Continuing Education Activity

The Food and Drug Administration (FDA)-approved indications for oral risperidone (tablets, oral solution, and M-TABs) include the treatment of schizophrenia (in adults and children aged 13 and up), bipolar I acute manic or mixed episodes as monotherapy (in adults and children aged 10 and up), bipolar I acute manic or mixed episodes adjunctive with lithium or valproate (in adults), and autism-associated irritability (in children aged 5 and up). Also, the long-acting risperidone injection has been approved for the use of schizophrenia and maintenance of bipolar disorder (as monotherapy or adjunctive to valproate or lithium) in adults. There are also many varied non-FDA-approved uses for risperidone. This activity outlines the indications, mechanism of action, administration methods, significant adverse effects, contraindications, and monitoring, of risperidone, so providers can direct patient therapy in treating conditions for which it is indicated as part of the interprofessional team.

Objectives:

• Identify the mechanism of action for risperidone.
• Summarize the indications for initiating therapy with risperidone.
• Review the contraindications and adverse event profile for risperidone.
• Explain the importance of improving care coordination among the interprofessional team to enhance care delivery for patients who can benefit from therapy with risperidone.

Indications

Risperidone is an atypical antipsychotic medication, first approved for use in the USA by the Food and Drug Administration (FDA) in 1993. The FDA-approved indications for oral risperidone (tablets, oral solution, and M-TABs) include the treatment of:

• Schizophrenia (in adults and children aged 13 and up)
• Bipolar I acute manic or mixed episodes as monotherapy (in adults and children aged ten and up)
• Bipolar I acute manic or mixed episodes adjunctive with lithium or valproate (in adults)
• Autism-associated irritability (in children aged five and up)

The long-acting risperidone injection has received FDA approval in the treatment of schizophrenia and maintenance of bipolar disorder (as monotherapy or adjunctive to valproate or lithium) in adults.

There are many varied non-FDA-approved uses for risperidone. It has been used to treat psychotic symptoms when they are present. It has also been used for borderline personality, delusional disorder, delirium, depression, brain injury, pedophilia, PTSD, bipolar disorder, conduct disorder, Lesch-Nyhan, Tourette, trichotillomania, stuttering, movement disorders, and developmental disorders.[1][2] In addition to psychotic symptoms, risperidone has utility in treating aggression and agitation in patients with dementia. Risperidone has also been used to augment antidepressant therapy in the treatment of non-psychotic unipolar depression. In addition to irritability associated with autism, risperidone has also been used for social impairment, stereotypical behaviors, cognitive problems, and hyperactivity in autism.[3][4]

Mechanism of Action

All antipsychotics have some degree of antagonism at D2 receptors. First-generation antipsychotics (FGAs) produce antipsychotic effects at 60% to 80% D2 occupancy. Second-generation antipsychotics (SGAs) like risperidone exhibit their therapeutic effects through some D2 blockade, but more from the blockade of serotonin receptors like 5HT2A. Second-generation antipsychotics have loose binding to D2 receptors and can quickly dissociate from the receptor, potentially accounting for the lower likelihood of causing extrapyramidal symptoms (EPS).[5]

Moreover, second-generation antipsychotics have agonism at the 5HT1A receptor. Serotonin and norepinephrine reuptake inhibition are potential mechanisms by which risperidone is postulated to produce antidepressant effects. The improvement of positive symptoms is thought to be accomplished through the blockade of D2 receptors, specifically in the mesolimbic pathway. The ability of antipsychotics to block D2 receptors in the prefrontal cortex and nucleus accumbens is important in improving certain psychiatric symptoms. Of note, risperidone does not cause anticholinergic effects, which may benefit patients in certain populations, including the elderly with dementia.

Administration

This medication may be administered in oral form (tablets, solution, or dissolvable M-TABs) or as a long-acting injection. Patients should not cut or chew the orally disintegrating tablet formulation. It is also available in injectable form.

Dosing based on indications follows:

• Schizophrenia:
  • For the first episode, age under 65 years: 1 to 3 mg/day orally divided into one or two doses. Stat at 1 mg daily, then increase the dose by 0.5 mg daily every six to seven days to target 2 mg daily. The maximum dose is 16 mg daily, but doses exceeding 4 mg per day are rarely more effective.
  • Maintenance dosing, age under 65 years: 1 to 4 mg/day orally divided into one or two doses. Stat at 1 to 2 mg daily, then increase the dose by 0.5 mg per day every three to seven days to target 4 mg daily. The maximum dose is 16 mg daily, but doses exceeding 4 mg per day are rarely more effective.
  • Age 65 and older: 1 to 4 mg/day orally divided into one or two doses. Stat at 0.25 to 0.5 mg daily, then increase the dose by 0.5 mg per day every six to seven days to target 2 mg daily. The maximum dose is 16 mg daily, but doses exceeding 4 mg per day are rarely more effective.
• Acute manic/mixed bipolar disorder:
  • 1 to 6 mg/day orally divided into one or two doses. Stat at 2 to 3 mg daily, then increase the dose by 1 mg per day no more frequently than every 24 hours to target 2 mg daily. The maximum dose is 6 mg daily.
• Tourette syndrome (off-label):
  • 0.2 to 3 mg daily by mouth divided once or twice daily. The maximum dose is 6 mg daily.

Renal dosing: If CrCl is less than 30, start at 0.5 mg orally twice daily; maybe increase by up to 0.5 mg twice daily until 1.5 mg twice a day, after which dosing should not increase more frequently than weekly.

Hepatic dosing: For Child-Pugh Class C, start at 0.5 mg orally twice daily; maybe increase by up to 0.5 mg twice daily until 1.5 mg twice a day, after which dosing should not increase more frequently than weekly.

Adverse Effects

Weight changes, metabolic changes, and sedation are significant concerns with risperidone. Risperidone may produce extrapyramidal symptoms (EPS), including acute dystonia, akathisia, tardive dyskinesia (TD), and parkinsonian features. Acute/early EPS can occur at the beginning of treatment or when the dose is adjusted. Late-onset EPS (tardive dyskinesia) typically results from chronic treatment. Akathisia is a feeling of restlessness and may manifest as the patient pacing. Acute dystonia includes muscle spasms that result in abnormal postures and typically affect the head and neck. Parkinsonian features include skeletal muscle rigidity (often described as "cogwheel rigidity"), tremor, shuffling gait, and bradykinesia. Movements of the limbs, torso, neck, and head (commonly involving the tongue and lips) characterize tardive dyskinesia. This may also appear as facial grimacing or oculogyric crisis. EPS is thought to be due to D2 blockade in the nigrostriatal pathway. Since acute EPS symptoms often are improved with the cessation of the medication, these side effects are a major cause of noncompliance with treatment. Although these side effects are thought to be reversible, the duration of parkinsonian features after discontinuation of the medication can vary. Tardive dyskinesia, however, will likely persist after the medication is discontinued and may be permanent. In addition to discontinuation of the antipsychotic, pharmacologic treatments are available that may help with certain extrapyramidal symptoms.[6][7]

Antagonism of D2 receptors in the tuberoinfundibular pathway is believed to precipitate a rise in prolactin level. The resulting hyperprolactinemia can precipitate sexual dysfunction, which has a prevalence of 45 to 80 percent among males and 30% to 80% among females taking this medication. Further, the elevated prolactin can contribute to decreased libido, impaired arousal, and difficulty attaining orgasm. Sexual side effects may also be precipitated by risperidone's action at adrenergic (alpha 1, alpha 2) and histamine (H2) receptors. Gynecomastia, galactorrhea, and priapism have been reported in male patients, while galactorrhea and amenorrhea have been reported in female patients. It is important to note that children may be more susceptible to certain susceptible to some side effects and require careful monitoring.[8]

Serious side effects of antipsychotic medications (like risperidone) can include neuroleptic malignant syndrome (NMS). Although the pathogenesis of NMS is not clear, it is a life-threatening condition that can manifest with altered mental status, fever, "lead pipe" rigidity, and autonomic instability, including hypertension, tachypnea, and tachycardia. The use of risperidone has also been linked to a higher probability of cerebrovascular events in elderly patients with dementia, leading to an FDA warning about using this medication in the context of dementia-related psychosis. Studies have even shown an increase in all-cause mortality among the elderly with dementia who are on this medication.[9]

Contraindications

Risperidone should not be given if a known allergy/hypersensitivity to risperidone or paliperidone (a metabolite of risperidone) is present. Hallucinogen persisting perception disorder or HPPD may be a relative contraindication for risperidone because some patients treated with risperidone for their HPPD reported that panic and visual symptoms intensified.

Monitoring

Although there are no mandatory requirements for therapeutic drug monitoring (TDM) with risperidone, monitoring plasma concentrations for this medication is strongly recommended by European guidelines because of data showing interdependent variability. Therapeutic monitoring can benefit assessing compliance and identifying low drug concentrations that may be low, resulting in therapeutic failure. Also, monitoring the drug level can aid in evaluating potential drug interactions and side effects.

Specific parameters should be monitored while the patient is on antipsychotics, especially in children who are more sensitive to adverse effects. When using risperidone, the clinician may derive patient benefit by monitoring serum prolactin level, hepatic functioning, metabolic functioning, thyroid functioning, weight/BMI, height, waist circumference, blood pressure, fasting plasma glucose, insulin, fasting lipid profile, and QTc.[10][11]

Enhancing Healthcare Team Outcomes

An interprofessional healthcare team, including the primary care provider, nurse practitioner, psychiatrist, or emergency department physician who prescribes risperidone, must follow the patient. Nurses and pharmacists also play a crucial role in patient monitoring and directing the administration of the drug. The drug has many adverse effects, of which the most important are weight gain, metabolic changes, and sedation. Unlike the older antipsychotics, tardive dyskinesia is less frequently seen with the newer atypical antipsychotics like risperidone.[12][13] Nevertheless, the onus is on the healthcare team to detect any movement disorder and manage it. Countless litigations have occurred chiefly due to the lack of proper management of the adverse effects of risperidone. The optimal means to achieving the best therapeutic goal is interprofessional communication and collaboration.[14] [Level 5]

Serious side effects of antipsychotic medications (like risperidone) can include neuroleptic malignant syndrome (NMS). Although the pathogenesis of NMS is not clear, it is a life-threatening condition that can manifest with altered mental status, fever, "lead pipe" rigidity, and autonomic instability, including hypertension, tachypnea, and tachycardia. The use of risperidone has also been linked to a higher probability of cerebrovascular events in elderly patients with dementia, leading to an FDA warning about the use of this medication in the context of dementia-related psychosis. Studies have even shown an increase in all-cause mortality among the elderly with dementia who are on this medication.[15][12]