Summary
- The mechanism of action of RISPERDAL CONSTA (risperidone long-acting injection [RLAI]), as with other drugs used to treat schizophrenia, is unclear. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) receptor antagonism. The clinical effect from RISPERDAL CONSTA results from the combined concentration of risperidone and its major active metabolite, 9-hydroxyrisperidone.1
- Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin 5HT2, D2, α1 and α2 adrenergic, and H1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.1
- PET (positron emission tomography) studies have shown positive correlations between plasma concentrations of risperidone plus 9-hydroxyrisperidone and brain D2 dopamine receptor occupancy.2-6
- Several PET studies found no significant correlation between prolactin levels and D2 receptor occupancy or plasma concentrations of risperidone plus 9-hydroxyrisperidone.2,5 However, single nucleotide polymorphisms (SNPs) in the NR1/2 gene (rs2472677C>T) are associated with prolactin levels, with the CC genotype associated with significantly lower levels than nonCC genotypes (P=0.032).7
- A multicenter, observational study evaluated RISPERDAL CONSTA plus oral antipsychotics in 108 patients with treatment-resistant schizophrenia or schizoaffective disorder who were divided into 2 groups based on the presence or absence of dopamine supersensitivity psychosis (DSP). After 2 years, there were significant differences between the DPS and nonDPS groups in mean Brief Psychotic Ratings Scale (BPRS) total, positive symptom, and negative symptom scores in favor of the DPS group (P≤0.02).8
- Additional information on the pharmacodynamic properties of risperidone oral may be obtained by contacting the Medical Information Center at 1-800-526-7736.
INTRACORTICAL MYELINATION TRAJECTORY CHANGES
Bartzokis et al (2012)9 assessed the effect of RISPERDAL CONSTA on intracortical myelin (ICM) volumes using imaging data from a randomized, open-label, 6-month trial of RISPERDAL CONSTA vs oral risperidone in first-episode schizophrenia patients. Patients were randomly allocated to oral risperidone or RISPERDAL CONSTA after a 10-week run-in period of oral risperidone treatment. The primary endpoint was the change in ICM volume scores from baseline to 6 months, as assessed by rater-blinded magnetic resonance imaging (MRI) evaluation. Age-matched healthy controls were used for standardization. Other than race/ethnicity, all other baseline characteristics, including prior antipsychotic exposure, were similar between groups. The mean dose was 26.4 mg for RISPERDAL CONSTA and 2.9 mg for oral risperidone. Approximately one-third of patients discontinued the MRI study over the 6-month study period, with no significant difference in discontinuations between treatment groups. In the final analysis, scores of patients who received RISPERDAL CONSTA (n=9) or oral risperidone (n=13) were standardized according to z-scores calculated from the scores of healthy controls (n=12), whose mean score was considered to be 0. Standardized frontal ICM volume increased significantly from baseline for patients who received RISPERDAL CONSTA (mean change per month, +1.53; P=0.005), but the increase observed in the oral risperidone group was not significant (mean change per month, +0.22; P=0.39). There was no significant between group difference (F=3.31; P=0.093; d=0.81). Medication administration mode and adherence were found to be strong confounding variables for change in ICM. Receipt of RISPERDAL CONSTA and good adherence (defined as <1.20 on a Likert scale, where 1=perfect adherence and 5=poorest adherence) were significantly associated with large ICM volume increases (Chi square test, P≤0.033 for both). Only 1 patient who received RISPERDAL CONSTA had a less-than-perfect adherence score. ICM volume was not associated with changes in psychiatric symptoms. The authors concluded that RISPERDAL CONSTA may promote ICM development in first-episode schizophrenia patients, and that LAI, not oral meds, may modify the ICM trajectory, which underlies the pathogenesis of illness.
Pharmacogenetic Studies
|
|
|---|
Choong et al (2013)7 conducted a naturalistic, cross-sectional, multicenter study (N=42) evaluating the impact of select gene polymorphisms on RIS metabolism and transport in patients at steady state who were receiving a stable dose of RLAI for ≥2 months. Blood samples were drawn prior to the next scheduled dose (postinjection day 14±3 days).
All patients had received RLAI at a stable dose for ≥4 prior consecutive biweekly injections. Changes in concomitant medications were not allowed within 1 week of study entry (2 months for fluoxetine).
| |
Gasso et al (2009)10 conducted a prospective, open-label cohort study (N=270) evaluating the association of genetic polymorphisms in 7 dopamine linked genes with the risk of antipsychotic-induced EPS in inpatients with schizophrenia or schizophrenia-related disorders (n=197), bipolar disorders (n=42), or other diagnoses (n=31) who received at least 15 days of antipsychotic medication. Case cohort included patients with EPS and/or history of movement disorders (n=81) and controls included patients without EPS (n=189).
Case patients: 48/81 (60%); 1 pt received RLAI
Control patients: 84/189 (44%); 1 pt received RLAI
| |
Abbreviations: CGI, Clinical Global Impression; D3, dopamine type 3; EPS, extrapyramidal symptoms; GT, genotype; HDL, high-density lipoprotein; OH-RIS, hydroxyrisperidone; pt, patient; RIS, risperidone; RLAI, risperidone long-acting injection; SAS, Simpson-Angus Scale; SNP, single nucleotide polymorphisms.
|
D2 RECEPTOR OCCUPANCY STUDIES
D2 Receptor Occupancy Studies
|
|
|---|
Ikai et al (2016)11 conducted a naturalistic follow-up study of clinical outcomes over 3 years for 36 patients with schizophrenia who participated in an earlier cross-sectional study (Ikai et al [2012]12). Twenty patients continued RLAI for 3 years (mean dose was 37.5 mg) and 16 changed regimens.
D2 receptor occupancy estimated using data from 10 patients on RLAI and other antipsychotics (mean CPZE 331 mg/day) for 3 years.
| |
Ikai et al (2012)12 conducted a cross-sectional study in patients with stable schizophrenia (N=36) maintained on RLAI for at least 3 months. The purpose of the study was to evaluate the association between active moiety (RIS plus 9-OH-RIS) and estimated D2 occupancy levels with EPS and symptom ratings.
RLAI 25 mg: 38.9% (14/36)
RLAI 37.5 mg: 16.7% (6/36)
RLAI 50 mg: 44.4% (16/36)
The majority of patients (69.4%; 25/36) received RLAI injections every 2 weeks.
| |
Catafau et al (2009)6 conducted a prospective, open label, crossover study (N=20) to evaluate differences in striatal D2 receptor occupancyb in patients with schizophrenia who had been receiving stable doses of monotherapy with various antipsychotic medications for ≥1 month. Ten healthy volunteers were included as controls. Blood samples were collected before and after the scans.
Two of the 20 patients with schizophrenia were receiving monotherapy with RLAI (37.5 mg, n=1; 50 mg, n=1).
| |
Uchida et al (2008)5 conducted a PET study (N=7) examining striatal D2 receptor occupancyc in patients with schizophrenia or schizoaffective disorder who received RLAI and were originally enrolled in a 52 week, multicenter study (Gharabawi et al [2007]13). PET scan was performed within 4 days of each patients’ next planned injection. Blood samples were collected at the time of the PET scan. Prolactin level was also evaluated.
All patients in the PET study had been enrolled at a single center from the parent study and had received 3 monthly injections of RLAI 50 mg.
| |
Remington et al (2006)2 conducted a PET study (N=9) to examine striatal D2 receptor occupancyc in patients with schizophrenia or schizoaffective disorder who received RLAI as part of a larger clinical study (Fleischhacker et al [2003]14). PET scan was performed post-injection (within 3 days after an injection) and preinjection (within 5 days before the next injection). Prolactin level was also evaluated.
All patients received injections every 2 weeks and had received ≥5 RLAI injections prior to PET scan.
RLAI 25 mg: 22.2% (2/9)
RLAI 50 mg: 55.6% (5/9)
RLAI 75 mg: 22.2% (2/9)
| Mean D2 receptor occupancy levelsc
Post-injection
Preinjection
|
Gefvert et al (2005)3 conducted an open label, nonrandomized study (N=13) evaluating the pharmacokinetics and central D2 receptor occupancy of RLAI in stable adult outpatients with schizophrenia. No oral RIS or clozapine was permitted within 2 weeks of study entry and no depot antipsychotics were permitted within the last year. Blood samples were collected before and multiple times after each injection for a total of 34 blood draws for study completers (n=11). PET scansc of the putamen were performed in 8 patients.
All patients received 5 consecutive RLAI injections (25, 50, or 75 mg; dose determined by treating physician) every 2 weeks.
| Across all dose groups, the steady-state peak and mean plasma concentrations of active moiety showed a dose-proportional trend.
Mean D2 receptor occupancy levelsc
|
Farde et al (2002)4 conducted an endpoint analysis (N=233) evaluating D2 receptor occupancyd in patients who participated in a 12-week, double-blind, placebo-controlled efficacy study and completed ≥28 days of treatment (Kane et al [2003]16).
RLAI 25 mg: 31.3% (73/233)
RLAI 50 mg: 36.9% (86/233)
RLAI 75 mg: 31.8% (74/233)
| |
Abbreviations: 9-OH-RIS, 9-hydroxyrisperidone (active metabolite); AIMS, Abnormal Involuntary Movement Scale; BAS, Barnes Akathisia Scale; BPRS, Brief Psychiatric Rating Scale; CPZE, chlorpromazine equivalent; D2, dopamine type 2; ED50, the plasma concentration of antipsychotic drug associated with 50% D2 occupancy; EPS, extrapyramidal symptoms; IBZM, 123I-iodobenzamide; PANSS, Positive and Negative Symptoms Scale; PET, positron emission tomography; RIS, risperidone; RLAI, risperidone long-acting injection; SAS, Simpson-Angus Scale; SPECT, single photon emission computed tomography.
aCalculated using the 1 site binding model: % occupancy = 100 × (plasma concentration/[plasma concentration + ED50]); ED50 was estimated from 2 previous studies using PET.
bMeasured with [123I] IBZM SPECT and [11C] Raclopride PET on different days during a 1-week period; performed at a fixed time interval after the last dose of antipsychotic medication.
cMeasured with [11C] Raclopride PET.
dEstimated using an ED50 plasma concentration level of 9.9 ng/mL in brain tissue, derived from another study.
|
DOPAMINE SUPERSENSITIVTY PSYCHOSIS STUDIES
Kimura et al (2014)17 conducted a multicenter, prospective, observational study in patients with treatment-resistant schizophrenia or schizoaffective disorder who had dopamine supersensitivity psychosis (DSP) (n=61) or nonDPS (n=33). The diagnosis of DSP was made by 2 investigators based on standard criteria such as an acute relapse or exacerbation following antipsychotic dose reduction or discontinuation, the development of antipsychotic tolerance, the development of new or more severe psychotic symptoms after a dose reduction, or a history of tardive dyskinesia. Patients were treated with RISPERDAL CONSTA every 2 weeks in combination with other oral antipsychotics. The primary endpoint was the change in BPRS score, with response defined as >20% reduction from the baseline score. Secondary endpoints included the change in scores for Clinical Global Impression - Severity of Illness (CGI-S), Global Assessment of Functions Scale (GAF), and Extrapyramidal Symptom Rating Scale (ESRS) over the 12-month follow-up period.
Most patients (~65%) were treated with RISPERDAL CONSTA 50 mg every 2 weeks and the mean antipsychotic dose (chlorpromazine-equivalent) was 1040 mg. After 12 months of treatment, the mean BPRS total score, BPRS positive symptom score, and BPRS negative symptom score improved significantly compared with baseline values in the DSP group (by 32-33% each endpoint) (P<0.01). There were significant differences from baseline for these 3 endpoints as early as 3 months. In the nonDSP group, there were significant differences from baseline only for the BRPS total score and BPRS negative symptom score (by 17% each endpoint) at 12 months (P<0.01). The responder rate was 62.3% in the DSP group and 21.2% in the nonDSP group (P<0.001). There were also significant improvements from baseline in CGI-S and GAF scores in both treatment groups at 12 months, but ESRS improved only in the DSP group (P<0.01 for all comparisons).
Kimura et al (2016)8 reported 2-year follow-up data from an earlier study (Kimura et al [2014])17 evaluating RISPERDAL CONSTA in patients with treatment-resistant schizophrenia or schizoaffective disorder who had DSP (n=72) or nonDSP (n=36). The mean antipsychotic dose (chlorpromazine equivalent) at study initiation was 1053.0 mg in the DSP group and 863.7 mg in the nonDPS group. Baseline characteristics were balanced except for age (mean 43 vs. 48.5 years) and the mean BPRS negative symptoms scores (13.0 vs 10.7) and the ESRS scores (32.7 vs 18.8) were significantly higher in the DPS group than the nonDPS group (P≤0.05 for all). Fifty-eight patients (DPS, n=40; nonDPS, n=18) completed 2 years of therapy.
At 2 years, scores for BPRS (total, positive symptoms, and negative symptoms) and CGI-S decreased from baseline values in both groups. All 3 BPRS scores decreased by 29-33% in the DPS group and by 23-25% in the nonDPS group at the 2-year assessment. There were significant differences between the DPS and nonDPS groups in BPRS scores for each comparison (P≤0.02). CGI-S and ESRS scores decreased in the DPS group over the course of the trial and were similar to those of the nonDPS group at 2 years. The mean RISPERDAL CONSTA dose at 2 years was 44.7 mg in the DSP group and 43.8 mg in the nonDPS group. Combined doses of oral antipsychotics and RISPERDAL CONSTA (>850 mg chlorpromazine equivalent) were continued throughout the trial.
Kimura et al (2013)18 reported on 2 cases of DSP in Japanese male patients with schizophrenia who were in long-term clinical recovery or remission on stable oral antipsychotic regimens (patient 1, risperidone 5 mg; patient 2, haloperidol 12 mg and clocapramine 75 mg), but relapsed after self-discontinuation of medications. Both patients were hospitalized. After several weeks of inadequate symptomatic improvement with oral antipsychotics, including oral risperidone, both patients were started on RISPERDAL CONSTA 25 mg every 2 weeks, which was titrated to a dose of 50 mg every 2 weeks. Gradual improvement was seen in both patients, with 1 patient returning to pre-episode daily functioning.
OTHER RELEVANT LITERATURE
An additional citation, evaluating D2 receptor occupancy of risperidone long-acting injection when coadministered with the phosphorylated glycoprotein (P-gp) inhibitor ketoconazole, has been included in the References section for your information.19
LITERATURE SEARCH
A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 15 February 2024.
| 1 | RISPERDAL CONSTA (risperidone long-acting injection) [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/RISPERDAL+CONSTA-pi.pdf. |
| 2 | Remington G, Mamo D, Labelle A, et al. A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone. Am J Psychiatry. 2006;163(3):396-401. |
| 3 | Gefvert O, Eriksson B, Persson P, et al. Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal ConstaTM) in patients with schizophrenia. Int J Neuropsychopharmacol. 2005;8(1):27-36. |
| 4 | Farde L, Eerdekens M, Eerdekens E, et al. Relationship between plasma concentrations, D2-receptor occupancy and efficacy of Risperdal CONSTA. Poster presented at: 41st Annual Meeting of the American College of Neuropsychopharmacology; December 8-12, 2002; San Juan, PR. |
| 5 | Uchida H, Mamo DC, Kapur S, et al. Monthly administration of long-acting injectable risperidone and striatal dopamine D2 receptor occupancy for the management of schizophrenia. J Clin Psychiatry. 2008;69(8):1281-1286. |
| 6 | Catafau AM, Suarez M, Bullich S, et al. Within-subject comparison of striatal D2 receptor occupancy measurements using [123I]IBZM SPECT and [11C]Raclopride PET. Neuroimage. 2009;46(2):447-458. |
| 7 | Choong E, Polari A, Kamdem KH, et al. Pharmacogenetic study on risperidone long-acting injection: influence of cytochrome P450 2D6 and pregnane X receptor on risperidone exposure and drug-induced side-effects. J Clin Psychopharmacol. 2013;33(3):289-298. |
| 8 | Kimura H, Kanahara N, Sasaki T, et al. Risperidone long-acting injectable in the treatment of treatment-resistant schizophrenia with dopamine supersensitivity psychosis: results of a 2-year prospective study, including an additional 1-year follow-up. J Psychopharmacol. 2016;30(8):795-802. |
| 9 | Bartzokis G, Lu PH, Raven EP, et al. Impact on intracortical myelination trajectory of long acting injection versus oral risperidone in first-episode schizophrenia. Schizophr Res. 2012;140(1-3):122-128. |
| 10 | Gassó P, Mas S, Bernardo M, et al. A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms. Pharmacogenomics J. 2009;9(6):404-410. |
| 11 | Ikai S, Suzuki T, Mimura M, et al. Plasma levels and estimated dopamine D2 receptor occupancy of long-acting injectable risperidone during maintenance treatment of schizophrenia: a 3-year follow-up study. Psychopharmacology (Berl). 2016;233(23-24):4003-4010. |
| 12 | Ikai S, Remington G, Suzuki T, et al. A cross-sectional study of plasma risperidone levels with risperidone long-acting injectable: implications for dopamine D2 receptor occupancy during maintenance treatment in schizophrenia. J Clin Psychiatry. 2012;73(8):1147-1152. |
| 13 | Gharabawi GM, Gearhart NC, Lasser RA, et al. Maintenance therapy with once-monthly administration of long-acting injectable risperidone in patients with schizophrenia or schizoaffective disorder: a pilot study of an extended dosing interval. Ann Gen Psychiatry. 2007;6:3. |
| 14 | Fleischhacker WW, Eerdekens M, Karcher K, et al. Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic. J Clin Psychiatry. 2003;64(10):1250-1257. |
| 15 | Nyberg S, Eriksson B, Oxenstierna G, et al. Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2a receptor occupancy in schizophrenic patients. Am J Psychiatry. 1999;156(6):869-875. |
| 16 | Kane JM, Eerdekens M, Lindenmayer JP, et al. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry. 2003;160(6):1125-1132. |
| 17 | Kimura H, Kanahara N, Komatsu N, et al. A prospective comparative study of risperidone long-acting injectable for treatment-resistant schizophrenia with dopamine supersensitivity psychosis. Schizophr Res. 2014;155(1-3):52-58. |
| 18 | Kimura H, Kanahara N, Watanabe H, et al. Potential treatment strategy of risperidone in long-acting injectable form for schizophrenia with dopamine supersensitivity psychosis. Schizophr Res. 2013;145(1-3):130-131. |
| 19 | Reist C, Wu JC, Lilja Y, et al. Ketoconazole-associated preferential increase in dopamine D2 receptor occupancy in striatum compared to pituitary in vivo: role for drug transporters? J Clin Psychopharmacol. 2012;32(1):110-113. |
