A occupancy compared to low rates for typical agents. However, there is no association between striatal D₂ receptor occupancy rates and antipsychotic efficacy but 5-HT_2A occupancy rates are associated with favorable treatment for depressive symptoms within schizophrenia and improvement of cognitive function. The availability of ligands for measurement of extrastriatal D₂ receptors or different 5-HT receptors (e.g. 5-HT_1A) will further shed light on the pathophysiology of schizophrenia as well as possible psychopharmacological treatment perspectives.     

International multisite double-blind trial of the atypical antipsychotics risperidone and olanzapine in 175 elderly patients with chronic schizophrenia.

OBJECTIVE: The authors compared the effects of the two most commonly used atypical antipsychotics, risperidone and olanzapine, in elderly patients with schizophrenia. METHODS: In an 8-week, international, double-blind study, patients (outpatients, hospital inpatients, and residents of nursing or boarding homes) were randomly assigned to receive risperidone (1 mg to 3 mg/day) or olanzapine (5 mg to 20 mg/day). The main outcome measures were changes in Positive and Negative Syndrome Scale (PANSS) total scores and rates of extrapyramidal symptoms (EPS). RESULTS: Subjects were 175 patients age 60 years or over with schizophrenia or schizoaffective disorder. The mean duration of illness was 36.5 years. Median doses were 2 mg/day of risperidone and 10 mg/day of olanzapine. PANSS total scores and four of the five PANSS factor scores (positive symptoms, negative symptoms, disorganized thoughts, and anxiety/depression) improved significantly at all time-points and at endpoint in both groups; between-treatment differences were not significant. EPS-related adverse events were reported by 9.2% of patients in the risperidone group and 15.9% in the olanzapine group; the between-treatment difference was not significant. Total scores on the Extrapyramidal Symptom Rating Scale were reduced in both groups at endpoint; between-treatment differences were not significant. Clinically relevant weight gain was seen in both groups, but was significantly less frequent in risperidone patients than in olanzapine patients. CONCLUSIONS: Stable elderly patients with chronic schizophrenia receiving appropriate doses of risperidone or olanzapine over an 8-week period experienced significant reductions in the severity of psychotic and extrapyramidal symptoms, with a relatively low risk of side effects.     

A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats

It is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D₂-receptor occupancy by antipsychotics within the striatum must exceed 60?65%. However, at high levels of D₂-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D₂-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak?trough fluctuations and consistent D₂-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.     

Double-blind olanzapine vs. haloperidol D2 dopamine receptor blockade in schizophrenic patients: a baseline-endpoint

The aim of this study was to compare in vivo striatal D2 dopamine receptor occupancy induced by olanzapine and haloperidol in schizophrenic patients using a baseline-endpoint [(123)I]IBZM single photon computed emission tomography (SPECT) design. The relationships of striatal D2 receptor occupancy with clinical efficacy and extrapyramidal symptoms (EPS) were also assessed. Twenty-seven inpatients with schizophrenia or schizophreniform disorder were included in a 4-week prospective, randomized, double-blind, parallel and comparative clinical trial. Thirteen patients were treated with haloperidol (10 mg/day) and 14 with olanzapine (10 mg/day). Ratings of clinical status and EPS were obtained weekly. The percentage of D2 receptor occupancy was estimated by using basal ganglia (striatum)/frontal cortex IBZM uptake ratios obtained from each patient before and after 4 weeks of maintained antipsychotic treatment. Olanzapine led to a mean striatal D2 receptor occupancy of 49% (range 28-69%), which was significantly lower than that induced by haloperidol (mean 64%, range 46-90%). The baseline-endpoint SPECT design used in this study revealed lower antipsychotic D2 occupancy percentage values than those reported in the literature, using other approaches. The degree of striatal D2 receptor occupancy correlated to the EPS, which predominantly appeared in patients on haloperidol. No relationship was found between the striatal D2 receptor occupancy and clinical improvement. Olanzapine induced a lower striatal D2 occupancy than haloperidol. This low striatal D2 occupancy, together with the lower incidence of EPS in olanzapine-treated patients, contributed to confirm the atypical behavior of this new antipsychotic drug. Nevertheless, conclusions based on SPECT-estimated percentages of antipsychotic D2 occupancy should be cautious, since the SPECT design could influence the results. In this regard, SPECT studies including baseline and endpoint examinations should be encouraged.     

Differential effects of subchronic treatments with atypical antipsychotic drugs on dopamine D2 and serotonin 5-HT2A receptors in the rat brain

Summary. The effects of 3-week treatment with a typical antipsychotic drug chlorpromazine and three atypical antipsychotic drugs (risperidone, olanzapine and perospirone) on the binding to dopamine D₂ and serotonin 5-HT_2A receptors were examined in the rat stratum and frontal cortex, respectively. Subchronic treatment with chlorpromazine (10 mg/kg) and perospirone (1 mg/kg) significantly increased D₂ receptors, while no increase was observed with lower dose of chlorpromazine (5 mg/kg), perospirone (0.1 mg/kg), risperidone (0.25, 0.5 mg/kg) or olanzapine (1, 2 mg/kg). On the other hand, 3-week administration of chlorpromazine (5, 10 mg/kg) and olanzapine (1, 2 mg/kg) significantly decreased 5-HT_2A receptors, but risperidone (0.25, 0.5 mg/kg) or perospirone (0.1, 1 mg/kg) had no effect. The measurement of in vivo drug occupation for D₂ and 5-HT_2A receptors using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) suggested that high occupation of 5-HT_2A receptors with lower D₂ receptor occupancy might be involved in the absence of up-regulation of D₂ receptors after subchronic treatment with some atypical antipsychotic drugs. Received September 24, 1999; accepted December 1, 1999     

Long‐term effects of iloperidone on cerebral dopamine receptor subtypes

The atypical antipsychotic drug iloperidone has high affinity for a wide range of neurotransmitter receptors, including dopaminergic (DA), serotonergic, and adrenergic receptors. We examined the long‐term effects of multiple doses of iloperidone on DA D₁, D₂, D₃, and D₄ receptor subtypes. Sprague‐Dawley adult rats (n = 8/group) received daily intraperitoneal injections of iloperiodone (0.5, 1, or 5 mg/kg) or vehicle for 4 weeks. Receptor autoradiography quantified the levels of DA receptors in medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus (HIP). Four weeks of iloperidone treatment at 5 mg/kg significantly increased D₁ receptors in NAc (36%) and CPu (38%). Iloperidone (1.5 and 5 mg/kg) dose‐dependently increased D₂ receptors in MPC (37 and 47%) and HIP (32 and 40%). Only the high dose of iloperidone (5 mg/kg) increased D₂ receptors in NAc (39%) and CPu (38%). Repeated treatment with iloperidone (1.5 and 5 mg/kg) increased D₄ receptors in the NAc (39 and 78%), CPu (42 and 83%) and HIP (54 and 72%). The three doses of iloperidone failed to alter D₃ receptors in the brain regions examined in this study. These results suggest that iloperidone exerts region‐ and dose‐specific effects on forebrain DA receptor subtypes, which may contribute to its therapeutic benefits in improving the positive and negative symptoms of schizophrenia with minimal extrapyramidal side effects.     

Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia

OBJECTIVE: Since all antipsychotics block dopamine D(2) receptors, the authors investigated how well D(2) receptor occupancy in vivo predicts clinical response, extrapyramidal side effects, and hyperprolactinemia. METHOD: In a double-blind study, 22 patients with first-episode schizophrenia were randomly assigned to 1.0 or 2. 5 mg/day of haloperidol. After 2 weeks of treatment, D(2) receptor occupancy was determined with [(11)C]raclopride and positron emission tomography, and clinical response, extrapyramidal side effects, and prolactin levels were measured. Patients who showed adequate responses continued taking their initial doses, those who did not respond had their doses increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for all patients. RESULTS: The patients showed a wide range of D(2) occupancy (38%-87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D(2) occupancy exceeded 65%, 72%, and 78%, respectively. CONCLUSIONS: The study confirms that D(2) occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a "target and trigger" hypothesis of antipsychotic action, i.e., that the D(2) receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D(2) occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.     

Dopamine D2 receptor occupancy by olanzapine or risperidone in young patients with schizophrenia

A crucial characteristic of antipsychotic medication is the occupancy of the dopamine (DA) D2 receptor. We assessed striatal DA D2 receptor occupancy by olanzapine and risperidone in 36 young patients [31 males, 5 females; mean age 21.1 years (16-28)] with first episode schizophrenia, using [123I]iodobenzamide (IBZM) SPECT. The occupancy of DA D2 receptors was not significantly different between olanzapine and risperidone. However, in subgroups of most prescribed doses, DA D2 occupancy was higher in the risperidone 4-mg group (79%) compared to the olanzapine 15-mg group (62%). [123I]IBZM binding ratios decreased with olanzapine dose (r = -0.551; P < 0.01), indicating higher DA D2 receptor occupancy with higher olanzapine dose. Akathisia and positive symptoms were correlated with [123I]IBZM binding ratio (r = -0.442; P < 0.01; and r = -0.360; P < 0.05, respectively). Prolactin (PRL) levels were elevated in the risperidone, but not in the olanzapine group, at comparable D2 receptor occupancy levels. In the olanzapine group, PRL levels were correlated with [123I]IBZM binding ratio (r = -0.551; P < 0.01). In conclusion, both olanzapine and risperidone induce a high striatal D2 receptor occupancy, dependent on dose and group formation. The lower incidence of prolactin elevation with olanzapine, compared to risperidone, may not be attributed to a lower D2 receptor occupancy.     

Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients.

OBJECTIVE: Multicenter trials with the novel antipsychotic risperidone have suggested a standard dose of 6 mg/day. However, a dose producing the highest response rate in fixed-dose studies is likely to exceed the minimal effective dose in most patients. The aim of this positron emission tomography (PET) study was to suggest a minimal effective dose of risperidone based on measurements of dopamine D2 and serotonin 5-HT2A receptor occupancy. METHOD: Eight first-episode or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for 4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks, with [11C]raclopride to measure D2 receptor occupancy and [11C]N-methylspiperone to measure 5-HT2A receptor occupancy. RESULTS: Seven patients completed the study and responded to treatment with risperidone. No patient had extrapyramidal side effects at the time of inclusion in the study. At the 6-mg/day dose, mean D2 receptor occupancy was 82% (range = 79%-85%), 5-HT2A receptor occupancy was 95% (range = 86%-109%), and six patients had developed extrapyramidal side effects. After dose reduction to 3 mg/day, D2 receptor occupancy was 72% (range = 53%-78%), and 5-HT2A receptor occupancy was 83% (range = 65%-112%). Three patients had extrapyramidal side effects at this time. CONCLUSIONS: Treatment with risperidone, 6 mg/day, is likely to induce unnecessarily high D2 receptor occupancy, with a consequent risk of extrapyramidal side effects. High 5-HT2A receptor occupancy did not prevent extrapyramidal side effects completely. The authors previously suggested an optimal interval for D2 receptor occupancy of 70%-80%. To achieve this, resperidone, 4 mg/day, should be a suitable initial dose for antipsychotic effect with a minimal risk of extrapyramidal side effects in most patients.     

In vivo occupation of dopamine D1, D2 and serotonin2A receptors by novel antipsychotic drug, SM-9018and its metabolite, in rat brain

Summary. In vivo occupation of dopamine D₁, D₂ and serotonin (5-HT)_2A receptors by a novel antipsychotic drug, SM-9018 (perospirone hydrochloride; cis-N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]cyclohexane-1,2-dicarboximide monohydrochloride) and its major metabolite (ID-15036; N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1-hydroxy-1,2-cyclohexanedicarboximide) was measured in rat brain using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist, at these receptor sites. SM-9018 and its metabolite, ID-15036, dose-dependently reversed EEDQ-induced 5-HT_2A and D₂ receptor inactivation, but not D₁ receptor inactivation. At lower doses (0.1 mg/kg i.p.), SM-9018 showed a preferential occupation of the 5-HT_2A receptors, with only a small effect on the D₂ receptors; while at higher doses (1.0 and 5.0 mg/kg i.p.), it was nearly equipotent in its occupation of both the D₂ (77.8%) and the 5-HT_2A receptors (78.6%). On the other hand, ID-15036 was more potent in occupying the 5-HT_2A than the D₂ receptors even at higher doses (1.0 and 5.0 mg/kg i.p.). We previously reported that atypical antipsychotic drugs, such as clozapine, were characterized by a high occupancy of the 5-HT_2A receptors, with a low or minimum occupancy of the D₂ receptors in vivo. The present study suggests that SM-9018 and its metabolite ID-15036 show a preferential tendency to occupy 5-HT_2A receptors, and that the clozapine-like atypical properties of SM-9018 may be due to some pharmacological action of both the SM-9018 itself and its metabolite, ID-15063. Accepted December 26, 1997; received July 23, 1997     

Brain imaging research: Does the science serve clinical practice?

Brain imaging represents a potent tool to characterize biomarkers, biological traits that are pathognomonic for specific neurological and neuropsychiatric disorders. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are imaging techniques used to identify alterations in the density and distribution of neurotransmitters, neuroreceptors, and transporters in specific regions of the brains of people with these disorders. Brain imaging research currently facilitates the elucidation of dysfunction of dopamine, serotonin, acetylcholine, and other substances in people with Alzheimer's and Parkinson's diseases, schizophrenia, alcoholism and other substance abuse disorders, attention deficit/hyperactivity disorder, and the syndromes of restless legs, Lesch-Nyhan, Rett, and Tourette. Thus, brain imaging research offers great potential for the diagnosis, treatment, prevention, and cure of neurological and neuropsychiatric disorders. Brain imaging research also facilitates new drug development and helps establish therapeutic doses of novel drugs. In particular, studies of specific receptors, such as the dopamine D₂ receptor, before and after the administration of doses of drugs that occupy these D₂ receptors, provide the means to determine receptor occupancy. For example, an optimal dose of D₂ antagonist antipsychotics produces occupancy of 65% to 80% of D₂ receptors, while a greater dose carries a risk of extrapyramidal side effects.     

Dopamine D2/3 receptor binding potential and occupancy in midbrain and temporal cortex by haloperidol, olanzapine and clozapine

Aims: Aberrant dopamine transmission in extrastriatal brain regions has been repeatedly illustrated among patients with schizophrenia. Differences between typical and second‐generation antipsychotics in dopamine D₂ receptor modulation within various brain areas remain a topic for debate. The aim of the present study was therefore to investigate dopamine D_2/3 receptor apparent binding potential (BP_app) and occupancy in midbrain and temporal cortex among clozapine‐, olanzapine‐ and haloperidol‐treated schizophrenia patients. Methods: Dopamine D_2/3 binding was studied on single‐photon emission computed tomography ligand [¹²³I]epidepride in 13 schizophrenia patients treated with medication (two with haloperidol, four with olanzapine and seven with clozapine), six drug‐naïve patients and seven healthy controls. Results: Statistically significant differences in midbrain dopamine D_2/3 receptor BP_app (P = 0.015) and occupancy (P = 0.016) were observed between the clozapine, olanzapine and haloperidol groups. The lowest occupancy was found in clozapine‐treated patients (5%), followed by olanzapine‐treated patients (28%), compared to haloperidol‐treated patients (40%). No significant differences were observed in the temporal poles. Occupancy changed substantially depending on the comparison group used (either drug‐naïve vs healthy controls) in the examined brain areas (P = 0.001), showing an overestimation with all antipsychotics when the healthy control group was used. Conclusion: Both typical and second‐generation antipsychotics occupy cortical dopamine D_2/3 receptors, thus mediating therapeutic efficacy. Observed differences in midbrain dopamine D_2/3 occupancy between classical antipsychotics and second‐generation antipsychotics may have clinical relevance by modulating altered nigrostriatal dopamine neurotransmission during the acute phase of schizophrenia.     

No direct correlation between behaviorally active doses of the dopamine D2 agonist LY 171555 and displacement of [123I]IBZM as measured with SPECT in MPTP monkeys

Almost no information is available concerning the link between clinical effects of dopamine D₂ receptor agonists in the treatment of Parkinson's disease (PD) and the extent of D₂ receptor occupancy in the brain. Therefore, we investigated the possible correlation between adminis tration of behaviorally active doses of the selective D₂agonist LY 171555 and in vivo D₂ receptor occupancy in the unilateral 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine(MPTP)-lesioned rhesus monkey model of PD. Single photon emission computed tomography (SPECT) with the D₂ receptor antagonist (¹²³I)IBZM (iodobenzamide) as radioligand was used to estimate the receptor occupancy. The MPTP-lesioned monkeys consistenty showed signs of unilateral parkinsonism. LY 171555 (0.01 or 0.3 mg/kg) significantly increased contralateral rotation (away from the lesion), being most effective at the lower dose. In the MPTP-lesioned monkeys [¹²³]IBZM activity in the left (lesioned) striatum was significantly higher as compared to that in the right striatum. Only upon administration of 0.3 mg/kg LY 171555 a significant amount of receptor occupancy by LY 171555, as measured with [¹²³I]IBZM SPECT, at both lesioned and non-lesioned side, was detected. Using D₂ receptor mediated inhibition of the evoked release of [³H]acetylcholine from rat striatal tissue as a functional model, we showed that the lack of effect with 0.01 mg/kg LY 171555 was not due to non-competitive interaction between LY 171555 and IBZM at the D₂ receptor. We conclude that the D₂ antagonist [¹²³I]IBZM is not a suitable SPECT ligand to study the relationship between behavioral effects of the selective D₂ agonist LY 171555 in unilaterally MPTP-lesioned monkeys and the D₂ receptor occupancy in vivo in this animal model of PD. © 1994 Wiley-Liss. Inc.     

Subjective experience and D2 receptor occupancy in patients with recent-onset schizophrenia treated with low-dose olanzapine or haloperidol: a randomized,double-blind study

OBJECTIVE: The authors tested the hypothesis that a dopamine D(2) receptor occupancy level between 60% and 70% in patients with recent-onset schizophrenia would result in optimal subjective experience. In addition, they sought preliminary evidence on whether subjective experience is better with low-dose olanzapine than with low-dose haloperidol. METHOD: Subjects (N=24) who met DSM-IV criteria for schizophrenia were randomly assigned to 6 weeks of double-blind treatment with either olanzapine, 7.5 mg/day, or haloperidol, 2.5 mg/day. Subjective experience, psychopathology, and extrapyramidal symptoms were assessed at baseline and at endpoint. After 6 weeks, D(2) receptor occupancy was assessed with [(123)I]iodobenzamide single photon emission computed tomography. RESULTS: The two study groups were similar at baseline. After 6 weeks, patients receiving olanzapine had a significantly lower mean dopamine D(2) receptor occupancy (51.0%, range=36%-67%) than those given haloperidol (65.5%, range=45%-75%). Receptor occupancy between 60% and 70% was associated with optimal subjective experience, and subjective experience improved significantly in the haloperidol group. CONCLUSIONS: A level of D(2) receptor occupancy between 60% and 70% is optimal for subjective experience of patients with recent-onset schizophrenia. Substantial interindividual variation in D(2) receptor occupancy was seen at fixed low-dose levels of olanzapine and haloperidol. Olanzapine, 7.5 mg/day, showed no superior subjective response over haloperidol, 2.5 mg/day. Olanzapine may need to be dosed higher than 7.5 mg/day for most patients with recent-onset schizophrenia, and haloperidol needs to be individually titrated in the very low dose range to reach optimal occupancy.     

Neuroleptics and animal models: feasibility of oral treatment monitored by plasma levels and receptor occupancy assays

The administration of neuroleptics in animal models has been extensively reported and plays an important role in the study of schizophrenia. Our study was designed to address the following questions: (1) Is it possible to achieve steady-state receptor occupancy levels administering neuroleptics in drinking water? (2) Is there an appropriate dose to obtain clinically comparable receptor occupancies? (3) Is there a correlation between plasma drug levels and receptor occupancy? Thus, we tested three neuroleptic drugs administered in drinking water for 7 days. Plasma drug levels were measured, and in vivo receptor occupancy assays were performed in order to determine peak and trough dopamine D₂ receptor occupancies in striatal brain samples. Overall, our study indicates that in rodents the administration of appropriate doses of haloperidol and olanzapine in drinking water achieves receptor occupancies comparable to the clinical occupancy levels, but this appears not to be the case for clozapine.     

Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: A cross-sectional study

In treating schizophrenia, it has been established that 65-80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain response. In this study, daily peak and trough D2 receptor occupancy levels were estimated in clinically stable patients with schizophrenia (DSM-IV) who were receiving risperidone or olanzapine. Using two collected plasma samples, plasma antipsychotic concentrations at peak and trough were estimated with population pharmacokinetic techniques. Corresponding dopamine D2 receptor occupancy levels were then estimated, using a recently developed model. 35 subjects with stable schizophrenia completed the study (mean±SD age, 48.8±13.8years; male [N=14]; Asians [N=23], Caucasians [N=12]; risperidone [N=20] at 3.2±2.3mg/day, and olanzapine [N=15] at 9.2±4.9mg/day) between September and December 2010. 48.6% (N=17) did not achieve a continuous blockade of ≥65%. Moreover, 11.4% (N=4) did not achieve the 65% threshold at estimated peak concentrations. In conclusion, approximately half the subjects with stable schizophrenia did not achieve estimated continuous blockade of D2 receptor occupancy of ≥65%. The results suggest that sustained D2 receptor occupancy levels of ≥65% may not always be necessary for the maintenance treatment of schizophrenia.     

Olanzapine: a basic science update

Olanzapine, an atypical antipsychotic, has a broad receptor binding profile, which may account for its pharmacological effects in schizophrenia. In vitro receptor binding studies showed a high affinity for dopamine D2, D3, and D4 receptors; all 5-HT2 receptor subtypes and the 5-HT6 receptor; muscarinic receptors, especially the M1 subtype: and alpha 1-adrenergic receptors. In vivo studies showed that olanzapine had potent activity at D2 and 5-HT2A receptors, but much less activity at D1 and muscarinic receptors, and that it inhibited dopaminergic neurons in the A10 but not the A9 tract, suggesting that this agent will not cause extrapyramidal side-effects (EPS). Microdialysis studies showed that olanzapine increased the extracellular levels of norepinephrine and dopamine, but not 5-HT, in the prefrontal cortex, and increased extracellular dopamine levels in the neostriatum and nucleus accumbens, areas of the brain associated with schizophrenia. Studies of gene expression showed that olanzapine 10 mg/kg also increased Fos expression in the prefrontal cortex, the dorsolateral striatum, and the nucleus accumbens. These findings are consistent with the effectiveness of olanzapine on both negative and positive symptoms and suggest that, with careful dosing, olanzapine should not cause EPS.