Risperidone

🧬 Receptor activity

Target	Action	Affinity	Source
5-hydroxytryptamine receptor 2A	—	Ki 0.099 nM	CHEMBL
Serotonin 2 (5-HT2) receptor	—	Ki 0.14 nM	CHEMBL
Rattus norvegicus	—	Ki 0.32 nM	CHEMBL
Alpha-1A adrenergic receptor	—	Ki 0.4 nM	CHEMBL
D(2) dopamine receptor	—	Ki 0.44 nM	CHEMBL
Dopamine D2 receptor and Serotonin 2a receptor (D2 and 5HT2a)	—	Ki 0.54 nM	CHEMBL
Adrenergic receptor alpha-1	—	Ki 0.69 nM	CHEMBL
5-hydroxytryptamine receptor 7	—	Ki 1 nM	CHEMBL
Alpha-1B adrenergic receptor	—	Ki 1.079 nM	CHEMBL
Alpha-2C adrenergic receptor	—	Ki 1.389 nM	CHEMBL
Adrenergic receptor alpha-2	—	Ki 1.8 nM	CHEMBL
Histamine H1 receptor	—	Ki 2.6 nM	CHEMBL
Alpha-2A adrenergic receptor	—	Ki 3.628 nM	CHEMBL
Alpha-1D adrenergic receptor	—	Ki 4.913 nM	CHEMBL
D(4) dopamine receptor	—	Ki 6.2 nM	CHEMBL
5-hydroxytryptamine receptor 2C	—	Ki 6.4 nM	CHEMBL
D(3) dopamine receptor	—	Ki 6.7 nM	CHEMBL
5-hydroxytryptamine receptor 1B	—	Ki 10 nM	CHEMBL
Alpha-2B adrenergic receptor	—	Ki 12 nM	CHEMBL
Unchecked	—	Ki 13 nM	CHEMBL
5-hydroxytryptamine receptor 2B	—	Ki 15 nM	CHEMBL
D(1A) dopamine receptor	—	Ki 21 nM	CHEMBL
5-hydroxytryptamine receptor 1A	—	Ki 21 nM	CHEMBL
5-hydroxytryptamine receptor 6	—	Ki 224 nM	CHEMBL
Serotonin 1 (5-HT1) receptor	—	Ki 339 nM	CHEMBL
Voltage-gated inwardly rectifying potassium channel KCNH2	—	Ki 920 nM	CHEMBL
5-hydroxytryptamine receptor 5A	—	Ki 1000 nM	CHEMBL
D(1B) dopamine receptor	—	Ki 1000 nM	CHEMBL
Muscarinic acetylcholine receptor M2	—	Ki 1000 nM	CHEMBL
Muscarinic acetylcholine receptor M1	—	Ki 1000 nM	CHEMBL
Muscarinic acetylcholine receptor M3	—	Ki 1000 nM	CHEMBL
5-hydroxytryptamine receptor 1E	—	Ki 1000 nM	CHEMBL
5-hydroxytryptamine receptor 1D	—	Ki 1000 nM	CHEMBL
5-hydroxytryptamine receptor 3A	—	Ki 1000 nM	CHEMBL
Sodium-dependent serotonin transporter	—	Ki 1400 nM	CHEMBL
Histamine H2 receptor	—	Ki 1458 nM	CHEMBL
Sigma non-opioid intracellular receptor 1	—	Ki 4300 nM	CHEMBL
Muscarinic acetylcholine receptor	—	Ki 5000 nM	CHEMBL
Norepinephrine transporter	—	Ki 5454 nM	CHEMBL
Beta-1 adrenergic receptor	—	Ki 22000 nM	CHEMBL
Transporter	—	Ki 28000 nM	CHEMBL

Mechanism of action

Though its precise mechanism of action is not fully understood, current focus is on the ability of risperidone to inhibit the D2 dopaminergic receptors and 5-HT2A serotonergic receptors in the brain. Schizophrenia is thought to result from an excess of dopaminergic D2 and serotonergic 5-HT2A activity, resulting in overactivity of central mesolimbic pathways and mesocortical pathways, respectively. D2 dopaminergic receptors are transiently inhibited by risperidone, reducing dopaminergic neurotransmission, therefore decreasing positive symptoms of schizophrenia, such as delusions and hallucinations. Risperidone binds transiently and with loose affinity to the dopaminergic D2 receptor, with an ideal receptor occupancy of 60-70% for optimal effect. Rapid dissociation of risperidone from the D2 receptors contributes to decreased risk of extrapyramidal symptoms (EPS), which occur with permanent and high occupancy blockade of D2 dopaminergic receptors. Low-affinity binding and rapid dissociation from the D2 receptor distinguish risperidone from the traditional antipsychotic drugs. A higher occupancy rate of D2 receptors is said to increase the risk of extrapyramidal symptoms and is therefore to be avoided. Increased serotonergic mesocortical activity in schizophrenia results in negative symptoms, such as depression and decreased motivation. The high-affinity binding of risperidone to 5-HT2A receptors leads to a decrease in serotonergic activity. In addition, 5-HT2A receptor blockade results in decreased risk of extrapyramidal symptoms, likely by increasing dopamine release from the frontal cortex, and not the nigrostriatal tract. Dopamine level is therefore not completely inhibited. Through the above mechanisms, both serotonergic and D2 blockade by risperidone are thought to synergistically work to decrease the risk of extrapyramidal symptoms. Risperidone has also been said to be an antagonist of alpha-1 (α1), alpha-2 (α2), and histamine (H1) receptors. Blockade of these receptors is thought to improve symptoms of schizophrenia, however the exact mechanism of action on these receptors is not fully understood at this time.
Risperidone has high affinity for several receptors, including serotonin receptors (5-HT 2A/2C), D2 dopamine receptors and alpha1 and H1 receptors. It has no appreciable activity at M1 receptors. Its primary metabolite (9-hydroxyrisperidone) is nearly equipotent compared with the parent compound at D2 and 5-HT 2A receptors.
The exact mechanism of antipsychotic action of risperidone has not been fully elucidated but, like that of clozapine, appears to be more complex than that of most other antipsychotic agents and may involve antagonism of central type 2 serotonergic (5-HT2) receptors and central dopamine D2 receptors.
Risperidone is an atypical antipsychotic drug that is widely prescribed to young patients with different psychotic disorders. The long-term effects of this antipsychotic agent on neuronal receptors in developing brain remain unclear and require further investigation. In this study, we examined the effects of long-term treatment of risperidone on two serotonin receptor subtypes in brain regions of juvenile rat. Levels of 5-HT(1A) and 5-HT(2A) receptors in forebrain regions of juvenile rats were quantified after 3 weeks of treatment with three different doses of risperidone (0.3, 1.0 and 3.0mg/kg). Findings were compared to previously reported changes in 5-HT receptors after risperidone treatment (3.0mg/kg) in adult rat brain. The three doses of risperidone selectively and dose-dependently increased levels of 5-HT(1A) receptors in medial-prefrontal and dorsolateral-frontal cortices of juvenile animals. The higher doses (1.0 and 3.0mg/kg) of risperidone also increased 5-HT(1A) receptor binding in hippocampal CA(1) region of juvenile but not adult rats. In contrast, the three doses of risperidone significantly reduced 5-HT(2A) labeling in medial-prefrontal and dorsolateral-frontal cortices in juvenile as well as in adult animals in an equipotent fashion. 5-HT(1A) and 5-HT(2A) receptors in other forebrain regions were not altered by repeated risperidone treatment. These findings indicate that there are differential effects of risperidone on 5-HT(1A) and 5-HT(2A) receptors in juvenile animals, and that the 5-HT system in developing animals is more sensitive than adults to the long-term effects of risperidone.
The main class of atypical antipsychotic drugs (APDs) in current use includes the protypical atypical APD, clozapine, as well as aripiprazole, asenapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone. At clinically effective doses, these agents produce extensive blockade of serotonin (5-HT)(2A) receptors, direct or indirect stimulation of 5-HT(1A) receptors, and to a lesser extent, reduction in dopamine (DA) D(2) receptor-mediated neurotransmission. This contrasts with typical APDs, for example haloperidol and perphenazine, which are mainly DA D(2/)D(3) receptor antagonists and have weaker, if any, potency as 5-HT(2A) receptor antagonists. Some, but not all, atypical APDs are also effective 5-HT(2C) receptor inverse agonists or neutral antagonists, 5-HT(6) or 5-HT(7) receptor antagonists. This diverse action on 5-HT receptors may contribute to significant differences in efficacy and tolerability among the atypical APDs. There is considerable preclinical and some clinical evidence that effects on 5-HT receptors contribute to the low risk of producing extrapyramidal side effects, which is the defining characteristic of an atypical APD, the lack of elevation in plasma prolactin levels (with risperidone and 9-hydroxyrisperidone being exceptions), antipsychotic action, and ability to improve some domains of cognition in patients with schizophrenia. The serotonergic actions of the atypical APDs, especially 5-HT(2A) receptor antagonism, are particularly important to the differential effects of typical and atypical APDs to overcome the effects of acute or subchronic administration of N-methyl-d-aspartate (NMDA) receptor antagonists, such as phencyclidine, ketamine, and dizocipline (MK-801). 5-HT(1A) receptor stimulation and 5-HT(6) and 5-HT(7) receptor antagonism may contribute to beneficial effects of these agents on cognition. In particular, 5-HT(7) receptor antagonism may be the basis for the pro-cognitive effects of the atypical APD, amisulpride, a D(2)/D(3) receptor antagonist, which has no effect on other 5-HT receptor. 5-HT(2C) receptor antagonism appears to contribute to the weight gain produced by some atypical APDs and may also affect cognition and psychosis via its influence on cortical and limbic dopaminergic activity.
Paliperidone is an active metabolite of the second-generation atypical antipsychotic, risperidone recently approved for the treatment of schizophrenia and schizoaffective disorder. Because paliperidone differs from risperidone by only a single hydroxyl group, questions have been raised as to whether there are significant differences in the effects elicited between these two drugs. /The researchers/ compared the relative efficacies of paliperidone versus risperidone to regulate several cellular signalling pathways coupled to four selected GPCR targets that are important for either therapeutic or adverse effects: human dopamine D2 , human serotonin 2A receptor subtype (5-HT2A ), human serotonin 2C receptor subtype and human histamine H1 receptors. Whereas the relative efficacies of paliperidone and risperidone were the same for some responses, significant differences were found for several receptor-signalling systems, with paliperidone having greater or less relative efficacy than risperidone depending upon the receptor-response pair. Interestingly, for 5-HT2A -mediated recruitment of beta-arrestin, 5-HT2A -mediated sensitization of ERK, and dopamine D2 -mediated sensitization of adenylyl cyclase signalling, both paliperidone and risperidone behaved as agonists. These results suggest that the single hydroxyl group of paliperidone promotes receptor conformations that can differ from those of risperidone leading to differences in the spectrum of regulation of cellular signal transduction cascades. Such differences in signalling at the cellular level could lead to differences between paliperidone and risperidone in therapeutic efficacy or in the generation of adverse effects.

Pharmacodynamics

The primary action of risperidone is to decrease dopaminergic and serotonergic pathway activity in the brain, therefore decreasing symptoms of schizophrenia and mood disorders. Risperidone has a high binding affinity for serotonergic 5-HT2A receptors when compared to dopaminergic D2 receptors in the brain. Risperidone binds to D2 receptors with a lower affinity than first-generation antipsychotic drugs, which bind with very high affinity. A reduction in extrapyramidal symptoms with risperidone, when compared to its predecessors, is likely a result of its moderate affinity for dopaminergic D2 receptors.

Pharmacokinetics

Half-life

3 hours in extensive metabolizers Up to 20 hours in poor metabolizers
The apparent half-life of risperidone plus 9-hydroxyrisperidone following Risperdal Consta administration is 3 to 6 days, and is associated with a monoexponential decline in plasma concentrations. This half-life of 3-6 days is related to the erosion of the microspheres and subsequent absorption of risperidone.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.

Absorption

Well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.
Risperidone is extensively metabolized in the liver. In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives are prolonged compared to young healthy subjects.
The volume of distribution of risperidone is approximately 1 to 2 L/kg.
Risperidone is cleared by the kidneys. Clearance is decreased in the elderly and those with a creatinine clearance (ClCr) between 15-59 mL/min, in whom clearance is decreased by approximately 60%.
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and a1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 ug/mL), warfarin (10 ug/mL), and carbamazepine (10 ug/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.

Metabolism

Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone (i.e. [paliperidone]), which has approximately the same receptor binding affinity as risperidone. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase. Risperidone also undergoes N-dealkylation to a lesser extent.
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.
Risperidone has known human metabolites that include 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 3-[2-[4-(6-fluoro-2-hydroxy-1,2-benzoxazol-2-ium-3-yl)piperidin-1-yl]ethyl]-2,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, Paliperidone, 9-Hydroxy-risperidone, and 3-ethyl-2,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one.
Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone, which has approximately the same receptor binding affinity as risperidone. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase. Risperidone also undergoes N-dealkylation to a lesser extent.
Route of Elimination: Risperidone is extensively metabolized in the liver.In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Half Life: 20-24 hours

Protein binding

Risperidone and its active metabolite, 9-hydroxyrisperidone, are ~88% and ~77% protein-bound in human plasma, respectively. They each bind to both serum albumin and alpha-1-acid glycoprotein.