A PET Study Evaluating Dopamine D 2 Receptor Occupancy for Long-Acting Injectable Risperidone

Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ont. M5T 1R8, Canada.
American Journal of Psychiatry (Impact Factor: 12.3). 04/2006; 163(3):396-401. DOI: 10.1176/appi.ajp.163.3.396
Source: PubMed


Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks.
After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone.
Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy.
All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

5 Reads
  • Source
    • "If the total dosages were too low to achieve optimal receptor occupancy, or if the elimination half-life of the oral drugs was too short to maintain optimal occupancy, RLAI therapy may not be sufficient to control disease symptoms. In Japan, the maximum dose of RLAI is limited to 50 mg/2-week, which is estimated to produce an occupancy range of 65.4 to 74.4% (Remington et al., 2006), corresponding to the optimal range for patients with a first schizophrenic episode (Kapur et al., 2000). Further studies are needed to clarify the accuracy of this data and its validity for subsequent episodes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Dopamine supersensitivity psychosis (DSP) is considered to be one cause of treatment-resistant schizophrenia (TRS). The authors investigated the efficacy of risperidone long-acting injections (RLAI) in patients with TRS and DSP. Method This is a multicenter, prospective, 12-month follow-up, observational study that included unstable and severe TRS patients with and without DSP. 115 patients with TRS were recruited and divided into two groups according to the presence or absence of DSP which was judged on the basis of the clinical courses and neurological examinations. RLAI was administered adjunctively once every 2 weeks along with oral antipsychotics. We observed changes in scores for the Brief Psychiatric Rating Scales (BPRS), Clinical Global Impression—Severity of Illness (CGI-S), Global Assessment of Functioning Scale (GAF), and Extrapyramidal Symptom Rating Scale (ESRS) during the study. Of the assessed 94 patients, 61 and 33 were categorized into the DSP and NonDSP groups, respectively. Results While baseline BPRS total scores, CGI-S scores and GAF scores did not differ, the ESRS score was significantly higher in the DSP group compared with the NonDSP group. Treatment significantly reduced BPRS total scores and CGI-S scores, and increased GAF scores in both groups, but the magnitudes of change were significantly greater in the DSP group relative to the NonDSP group. ESRS scores were also reduced in the DSP group. Responder rates (≥ 20% reduction in BPRS total score) were 62.3% in the DSP group and 21.2% in the NonDSP group. Conclusions It is suggested that DSP contributes to the etiology of TRS. Atypical antipsychotic drugs in long-acting forms, such as RLAI, can provide beneficial effects for patients with DSP. Clinical trials registration: UMIN (UMIN000008487).
    Schizophrenia Research 05/2014; 155(1-3). DOI:10.1016/j.schres.2014.02.022 · 3.92 Impact Factor
  • Source
    • "In this study, a median plasma paliperidone concentration of above 7.5 ng/mL, which is associated with a central D2-receptor occupancy of approximately 60% [28], was reached within 2 to 4 days after the first dose. This is within the range (60-80%) associated with antipsychotic efficacy [29-33]. This also confirms that the 150 mg eq. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There are no previous reports of paliperidone palmitate's (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. This study evaluates safety and tolerability, as well as pharmacokinetics, of the highest marketed dose of PP (150 mg eq. [234 mg]) in stable patients with schizophrenia over a 1-year period. In this 1-year prospective study, eligible patients (aged 18-65 years; Positive and Negative Syndrome Scale's total score ≤ 70) received an initial deltoid injection of PP 150 mg eq. The second injection one week later and subsequent once-monthly injections were deltoid or gluteal. All injections were to be PP 150 mg eq. Patients willing to participate in intensive pharmacokinetic sampling were classified as Treatment A. Patients unwilling to undergo intensive pharmacokinetic sampling or unable to tolerate the 150 mg eq. dose (consequently receiving flexible doses of 50, 100 or 150 mg eq.) were classified as Treatment B. Of the 212 patients (safety analysis set), 73% were men; 45% white; 20% black; 34% Asians; mean (SD) age 41 (10.2) years, and mean (SD) baseline Positive and Negative Syndrome Scale total score 54.9 (9.03). A total of 53% (n = 113) patients completed the study and 104 received PP 150 mg eq. throughout. Mean (SD) mode dose of PP was 144.8 (19.58) mg eq. The dosing initiation regimen resulted in rapidly achieved and maintained therapeutic paliperidone levels over the study (average concentrations during the dosing interval were 34.7, 40.0, and 47.8 ng/mL after the 2nd, 8th, and 14th injection respectively). Most frequent (≥ 10%) treatment-emergent adverse events were nasopharyngitis (n = 37), insomnia (n = 32), injection-site pain (n = 32), headache (n = 28), and tachycardia (n = 27). Akathisia (n = 19) and tremor (n = 11) were the most common extrapyramidal adverse events. 33 patients had an SAE and 27 discontinued due to treatment-emergent adverse events. No deaths were reported. Mean (SD) weight change from baseline was 2.5 (5.41) kg at endpoint. Patients' psychoses remained stable. Safety results after one-year therapy with the highest available dose of once-monthly paliperidone palmitate were consistent with results from previous studies, with no new concerns noted. Plasma concentrations were within the expected range. TRIAL REGISTRATION NO: NCT01150448.
    BMC Psychiatry 03/2012; 12(1):26. DOI:10.1186/1471-244X-12-26 · 2.21 Impact Factor
  • Source
    • "The E max model is based on the basic pharmacology of drug interactions with receptors and reflects a saturable process of receptor occupancy by drugs (Alvan et al, 1999). While it is necessary to characterize both the PK and PD behavior of a drug to fully predict its action in vivo and determine its dosing (Meibohm and Derendorf, 1997), most studies of antipsychotic drugs have just applied the E max model to characterize the relationship between plasma drug concentration and dopamine receptor occupancy (Grunder et al, 2008; Mamo et al, 2004; Remington et al, 2006; Vernaleken et al, 2008). This approach makes two assumptions: first that the drug concentration at the site relevant to its action rapidly reaches equilibrium with the drug concentration in plasma, and second that the effect of the drug is immediate following its arrival at the site (Holford and Sheiner, 1981a; Sheiner et al, 1979). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Positron emission tomography (PET) studies of dopamine receptor occupancy can be used to assess dosing of antipsychotics. Typically, studies of antipsychotics have applied pharmacodynamic (PD) modeling alone to characterize the relationship between antipsychotic dose and its effect on the brain. However, a limitation of this approach is that it does not account for the discrepancy between the time courses of plasma concentration and receptor occupancy by antipsychotics. Combined pharmacokinetic-PD (PK-PD) modeling, by incorporating the time dependence of occupancy, is better suited for the reliable analysis of the concentration-occupancy relationship. To determine the effect of time on the concentration-occupancy relationship as a function of analysis approach, we measured dopamine receptor occupancy after the administration of aripiprazole using [(11)C]raclopride PET and obtained serial measurements of the plasma aripiprazole concentration in 18 volunteers. We then developed a PK-PD model for the relationship, and compared it with conventional approach (PD modeling alone). The hysteresis characteristics were observed in the competitor concentration-occupancy relationship and the value of EC(50) was different according to the analysis approach (EC(50) derived from PD modeling alone=11.1 ng/mL (95% confidence interval (CI)=10.1 to 12.1); while that derived from combined PK-PD modeling=8.63 ng/mL (95% CI=7.75 to 9.51)). This finding suggests that PK-PD modeling is required to obtain reliable prediction of brain occupancy by antipsychotics.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2011; 32(4):759-68. DOI:10.1038/jcbfm.2011.180 · 5.41 Impact Factor
Show more


5 Reads
Available from