5-HT_2A Receptor ( Ki = 4.8 nM ); D₂ Receptor ( Ki = 5.9 nM ); P-glycoprotein

Risperidone has a Kis of 4.8 and 5.9 nM for the 5-HT2A and D2 dopamine receptors, respectively, making it a strong antagonist of the dopamine receptor, a P-Glycoprotein inhibitor, and a blocker of the serotonin 5-HT2 receptor. In contrast to its dose-dependent induction of IL-10 production, risperidone inhibited the release of IL-12 in mature DCs. Maturated DCs may release TNF-α when given a high dose of risperidone [3].

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 Antipsychotic drugs (APDs) that bind mainly to the dopamine D2 receptor or the type II 5-HT receptor have been used to ease the symptoms of schizophrenia. Several studies have reported that APDs can also regulate the immune response. Dendritic cells (DCs) are the major antigen-presenting cells in the immune system. DCs can release 5-HT and dopamine to modulate T-cell activation and differentiation. In this study, we use the monocyte-derived DCs to investigate the drug effects of typical APD (haloperidol) and atypical APD (risperidone) on DCs in vitro. Our studies revealed that only risperidone but not haloperidol affected the cytokine and chemokine production of mature DCs. Risperidone increased the production of IL-10 and MDC as well as the proinflammatory cytokines, such as IL-6, IL-8, and TNF-α, but decreased the production of IP-10 and IL-12. Furthermore, the exposure of DCs to risperidone led to lower IFN-γ production by T-cells. The results suggested that risperidone can modulate the DCs' immune function by inhibiting the potent Th1 cytokines and increasing the potent Th2 cytokines. In addition, the production of TNF-α by risperidone-treated mature DCs will induce the death of neutrophils. [2]

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  Risperidone (RSP) and its major active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the drug transporter P-glycoprotein (P-gp). The goal of this study was to examine the in vitro effects of RSP and PALI on P-gp-mediated transport. The intracellular accumulation of rhodamine123 (Rh123) and doxorubicin (DOX) were examined in LLC-PK1/MDR1 cells to evaluate P-gp inhibition by RSP and PALI. Both compounds significantly increased the intracellular accumulation of Rh123 and DOX in a concentration-dependent manner. The IC(50) values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 microM, respectively, whereas the IC(50) values of PALI were >100 microM, indicating that PALI is a less potent P-gp inhibitor. Caco-2 and primary cultured rat brain microvessel endothelial cells (RBMECs) were utilized to investigate the possible influence of RSP on intestinal absorption and blood-brain barrier (BBB) transport of coadministered drugs that are P-gp substrates. RSP, 1-50 microM, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC(50) value of 5.87 microM. Following exposure to 10 microM RSP, the apparent permeability coefficient of Rh123 across Caco-2 and RBMECs monolayers was increased to 2.02 and 2.63-fold in the apical to basolateral direction, but decreased to 0.37 and 0.21-fold in the basolateral to apical direction, respectively. These data suggest that RSP and PALI, to a lesser extent, have a potential to influence the pharmacokinetics and hence the pharmacodynamics of coadministered drugs via inhibition of P-gp-mediated transport. However, no human data exist that address this issue. In particular, RSP may interact with its own active metabolite PALI by promoting its brain concentration through inhibiting P-gp-mediated efflux of PALI across endothelial cells of the BBB [3].

In the initial trial, it was discovered that the rats given Risperidone had a marginally, but statistically significant, decreased body weight with increasing age. Age-dependent variations in body weight are also noted in the second locomotor experiment among the three treatment groups. Postnatal days 35, 38, and 41 weight loss is observed in rats given a 3.0 mg/kg dose of risperidone as opposed to rats given a vehicle. Larger, mixed-sex litters are used in the third locomotor experiment, as opposed to the smaller, single-sex litters utilized in the first two. In the third trial, rats given risperidone experienced a decrease in weight gain that was age-dependent, as was observed in the first two[4].

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It has been suggested that a combined blockade of 5-HT2 and D2 dopamine receptors may be superior to D2 dopamine antagonists alone in the treatment of schizophrenia. Risperidone, which has a high affinity for 5-HT2 and D2 dopamine receptors in vitro, is a new antipsychotic drug that has been developed according to this hypothesis. The aim of this study was to examine if risperidone indeed induces 5-HT2 and D2 dopamine receptor occupancy in vivo in humans. Central receptor occupancy was examined by positron emission tomography (PET) in three healthy men after oral administration of 1 mg risperidone. [11C]N-methylspiperone ([11C]NMSP) was used as a radioligand for determination of 5-HT2 receptor occupancy in the neocortex. Both an equilibrium ratio analysis and a kinetic three-compartmental analysis indicated a 5-HT2 receptor occupancy about 60%. [11C]raclopride was used as a radioligand for determination of D2 dopamine receptor occupancy in the striatum and the calculated occupancy was about 50%. This is the first quantitative determination of 5-HT2 receptor occupancy induced by an antipsychotic drug in the living human brain. The results indicate that 5-HT2 receptor occupancy should be very high at the dose level of 4-10 mg risperidone daily, as suggested for clinical use. Risperidone is thus an appropriate compound for clinical evaluation of the benefit of combined 5-HT2 and D2 dopamine receptor blockade in the treatment of schizophrenia. [1]

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Risperidone is an antipsychotic drug approved for use in children, but little is known about the long-term effects of early-life risperidone treatment. In animals, prolonged risperidone administration during development increases forebrain dopamine receptor expression immediately upon the cessation of treatment. A series of experiments was performed to ascertain whether early-life risperidone administration altered locomotor activity, a behavior sensitive to dopamine receptor function, in adult rats. One additional behavior modulated by forebrain dopamine function, spatial reversal learning, was also measured during adulthood. In each study, Long-Evans rats received daily subcutaneous injections of vehicle or 1 of 2 doses of risperidone (1.0 and 3.0 mg/kg per day) from postnatal Days 14 to 42. Weight gain during development was slightly yet significantly reduced in risperidone-treated rats. In the first 2 experiments, early-life risperidone administration was associated with increased locomotor activity at 1 week postadministration through approximately 9 months of age, independent of changes in weight gain. In a separate experiment, it was found that the enhancing effect of early-life risperidone on locomotor activity occurred in males and female rats. A final experiment indicated that spatial reversal learning was unaffected in adult rats administered risperidone early in life. These results indicate that locomotor activity during adulthood is permanently modified by early-life risperidone treatment. The findings suggest that chronic antipsychotic drug use in pediatric populations (e.g., treatment for the symptoms of autism) could modify brain development and alter neural set points for specific behaviors during adulthood [4].

Intracellular Rh123 and DOX Accumulation Studies [3]
Intracellular accumulation of P-gp substrates Rh123 and DOX were measured to evaluate the P-gp activity in LLC-PK1/MDR1 and Caco-2 cells whereas LLC-PK1 was included as a negative control (van der Sandt et al, 2000). After reaching confluence, cells were preincubated at 37°C for 30 min with transport buffer (serum-free DMEM containing 25 mM N-2-hydroxyl piperazine-N′-2-ehane sulfonic acid, pH 7.4). Vehicle control (0.5% dimethylsulfoxide (DMSO)), specific concentrations of RSP/Risperidone, PALI, or PSC833 were added, then 5 μM of Rh123 or 10 μM of DOX were added for an additional 60 min incubation. After incubation, the solutions were discarded, and the cells were washed three times with ice-cold DPBS and solubilized with 1% Triton X-100. The fluorescence of Rh123 and DOX were measured by high-performance liquid chromatography (HPLC) assay. The concentrations were determined from the fluorescence value through the construction of Rh123 and DOX standard curves. The amount of Rh123 or DOX in each sample was standardized with the protein content as determined by the Lowry assay.

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Rh123 Transport Studies [3]
When RBMECs or Caco-2 cells reached confluence, the integrity of monolayers was checked by both TEER value and the transport rate of fluorescein, a recognized paracellular transport marker (van Bree et al, 1988). The qualified monolayers were rinsed two times with DPBS and preincubated with transport buffer at 37°C for 30 min. In all, 0.5% DMSO, RSP/Risperidone, or PSC833 was loaded at both sides of the monolayers, then Rh123 (5 μM) was added into the basolateral side for the basolateral to apical (B–A) transport study or apical side for the apical to basolateral (A–B) transport study. At designated times, 150 μl samples were taken from the receiver compartment, and the same volume of receiver compartment solution was replaced immediately after each sampling. Concentrations of Rh123 were determined by HPLC. Apparent permeability coefficients, Papp (cm/s) were calculated according to the following equation:

Rats: A total of 211 Long-Evans rats are utilized, comprising 56 females and 155 males. Three groups of approximately equal numbers of rats are injected with either 1.0 mg/kg of risperidone, 3.0 mg/kg of risperidone, or the vehicle used to administer the risperidone solution as a control within each study. Twenty-six male rats (n = 9 in the vehicle and 3.0 mg/kg Risperidone groups; n = 8 in the 1.0 mg/kg Risperidone group) are used in the first experiment. They are tested for locomotor activity for 20 minutes every day starting on postnatal day 49 and continuing every day until postnatal day 53. The long-term effects of early-life Risperidone treatment on locomotion were examined in a follow-up study. In a third experiment, the effects of sex on early-life Risperidone's locomotor effects in young adult rats are investigated. Sixty male (n = 20 per treatment group) and fifty-six female (n = 19 rats in the vehicle and 3.0 mg/kg dose group, n = 18 in the 1.0 mg/kg dose group) rats are treated in this experiment. In a fourth experiment, rats given risperidone early in life were evaluated for reversal learning during adulthood. Treatment is given to 42 male rats (n=14 per treatment group)[4].

Absorption, Distribution and Excretion
Risperidone is well absorbed. Its absolute oral bioavailability is 70% (CV = 25%). Compared to solution, the relative oral bioavailability of tablets is 94% (CV = 10%). Risperidone is extensively metabolized in the liver. Compared to young healthy subjects, renal clearance of risperidone and its metabolite 9-hydroxyrisperidone is decreased and the elimination half-life is prolonged in healthy elderly individuals. The volume of distribution of risperidone is approximately 1–2 L/kg. Risperidone is cleared by the kidneys. Clearance is decreased in elderly individuals and patients with creatinine clearance (ClCr) between 15 and 59 mL/min, with the latter showing a reduction of approximately 60%. Risperidone is well absorbed. Its absolute oral bioavailability is 70% (coefficient of variation CV = 25%). Compared to solution, the relative oral bioavailability of tablets is 94% (coefficient of variation CV = 10%). Risperidone is rapidly distributed, with a volume of distribution of 1–2 L/kg. In plasma, risperidone binds to albumin and α1-acid glycoprotein. The plasma protein binding rate of risperidone is 90%, while that of its major metabolite, 9-hydroxyrisperidone, is 77%. Risperidone and 9-hydroxyrisperidone do not interchange plasma protein binding sites. High concentrations of sulfadiazine (100 μg/mL), warfarin (10 μg/mL), and carbamazepine (10 μg/mL) only result in a slight increase in the free fractions of risperidone (10 ng/mL) and 9-hydroxyrisperidone (50 ng/mL), the clinical significance of which is unclear. Within a dose range of 1 to 16 mg daily (0.5 to 8 mg twice daily), the plasma concentrations of risperidone, its major metabolite 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose-dependent. After oral administration of solution or tablets, the mean peak plasma concentration of risperidone occurs approximately 1 hour later. In rapid metabolizers, peak concentrations of 9-hydroxyrisperidone occur at approximately 3 hours, while in slow metabolizers, they occur at approximately 17 hours. Steady-state concentrations of risperidone are reached within 1 day in rapid metabolizers; in slow metabolizers, it is expected to take approximately 5 days to reach steady state. Steady-state concentrations of 9-hydroxyrisperidone are reached within 5–6 days (measured in rapid metabolizers). Risperidone and 9-hydroxyrisperidone are present in human milk. For more complete data on the absorption, distribution, and excretion of risperidone (a total of 6 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
Risperidone is primarily metabolized by the hepatic cytochrome P450 2D6 isoenzyme to 9-hydroxyrisperidone (i.e., paliperidone), which has approximately the same receptor affinity as risperidone. Hydroxylation depends on debromoquine 4-hydroxylase, and risperidone metabolism is influenced by debromoquine 4-hydroxylase gene polymorphism. Risperidone also undergoes minor N-dealkylation. Risperidone is primarily metabolized in the liver. Its main metabolic pathway involves hydroxylation of risperidone to 9-hydroxyrisperidone via the CYP2D6 enzyme. A secondary metabolic pathway involves N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity to risperidone. Therefore, the clinical efficacy of this drug depends on the combined concentration of risperidone and 9-hydroxyrisperidone. CYP2D6, also known as debromoquine hydroxylase, is an enzyme that metabolizes many antipsychotics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is influenced by genetic polymorphism (approximately 6%-8% of Caucasians and a very small number of Asians have very low or no CYP2D6 activity, classifying them as "weak metabolizers"), and is easily inhibited by various substrates and some non-substrate substances (especially quinidine). CYP 2D6 metabolizers rapidly convert risperidone to 9-hydroxyrisperidone, while CYP 2D6 poor metabolizers convert it much more slowly. Although risperidone concentrations are lower in fast metabolizers than in slow metabolizers, and 9-hydroxyrisperidone concentrations are higher, the pharmacokinetic characteristics of risperidone and 9-hydroxyrisperidone are similar in both fast and slow metabolizers after single and multiple administrations. Known metabolites of risperidone include 9-hydroxyrisperidone, paliperidone, 3-[2-[4-(6-fluoro-2-hydroxy-1,2-benzoxazol-2-onthiol-3-yl)piperidin-1-yl]ethyl]-2,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, 3-ethyl-2,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, etc. 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole. It is primarily metabolized by the hepatic cytochrome P450 2D6 isoenzyme to 9-hydroxyrisperidone, which has a roughly similar receptor binding affinity to risperidone. Hydroxylation depends on debromoquine 4-hydroxylase, and metabolism is influenced by debromoquine 4-hydroxylase gene polymorphisms. Risperidone also undergoes minor N-dealkylation. Elimination pathway: Risperidone is primarily metabolized in the liver. In healthy older adults, the renal clearance of both risperidone and its metabolite 9-hydroxyrisperidone is reduced, and the elimination half-life is prolonged compared to younger, healthy subjects.
Half-life: 20-24 hours

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Biological half-life
The half-life is 3 hours for vigorous metabolizers and up to 20 hours for weak metabolizers.
After administration of risperidone extended-release tablets (Risperdal Consta), the apparent half-life of risperidone and its metabolite 9-hydroxyrisperidone is 3 to 6 days, with plasma concentrations showing a single exponential decrease. The half-life of risperidone is 3-6 days, which is related to microsphere erosion and subsequent risperidone absorption.
In rapid metabolizers, the apparent half-life of risperidone is 3 hours (CV=30%), and in slow metabolizers it is 20 hours (CV=40%). In rapid metabolizers, the apparent half-life of 9-hydroxyrisperidone is approximately 21 hours (CV=20%), and in slow metabolizers it is approximately 30 hours (CV=25%). After single and multiple administrations, the pharmacokinetics of risperidone and 9-hydroxyrisperidone in combination were similar in fast metabolizers and slow metabolizers, with an overall mean elimination half-life of approximately 20 hours.

Toxicity Summary
Blocking dopamine D2 receptors in the limbic system can alleviate positive symptoms of schizophrenia, such as hallucinations, delusions, and behavioral and speech abnormalities. Blocking serotonin 2 (5-HT2) receptors in the mesocortical pathway leads to dopamine overdose and enhanced dopamine transmission, thereby enhancing dopamine delivery and eliminating core negative symptoms. Risperidone does not affect dopamine receptors in the nigrostriatal pathway, thus avoiding extrapyramidal side effects. Like other 5-HT2 receptor antagonists, risperidone binds to α1-adrenergic receptors and weakly to histamine H1 and α2-adrenergic receptors. Toxicity Data
LD50 = 82.1 mg/kg (oral administration to mice). Interactions
Given that risperidone primarily acts on the central nervous system, caution should be exercised when risperidone is used concomitantly with other centrally acting drugs and alcohol.
Ripardone may antagonize the effects of levodopa and dopamine agonists.
When risperidone is used in combination with enzyme inducers (e.g., carbamazepine), the dose of risperidone should be increased to twice the patient’s usual dose. When enzyme inducers such as carbamazepine are discontinued, the dose of risperidone may need to be reduced [see Drug Interactions (7.1)]. A similar situation may occur when risperidone is used in combination with other enzyme inducers (e.g., phenytoin sodium, rifampin, and phenobarbital).
Prolonged use of clozapine and risperidone may reduce the clearance of risperidone.
For more complete data on risperidone interactions (of 10 items), please visit the HSDB record page.

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Hepatotoxicity
Up to 30% of patients taking risperidone long-term may experience liver dysfunction, usually within the first 8 weeks of treatment. Elevations in ALT are usually mild and transient and may return to normal with continued use. More pronounced elevations in ALT and alkaline phosphatase, with or without symptoms, and jaundice have been reported in some patients. Damage typically occurs within days of starting risperidone and resolves rapidly upon discontinuation. There are also reports of acute liver injury with jaundice occurring in some patients months or even years after starting risperidone. Serum enzyme elevations are usually cholestatic, but hepatocellular and mixed cases have also been reported. Immune allergic reactions (rash, fever, eosinophilia) are rare; one case of risperidone-induced autoimmune hepatitis has been reported, but most cases do not have autoimmune characteristics.

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Use during pregnancy and lactation
◉ Overview of use during lactation
Limited information suggests that low concentrations of risperidone in breast milk are observed when pregnant women take up to 6 mg daily. Infants ingesting risperidone through breast milk have been reported to experience sedation, growth retardation, restlessness, tremors, abnormal muscle movements, and respiratory depression. Due to limited published experience and a lack of long-term follow-up data regarding the use of risperidone during lactation, alternative medications may be preferred, especially for breastfed newborns or premature infants. A systematic review of second-generation antipsychotics concluded that, due to limited available data and the fact that risperidone is more readily excreted into breast milk compared to other medications, it appears appropriate to use risperidone as a second-line treatment during lactation. A safety rating system indicated that cautious use of risperidone during lactation is feasible. Infant somnolence, weight gain, tremors, respiratory rate, abnormal muscle movements, and developmental milestones should be monitored, especially in cases of concurrent use of other antipsychotics.
◉ Effects on Breastfed Infants
One woman took 4 mg of risperidone daily while breastfeeding. Her infant showed no developmental abnormalities in all examinations before 9 months of age. Another mother took 6 mg of risperidone daily while breastfeeding. Her infant showed no developmental abnormalities in all examinations before 12 months of age.
Two women who took 4 mg and 1.5 mg of risperidone daily, respectively, breastfed their infants at 3.3 months and 6 weeks of age, respectively. Both infants showed normal developmental milestones, and no adverse reactions were reported.
A woman started taking risperidone 2 mg daily one week postpartum, increasing to 3 mg daily after 10 days. She breastfed her infant six times a day. The infant underwent five weeks of inpatient observation, and a pediatric neurologist assessed that the infant's development was normal. No sedation or other adverse reactions were observed in the infant. After three months of risperidone treatment, both mother and infant were in good health.
An infant was exclusively breastfed for three months while the mother was taking 1 mg risperidone daily. Pediatric examination revealed no neurological or physical abnormalities in the infant, and the infant interacted normally.
In a telephone follow-up study, 124 mothers who were taking benzodiazepines while breastfeeding reported any signs of sedation in their infants. One mother taking 0.75 mg risperidone, 15 mg flurazepam, 0.25 mg clonazepam (twice daily), and 1 mg bupropion daily reported sedation in her breastfed infant. A woman diagnosed with schizophrenia took 1.5 mg of risperidone daily during late pregnancy and postpartum (breastfeeding duration not specified) while breastfeeding her full-term infant. Two weeks postpartum, due to a relapse of symptoms, haloperidol 0.8 mg/day was added. At this dose, the infant did not experience adverse reactions. However, due to a relapse of symptoms, the haloperidol dose was increased to 1.5 mg/day. Three days later, the infant developed excessive sedation, feeding difficulties, and motor retardation. Pediatric evaluation revealed no medical cause for these symptoms. After discontinuation of breastfeeding, the infant's symptoms completely resolved within 5 days. The infant's symptoms may have been caused by the combination of medications. A prospective cohort study conducted in a maternal and infant psychiatric ward in India followed seven infants who were exposed to risperidone through breast milk; most infants received partial supplemental therapy. One infant's mother took 4 mg of risperidone and 2 mg of lorazepam, and the infant experienced sedation, which resolved after discontinuation of lorazepam. An infant whose mother was taking risperidone 4 mg and trihexyphenidyl 2 mg daily and receiving electroconvulsive therapy developed constipation. The infants were followed up for 1 to 3 months after discharge. One infant had stunted growth in weight, one had stunted growth in height, one had intellectual disability, and another had both motor and intellectual disabilities. A woman with bipolar disorder was taking risperidone 2 mg orally at bedtime, 50 mg of long-acting risperidone intramuscularly every 2 weeks, citalopram 20 mg orally daily, and benzalkonium chloride 0.5 mg orally daily. She continued taking the same medications during pregnancy. Her infant was born at 35 weeks of gestation and was breastfed (the extent and duration of breastfeeding were not specified). The infant was developing well at 16 months of age, with all developmental milestones met. Patients taking second-generation antipsychotics while breastfeeding (n = 576) registered with the National Atypical Antipsychotics Pregnancy Registry were compared with a breastfeeding control group (n = 818) who were not taking second-generation antipsychotics. Among patients taking second-generation antipsychotics, 60.4% were concurrently taking two or more psychotropic medications. Pediatric case reviews showed no adverse reactions in infants, regardless of whether they received monotherapy or combination therapy with second-generation antipsychotics. The number of women taking risperidone was not reported. A premature infant, weighing 2.75 kg at 35 weeks gestation, received 2 minutes of assisted ventilation on a portable ventilator due to respiratory distress and received continuous oxygen for the first 18 hours after birth. Breastfeeding began on the second day after birth. On day 12, the mother began taking risperidone at 1 mg daily for the treatment of psychotic episodes. On day 13, the infant's respiratory rate decreased to 16 breaths/min without respiratory distress, and continuous positive airway pressure (CPAP) was administered for 12 hours, followed by gradual weaning and formula feeding. On day 15, the mother resumed breastfeeding, but the infant experienced respiratory depression again. The feeding method was changed to expressing breast milk before taking risperidone, feeding formula 6 hours after each dose, and then resuming direct breastfeeding. Respiratory depression did not recur for the next two days. The infant was discharged on day 24 and instructed to continue the previous feeding method. The respiratory depression was likely caused by risperidone in the breast milk.
A woman diagnosed with undifferentiated schizophrenia took 4 to 5 mg of risperidone and 2 mg of trihexyphenidyl daily during five pregnancies. She breastfed each infant for 20 to 24 months. None of the children experienced adverse developmental consequences. As of the time of this writing, the three oldest children (aged 26, 23, and 22) have completed their education and entered the workforce, while the two youngest children (aged 15 and 19) are performing well academically.

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◉ Effects on lactation and breast milk
Patients taking risperidone may experience elevated serum prolactin levels, gynecomastia, and galactorrhea. In one case, a 19-year-old male developed gynecomastia and galactorrhea while taking fluvoxamine, despite normal prolactin levels. A meta-analysis of three studies found that risperidone induced gynecomastia at a 4.3-fold higher risk than quetiapine. For mothers who have established lactation, their prolactin levels may not affect their ability to breastfeed. One study compared breastfeeding mothers on second-generation antipsychotics registered with the National Atypical Antipsychotic Pregnancy Registry (n = 576) with a control group of breastfeeding mothers with a primary diagnosis of major depressive disorder and anxiety disorder (n = 818). The control group typically received selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) but not second-generation antipsychotics. Among the women taking second-generation antipsychotics, 60.4% were also taking more than one other psychotropic medication, compared to 24.4% in the control group. Among women taking second-generation antipsychotics, 59.3% reported having breastfed, compared to 88.2% in the control group. At 3 months postpartum, 23% of women taking second-generation antipsychotics were still exclusively breastfeeding, compared to 47% in the control group. No reports were found regarding the number of women taking risperidone.
◈ What is risperidone?
Risperidone is a medication used to treat mental illnesses such as schizophrenia, bipolar disorder, and depression. It can be administered orally or by injection. Risperidone belongs to the atypical or second-generation antipsychotic class. Brand names for risperidone include Risperdal®, Risperdal Consta®, and Perseris®. Sometimes, when people find out they are pregnant, they consider changing their medication regimen or even stopping it entirely. However, it is essential to consult your healthcare provider before changing your medication regimen. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating the condition during pregnancy.
◈ I am taking risperidone. Will it affect my ability to get pregnant?
In some people, risperidone may increase levels of a hormone called prolactin. High levels of prolactin can suppress ovulation (the process by which the ovary releases an egg during the menstrual cycle). This can make it more difficult to conceive. If you have any concerns, your healthcare provider can test your prolactin levels.
◈ Does taking risperidone increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. Based on reviewed studies, risperidone is not expected to increase the risk of miscarriage.
◈ Does taking risperidone increase the risk of birth defects?
There is a 3-5% risk of birth defects at the start of each pregnancy. This is called background risk. Based on reviewed studies, risperidone is not expected to increase the risk of birth defects above the background risk.
◈ Does taking risperidone during pregnancy increase the risk of other pregnancy-related problems?
Based on reviewed studies, risperidone may lead to low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]). Risperidone may cause weight gain and blood sugar problems in pregnant women, increasing the risk of gestational diabetes. For more information about gestational diabetes, please see our fact sheet: https://mothertobaby.org/fact-sheets/diabetes-pregnancy/.
◈ I need to take risperidone throughout my pregnancy. Will it cause withdrawal symptoms in my baby after birth?
Taking certain medications during pregnancy can cause temporary symptoms in newborns shortly after birth, sometimes referred to as withdrawal symptoms. It is currently unclear whether taking risperidone alone increases the risk of withdrawal symptoms in newborns. Similar medications are associated with a risk of withdrawal symptoms, so infants exposed to risperidone around the time of delivery should be closely monitored for symptoms such as muscle stiffness or weakness, lethargy, irritability, tremors, difficulty breathing, and feeding difficulties. In most cases, these symptoms resolve on their own within a few days and do not have long-term health effects. It is important that your healthcare provider knows you are taking risperidone so that your baby can receive optimal care should symptoms occur.
◈ Will taking risperidone during pregnancy affect my child's future behavior or learning abilities?
Currently, there are no studies showing whether risperidone causes behavioral or learning problems in children.
◈ Is it safe to breastfeed while taking risperidone?
Information regarding the use of risperidone while breastfeeding is limited. Small amounts of risperidone can be detected in breast milk when taken up to 6 mg daily. A small number of breastfed infants exposed only to risperidone (up to 6 mg daily) have not reported side effects. Your infant may be at higher risk of side effects if you are taking risperidone with other medications. If you suspect your infant has any symptoms (drowsiness, feeding difficulties, irritability, or unusual movements), contact your child's healthcare provider. The product label for risperidone advises against using this medication while breastfeeding. However, the benefits of using risperidone may outweigh the potential risks. Your healthcare provider can discuss the use of risperidone with you and the best treatment option for you. Be sure to consult your healthcare provider about all questions regarding breastfeeding.
◈ If a man takes risperidone, will it affect fertility (the ability to impregnate a partner) or increase the risk of birth defects?
Taking risperidone may increase prolactin levels in the body, which may affect fertility. Currently, there is no research indicating whether risperidone increases the risk of birth defects on top of background risk. Generally, medication exposure to a father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please see the “Father Exposure” information sheet on the MotherToBaby website: https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

[1]. 5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone. Psychopharmacology (Berl). 1993;110(3):265-72.

[2]. Risperidone modulates the cytokine and chemokine release of dendritic cells and induces TNF-α-directed cellapoptosis in neutrophils. Int Immunopharmacol. 2012 Jan;12(1):197-204.

[3]. Risperidone and paliperidone inhibit p-glycoprotein activity in vitro. Neuropsychopharmacology. 2007 Apr;32(4):757-64.

[4]. Adult rats treated with risperidone during development are hyperactive. Exp Clin Psychopharmacol. 2013 Jun;21(3):259-67.

Therapeutic Uses
Antipsychotic; Dopamine antagonist; Serotonin antagonist. Risperdone (Risperdal) is indicated for the treatment of schizophrenia. Its efficacy has been demonstrated in 4 short-term trials in adults, 2 short-term trials in adolescents (13 to 17 years of age), and 1 long-term maintenance treatment trial in adults. /US Product Label/ Risperdone in combination with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with bipolar I disorder. Its efficacy has been demonstrated in one short-term trial in adults. /US Product Label/ Risperdone is indicated for the treatment of autism-related irritability symptoms, including aggression, intentional self-harm, temper tantrums, and rapid mood swings. Its efficacy has been demonstrated in 3 short-term trials in children and adolescents (5 to 17 years of age). /US Product Label Includes/ Risperdone is indicated for the treatment of acute manic or mixed episodes associated with bipolar I disorder. Efficacy has been demonstrated in two short-term trials in adults and one short-term trial in children and adolescents (10 to 17 years of age). /US product label contains/

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Drug Warning
/Black Box Warning/ Warning: Increased mortality in patients with dementia-related psychosis. Patients with dementia-related psychosis receiving antipsychotic medication have an increased risk of death. Risperdone (Risperdal) is not approved for the treatment of dementia-related psychosis.
Like other antipsychotics (such as phenothiazines), risperdone is associated with tardive dyskinesia. Although some studies have shown a lower risk of tardive dyskinesia with atypical antipsychotics, it is unclear whether there is a difference in the potential for tardive dyskinesia among different antipsychotics. In an open-label study, the annual incidence of tardive dyskinesia was 0.3% in patients with schizophrenia who received approximately 8–9 mg of oral risperdone daily for at least one year. The prevalence of this syndrome appears to be highest in older patients, particularly women. The risk of developing tardive dyskinesia and its potential for irreversibility appears to increase with the duration and cumulative dose of antipsychotic medication; however, the syndrome can occur even after relatively short periods of low-dose treatment, although much less frequently. Neuroleptic malignant syndrome (NMS) is a potentially fatal symptom cluster that has been reported in patients taking antipsychotic medication. NMS requires immediate discontinuation of the medication and intensive symptomatic and supportive care. Dose-related somnolence is a common side effect of risperidone treatment. In studies using direct questioning or checklists to detect adverse events, approximately 8% of adult patients with schizophrenia taking 16 mg of risperidone daily reported somnolence, compared to 1% in patients taking placebo. For more complete data on risperidone (41 total), please visit the HSDB record page. Pharmacodynamics: The primary action of risperidone is to reduce the activity of dopaminergic and serotonergic pathways in the brain, thereby alleviating symptoms of schizophrenia and mood disorders. Compared to dopamine D2 receptors in the brain, risperidone has a higher binding affinity for serotonin 5-HT2A receptors. The binding affinity of risperidone to D2 receptors is lower than that of first-generation antipsychotics, which have very high affinity for D2 receptors. Compared to previous medications, risperidone can alleviate extrapyramidal symptoms, possibly due to its moderate affinity for dopamine D2 receptors.

C24H31FN4O5S

506.59

506.2

C, 56.90; H, 6.17; F, 3.75; N, 11.06; O, 15.79; S, 6.33

666179-96-0

Risperidone; 106266-06-2; Risperidone hydrochloride; 666179-74-4

10413870

Solid powder

4.113

1

9

4

35

823

0

S(C([H])([H])[H])(=O)(=O)O[H].FC1C([H])=C([H])C2=C(C=1[H])ON=C2C1([H])C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C2=C(C([H])([H])[H])N=C3C([H])([H])C([H])([H])C([H])([H])C([H])([H])N3C2=O)C([H])([H])C1([H])[H]

OJUQOWYTFBZUKJ-UHFFFAOYSA-N

InChI=1S/C23H27FN4O2.CH4O3S/c1-15-18(23(29)28-10-3-2-4-21(28)25-15)9-13-27-11-7-16(8-12-27)22-19-6-5-17(24)14-20(19)30-26-22;1-5(2,3)4/h5-6,14,16H,2-4,7-13H2,1H3;1H3,(H,2,3,4)

3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one;methanesulfonic acid

Risperidone Mesylate salt; Risperidone Mesylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)