Dopamine D2 Occupancy Research Articles

Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques.

Pridopidine, in development for Huntington's disease, may modulate aberrant l-dopa-induced effects including l-dopa-induced dyskinesia (LID). This study investigated whether pridopidine could reduce LID in the MPTP macaque model of Parkinson's disease and characterized the observed behavioral effects in terms of receptor occupancy. The pharmacokinetic profile and effects of pridopidine (15-30 mg/kg) on parkinsonism, dyskinesia, and quality of on-time, in combination with l-dopa, were assessed in MPTP macaques with LID. Pridopidine receptor occupancy was estimated using known in vitro binding affinities to σ1 and dopamine D2 receptors, in vivo PET imaging, and pharmacokinetic profiling across different species. Pridopidine produced a dose-dependent reduction in dyskinesia (up to 71%, 30 mg/kg) and decreased the duration of on-time with disabling dyskinesia evoked by l-dopa by 37% (20 mg/kg) and 60% (30 mg/kg). Pridopidine did not compromise the anti-parkinsonian benefit of l-dopa. Plasma exposures following the ineffective dose (15 mg/kg) were associated with full σ1 occupancy (>80%), suggesting that σ1 engagement alone is unlikely to account for the antidyskinetic benefits of pridopidine. Exposures following effective doses (20-30 mg/kg), while providing full σ1 occupancy, provide only modest dopamine D2 occupancy (<40%). However, effective pridopidine doses clearly engage a range of receptors (including adrenergic-α2C , dopamine-D3 , and serotoninergic-5-HT1A sites) to a higher degree than D2 and might contribute to the antidyskinetic actions. In MPTP macaques, pridopidine produced a significant decrease in LID without compromising the antiparkinsonian benefit of l-dopa. Although the actions of pridopidine were associated with full σ1 occupancy, effective exposures are more likely associated with occupancy of additional, non-sigma receptors. This complex pharmacology may underlie the effectiveness of pridopidine against LID. © 2018 International Parkinson and Movement Disorder Society.

Dose reduction of risperidone and olanzapine and estimated dopamine D₂ receptor occupancy in stable patients with schizophrenia: findings from an open-label, randomized, controlled study.

While acute-phase antipsychotic response has been attributed to 65%-80% dopamine D₂ receptor blockade, the degree of occupancy for relapse prevention in the maintenance treatment of schizophrenia remains unknown. In this secondary study of an open-label, 28-week, randomized, controlled trial conducted between April 2009 and August 2011, clinically stable patients with schizophrenia (DSM-IV) treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50%) or maintenance group (dose kept constant). Plasma antipsychotic concentrations at peak and trough before and after dose reduction were estimated with population pharmacokinetic techniques, using 2 collected plasma samples. Corresponding dopamine D₂ occupancy levels were then estimated using the model we developed. Relapse was defined as worsening in 4 Positive and Negative Syndrome Scale-Positive subscale items: delusion, conceptual disorganization, hallucinatory behavior, and suspiciousness. Plasma antipsychotic concentrations were available for 16 and 15 patients in the reduction and maintenance groups, respectively. Estimated dopamine D₂ occupancy (mean ± SD) decreased following dose reduction from 75.6% ± 4.9% to 66.8% ± 6.4% at peak and 72.3% ± 5.7% to 62.0% ± 6.8% at trough. In the reduction group, 10 patients (62.5%) did not demonstrate continuous D₂ receptor blockade above 65% (ie, < 65% at trough) after dose reduction; furthermore, 7 patients (43.8%) did not achieve a threshold of 65% occupancy even at peak. Nonetheless, only 1 patient met our relapse criteria after dose reduction during the 6 months of the study. The results suggest that the therapeutic threshold regarding dopamine D₂ occupancy may be lower for those who are stable in antipsychotic maintenance versus acute-phase treatment. Positron emission tomography studies are warranted to further test our preliminary findings. UMIN Clinical Trials Registry identifier: UMIN000001834.

Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia: Analysis of the CATIE data

Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics. The dataset from 481 subjects (risperidone, N = 172, olanzapine, N = 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated. The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68-70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.). The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65-80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia.

Relationship Between Daily Dose, Plasma Concentrations, Dopamine Receptor Occupancy, and Clinical Response to Quetiapine

To assess the relationships among quetiapine blood concentration, daily dose, dopamine receptor occupancy, and clinical outcome in order, if possible, to define a target plasma level range in which therapeutic response is enhanced and adverse events are minimized. A search of the database Embase from 1974 to March 2009 and the databases MEDLINE and PubMed from 1966 to March 2009 was conducted. The drug name quetiapine was searched with each of the terms plasma levels, plasma concentration, therapeutic drug monitoring, and dopamine occupancy. The search uncovered 42 relevant articles. All published reports of quetiapine plasma or serum concentration were considered for inclusion if reported in relation to a dose, clinical outcome, or dopamine occupancy. After application of exclusion criteria, 20 articles remained. Trials designed primarily to investigate an interaction between quetiapine and another medication were excluded, as were those designed to compare methods of blood sample analysis. There was a weak correlation between quetiapine dose and measured plasma concentration (from trough samples). Quetiapine dose was correlated with central dopamine D(2) occupancy, although the relationship between plasma level and D(2) occupancy is less clear. The dose-response relationship for (immediate-release) quetiapine is established. Data on plasma concentration-response relationships are not sufficiently robust to allow determination of a therapeutic plasma level range for quetiapine. Therapeutic drug monitoring procedures are thus probably not routinely useful in optimizing quetiapine dose. Further examination of the relationship between peak quetiapine plasma concentration and clinical response is necessary.

Dopamine D2 Occupancy as a Biomarker for Antipsychotics: Quantifying the Relationship with Efficacy and Extrapyramidal Symptoms

For currently available antipsychotic drugs, blockade of dopamine D(2) receptors is a critical component for achieving antipsychotic efficacy, but it is also a driving factor in the development of extrapyramidal symptoms (EPS). To inform the clinical development of asenapine, generic mathematical models have been developed for predicting antipsychotic efficacy and EPS tolerability based on D(2) receptor occupancy. Clinical data on pharmacokinetics, D(2) receptor occupancy, efficacy, and EPS for several antipsychotics were collected from the public domain. Asenapine data were obtained from in-house trials. D(2) receptor occupancy data were restricted to published positron emission tomography studies that included blood sampling for pharmacokinetics. Clinical efficacy data were restricted to group mean endpoint data from short-term placebo-controlled trials, whereas EPS evaluation also included some non-placebo-controlled trials. A generally applicable model connecting antipsychotic dose, pharmacokinetics, D(2) receptor occupancy, Positive and Negative Syndrome Scale (PANSS) response, and effect on Simpson-Angus Scale (SAS) was then developed. The empirical models describing the D(2)-PANSS and D(2)-SAS relationships were used successfully to aid dose selection for asenapine phase II and III trials. A broader use can be envisaged as a dose selection tool for new antipsychotics with D(2) antagonist properties in the treatment of schizophrenia.

Effect of Olanzapine and Risperidone on Subjective Well-Being and Craving for Cannabis in Patients with Schizophrenia or Related Disorders: A Double-Blind Randomized Controlled Trial

To examine whether subjective well-being and craving for cannabis were different in patients with schizophrenia or related disorders treated with either olanzapine or risperidone. A 6-week, double-blind, randomized trial of olanzapine and risperidone was carried out in 128 young adults with recent onset schizophrenia or related disorders. Primary efficacy measures were the mean baseline-to-endpoint change in total scores on the Subjective Well-Being under Neuroleptics scale, the Obsessive-Compulsive Drug Use Scale, the Drug Desire Questionnaire, and the cannabis use self-report. An analysis of covariance was used to test between-group differences. Estimated D(2) receptor occupancy did not differ between olanzapine (n = 63) and risperidone (n = 65). Similar improvements in subjective well-being were found in both groups. In the comorbid cannabis-using group (n = 41, 32%), a similar decrease in craving for cannabis was found in both treatment conditions. Both olanzapine and risperidone were associated with improved subjective well-being. No evidence was found for a differential effect of olanzapine or risperidone on subjective experience or on craving for cannabis in dosages leading to comparable dopamine D(2) occupancy. ISRCTN46365995.

Sertindole: efficacy and safety in schizophrenia

Sertindole is an antipsychotic drug with affinity for dopamine D2, serotonin 5-HT2A and 5-HT2C, and α1-adrenoreceptors. Preclinical studies suggest that sertindole acts preferentially on limbic and cortical dopaminergic neurons and clinical trials have confirmed that sertindole is effective at a low dopamine D2 occupancy level. The active substance has a long half-life. Oral administration once daily yields highly stable plasma levels. These features may explain the clinically observed low frequency of extrapyramidal side effects, including tardive dyskinesia. In contrast to most antipsychotics, sertindole seems to be void of sedative effects. However, although not strictly proven by objective neuropsychological tests, this asset of sertindole does not add to the cognitive problems inherent in schizophrenia. Administration of sertindole is more often associated with prolongation of QTc compared with most other currently used antipsychotics. However, large cohort analyses do not suggest that all-cause mortality is higher with sertindole than with, for example, risperidone or olanzapine. The effective antipsychotic dose range of sertindole is 12 – 20 mg/day, with small variations among patients. The frequency of most adverse events, for example extrapyramidal symptoms and somnolence, with such a dose does not differ from placebo. Three side effects have been more common than with placebo/haloperidol in short-term studies: weight gain, rinithis and a decreased ejaculation volume. Two head-to-head comparisons (one in treatment-resistant patients) of sertindole and risperidone showed equivalent effects on positive symptoms. For negative symptoms, one study obtained equivalent effects and one a superior effect of sertindole. Sertindole should not be used as first-line treatment for first-episode patients with schizophrenia because of the QTc prolongation. It has a side-effect profile that makes it an interesting alternative for many patients who do not respond well to the initial choice of antipsychotic drug.

Risperidone long-acting injection in practice - more questions than answers?

Two papers in this issue report on the clinical use of risperidone long-acting injection (RLAI). A UK study of 250 patients prescribed RLAI and followed-up for 1 year (1) shows rather disappointing outcome with respect to time spent in hospital. A Norwegian analysis of in-practice risperidone serum concentrations (2) identifies clear differences in serum levels produced by oral and injectable forms. Each of these findings is perplexing in its own way but the results of one may provide at least a partial explanation for the results of the other. In the UK study all subjects began RLAI treatment on 25 mg/2 weeks, a dose which, according to the second study, provides apparently sub-therapeutic plasma levels of risperidone and its major metabolite, 9-hydroxyrisperidone. In providing an explanation there also arises a question: what is an effective dose of RLAI in practice? Risperidone appears to exert its effect through the pharmacological activities of both the parent compound and its major metabolite 9-hydroxyrisperidone. These compounds are said to have similar activity at dopamine, D2 and serotonin, 5HT2 receptors (3) and are usually assumed to have equal antipsychotic activity. Serum levels of each are summed to provide an active moiety concentration. Oral risperidone is optimally efficacious at a dose of around 4 mg a day (4, 5), at least in patients suitable for inclusion in randomized, controlled trials. Oral doses of this magnitude have been said to give rise to plasma levels of around 40 ng/ml (97.4 nmol/l) (risperidone + 9-hydroxyrisperidone) (6). However, a human receptor occupancy study suggested sufficient dopamine D2 occupancy for clinical effect was provided by a dose of 3 mg a day and active moiety plasma levels averaging 18 ng/ml (43.8 nmol/l) (7). A readily apparent difficulty here is the variation in plasma level afforded by the same dose in different individuals – one study estimated concentration to dose ratios of between 1.8 and 36.8 (nmol/l)/mg/day (8). More predictable is the ratio of risperidone to 9-hydroxyrisperidone: 90–95% of activity seems to be provided by the metabolite (8, 9). The optimal dose of RLAI is perhaps less well established than that of oral risperidone. Fixed dose studies show no important differences in clinical outcome for doses ranging from 25 mg/2 weeks to 75 mg/2 weeks and nor was any trend for better response at higher doses identified (10, 11). However, it is possible that these studies were not designed or sufficiently powered to reveal anything but substantial advantages for higher doses. At least one naturalistic study has identified doses of >25 mg/week as being associated with improved clinical response (12). This is the same cohort of patients who did so poorly with respect to bed stay when initiated on 25 mg/2 weeks (1). The observation that the lowest licensed dose of RLAI gives rise to mean active moiety plasma levels of only 13.5 ng/ml (32.9 nmol/l) (albeit with proportionately more parent compound) (2) serves further to question to efficacy of 25 mg/2 weeks. Other studies have reported similar findings with respect to blood levels. A small naturalistic study found median active moiety plasma levels of 15.6 ng/ml (38 nmol/l) in subjects receiving 25 mg/2 weeks (13), another found levels ranged from 4.4 to 8.8 ng/ml (10.7–21.4 nmol/l) (14). Unsurprisingly, brain D2 receptor occupancy appears to be very low at these levels, ranging from 25% to 48% (14). The highest level reported for RLAI 25 mg/2 weeks is 22.7 ng/ml (55.3 nmol/l) and was significantly lower than that seen with risperidone 2 mg a day (32.9 ng/ml; 80.2 nmol/l) in the same study (15). Of course, 2 mg a day oral risperidone is known to be a sub-optimal dose, at least in relapsed schizophrenia (4). So, is a dose of 25 mg/2 weeks RLAI sufficient? It is difficult to see how it can be when this dose provides such low plasma levels and apparently sub-therapeutic in vivo D2 occupancies. Its sub-optimal effectiveness is certainly suggested by at least one naturalistic study (1, 12). Larger randomized, controlled trials of fixed doses are clearly needed but are unlikely to take place at this postmarketing stage of the preparation's life-span. Perhaps then, in clinical practice, it would be wise first to establish the effective dose of oral risperidone in an individual before starting RLAI and then to prescribe of dose of RLAI broadly equivalent to the oral dose (2 mg oral equating to 25 mg/2 weeks, and so forth) – a technique successfully used in a large, year long trial (11) and supported by in the product's official labelling.

Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive α2 adrenoceptor blockade: experimental evidence

Adjunctive treatment with the selective alpha2 adrenoceptor antagonist idazoxan augments the effect of conventional antipsychotics in treatment-resistant schizophrenics comparing favourably with clozapine. Clozapine has high affinity for alpha2 adrenoceptors. Previously, we found that adjunctive idazoxan treatment to the dopamine (DA) D2/3 antagonist raclopride enhanced raclopride-induced effects in an animal model of antipsychotic activity (conditioned avoidance response, CAR) and, similarly to clozapine, reversed the disruption of working memory induced by N-methyl-D-aspartate receptor blockade in rats with a concomitant increase in prefrontal DA efflux. To further investigate the significance of alpha2 adrenoceptor affinity for antipsychotic efficacy, we here investigated, in rats, the effects of adjunctive idazoxan treatment to low doses of a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug, both lacking appreciable alpha2 adrenoceptor affinity, on (i) CAR; (ii) catalepsy; and (iii) DA output in the prefrontal cortex and the nucleus accumbens using microdialysis. Adjunctive treatment with idazoxan to haloperidol or olanzapine enhanced suppression of CAR to a level predicting sufficient antipsychotic activity, increased DA output preferentially in the prefrontal cortex, and reversed haloperidol-induced catalepsy. Our data confirm and extend our previous findings as well as clinical observations, and suggest that adjunctive alpha2 adrenoceptor blockade both typical and atypical antipsychotic drugs, lacking appreciable affinity for the alpha2 adrenoceptor, may contribute to a more advantageous therapeutical profile of these drugs in schizophrenia treatment, allowing for reduced DA D2 occupancy and reduction of unwanted side-effects.

Dopamine D2 Receptor Occupancy Is a Common Mechanism Underlying Animal Models of Antipsychotics and Their Clinical Effects

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 D2 occupancy predicts antipsychotic response (at 65% D2 occupancy) and motor side-effects (at greater than 80%). To relate preclinical and clinical findings, this study examined the relationship between striatal D2 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 D2 receptor occupancy ⩾85%. The D2 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 D2 occupancy than was required for catalepsy. We suggest that the CAR and CAT models may have displayed high predictive accuracy because they share with the clinical condition a common underlying mechanism: dopamine D2 occupancy. The implications of this finding for understanding antipsychotic action as well as the continued use of these models in drug discovery is discussed.

Dopamine D2 Receptor Blockade by Haloperidol: 3H-Raclopride Reveals Much Higher Occupancy than EEDQ

Two techniques are commonly used to measure antipsychotic induced dopamine D2 occupancy in animals: competition with a reversible radioligand (3H-raclopride) or with an irreversible receptor inactivator (EEDQ). While both of these techniques have been used in the past, there is no direct and systematic comparison. In the first direct comparison of these two methods we find that the dose of haloperidol required for blocking 50% of the dopamine D2 receptors was 0.02 mg/kg/sc (95% CI 0.018–0.022 mg/kg) as measured using 3H-raclopride method; but was significantly higher with the EEDQ method 0.14 mg/kg/s.c. (95% CI 0.048–0.224 mg/kg). The 3H-raclopride method showed significantly lesser variance (p = 0.02) despite the higher sensitivity. This seven-fold difference in the sensitivity of the two techniques to measure antipsychotic-induced D2 occupancy explains discrepancies in the previous studies which have used these two methods and also suggest that for future studies the 3H-raclopride method is a more sensitive and, likely, a more valid reflector of true receptor occupancy.

Neuropsychological and conditioned blocking performance in patients with schizophrenia: assessment of the contribution of neuroleptic dose, serum levels and dopamine D2-receptor occupancy.

Patients with schizophrenia show impairments of attention and neuropsychological performance, but the extent to which this is attributable to antipsychotic medication remains largely unexplored. We describe here the putative influence of the dose of antipsychotic medication (chlorpromazine equivalents, CPZ), the antipsychotic serum concentration of dopamine (DA) D2-blocking activity and the approximated central dopamine D2-receptor occupancy (DA D2-occupancy), on conditioned blocking (CB) measures of attention and performance on a neuropsychological battery, in 108 patients with schizophrenia (compared with 62 healthy controls). Antipsychotic serum concentration and D2-occupancy were higher in patients with a paranoid versus non-paranoid diagnosis, and in female versus male patients (independent of symptom severity). Controlling for D2-occupancy removed the difference between high CB in paranoid and impaired low CB in non-paranoid patients. Similar partial correlations for antipsychotic drug dose and serum levels of DA D2-blocking activity with performance of the trail-making and picture completion tests (negative) and the block-design task (positive) showed the functional importance of DA-related activity. High estimates of central DA D2-occupancy were related to impaired verbal fluency but were associated with improved recall of stories, especially in paranoid patients. This, the first study of its kind, tentatively imputes a role for DA D2-related activity in left frontal (e.g. CB, verbal fluency) and temporal lobe functions (verbal recall) as well as in some non-verbal abilities mediated more in the right hemisphere in patients with schizophrenia.

Instrumentally Detected Changes in Motor Functioning in Patients with Low Levels of Antipsychotic Dopamine D2 Blockade

Extrapyramidal side-effects (EPSE) of antipsychotic medication are related to the occupancy of dopamine D2 receptors and there appears to be a threshold of D2 occupancy below which clinically EPSE are unlikely to occur. It is unclear whether there are motor changes produced by ‘subthreshold’ levels of D2 occupancy that are not detectable by clinical examination. This study was designed to investigate whether a number of electromechanical instrumental techniques could detect ‘subthreshold’ motor changes and whether these changes correlate with dopamine D2 occupancy as measured by [11C]-raclopride PET scan. Twenty medication naı̈ve patients were studied before and during treatment with low dose haloperidol. Instrumental techniques detected an asymmetrical worsening in motor function with drug treatment despite the failure of the group to experience significant EPSE. These changes did not correlate with D2 occupancy and measurements of rigidity, tremor, and bradykinesia did not closely inter-correlate.