Risperidone

Risperidone is mainly used for the treatment of schizophrenia, bipolar disorder, and irritability associated with autism. Schizophrenia Risperidone is effective in treating psychogenic polydipsia and the acute exacerbations of schizophrenia. Studies evaluating the utility of risperidone by mouth for maintenance therapy have reached varying conclusions. A 2012 systematic review concluded that evidence is strong that risperidone is more effective than all first-generation antipsychotics other than haloperidol, but that evidence directly supporting its superiority to placebo is equivocal. A 2011 review concluded that risperidone is more effective in relapse prevention than other first- and second-generation antipsychotics with the exception of olanzapine and clozapine. A 2016 Cochrane review suggests that risperidone reduces the overall symptoms of schizophrenia, but firm conclusions are difficult to make due to very low-quality evidence. Data and information are scarce, poorly reported, and probably biased in favour of risperidone, with about half of the included trials developed by drug companies. The article raises concerns regarding the serious side effects of risperidone, such as parkinsonism. A 2011 Cochrane review compared risperidone with other atypical antipsychotics such as olanzapine for schizophrenia, concluding it produced a somewhat higher risk of extrapyramidal side effects. Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations. The efficacy of risperidone long-acting injection appears to be similar to that of long-acting injectable forms of first-generation antipsychotics. Bipolar disorder Second-generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder. In children and adolescents, risperidone may be more effective than lithium or valproate, but has more metabolic side effects. As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes. The long-acting injectable form of risperidone may be advantageous over long-acting first-generation antipsychotics, as it is better tolerated (fewer extrapyramidal effects) and because long acting injectable formulations of first-generation antipsychotics may increase the risk of depression. Autism Compared to placebo, risperidone treatment reduces certain problematic behaviors in autistic children, including aggression toward others, self-injury, challenging behavior, and rapid mood changes. The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments. The risk of rapid weight gain is an important consideration when prescribing it. Some authors recommend limiting the use of risperidone and aripiprazole to those with the most challenging behavioral disturbances to minimize the risk of drug-induced adverse effects. Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive. Dementia While antipsychotic medications such as risperidone have a slight benefit in people with dementia, they have been linked to a higher incidence of death and stroke. Other uses Risperidone has demonstrated clinical benefit as an augmentation agent in the management of (unipolar) non-psychotic treatment-resistant depression alongside antidepressant treatment. Atypical antipsychotics, such as risperidone, are among the most common augments for antidepressant therapy. Such usage occurs off-label in most jurisdictions and the risk of adverse effects (e.g., weight gain, movement disorders) must be carefully weighed against the clinical benefit. Risperidone has shown promise in treating therapy-resistant obsessive–compulsive disorder, when serotonin reuptake inhibitors alone are not sufficient. Risperidone has proven to be effective in treatment of aggression associated with attention deficit hyperactivity disorder (ADHD), or with another mental condition. Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders, except for limited evidence in schizotypal personality disorder. Available forms Available forms of risperidone include tablet, orally dissolving tablet, oral solution, and powder and solvent for injection. ==Adverse effects==

Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight. Atypical antipsychotics, however, are associated with a greater amount of weight gain and other metabolic side effects. Dementia Older people with dementia-related psychosis are at a higher risk of death. ==Interactions==

• Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone. • Risperidone has been found to dose-dependently block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD). ==Pharmacology==

Pharmacodynamics Risperidone has been classified as a "qualitatively atypical" antipsychotic agent with a relatively low incidence of extrapyramidal side effects (when given at low doses) that has more pronounced serotonin antagonism than dopamine antagonism. Risperidone contains the functional groups of benzisoxazole and piperidine as part of its molecular structure. Although not a butyrophenone, it was developed with the structures of benperidol and ketanserin as a basis. It has actions at several 5-HT (serotonin) receptor subtypes. These are 5-HT2C, linked to weight gain, and 5-HT2A, linked to its antipsychotic action and relief of some of the extrapyramidal side effects experienced with typical antipsychotics. It has been found that D-amino acid oxidase, the enzyme that catalyses the breakdown of D-amino acids (e.g. D-alanine and D-serine — the neurotransmitters) is inhibited by risperidone. Risperidone acts on the following receptors: Dopamine receptors: This drug is an antagonist of the D1 (D1, and D5) as well as the D2 (D2, D3 and D4) family receptors, with 70-fold selectivity for the D2 family. It has "tight binding" properties, which means it has a long half-life. Like other antipsychotics, risperidone blocks the mesolimbic pathway, the prefrontal cortex limbic pathway, and the tuberoinfundibular pathway in the central nervous system. Risperidone may induce extrapyramidal side effects, akathisia and tremors, which is associated with diminished dopaminergic activity in the striatum. It can also cause sexual side effects, galactorrhoea, infertility, gynecomastia, and, with chronic use, reduced bone mineral density leading to breaks, all of which are associated with increased prolactin secretion. Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain. Voltage-gated sodium channels: Because it accumulates in synaptic vesicles, Risperidone inhibits voltage-gated sodium channels at clinically used concentrations. Pharmacokinetics Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease. ) == Society and culture ==

Legal status Risperidone was approved by the United States Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia. In 2003, the FDA approved risperidone for the short-term treatment of the mixed and manic states associated with bipolar disorder. In 2006, the FDA approved risperidone for the treatment of irritability in autistic children and adolescents. The FDA's decision was based in part on a study of autistic people with severe and enduring problems of violent meltdowns, aggression, and self-injury; risperidone is not recommended for autistic people with mild aggression and explosive behavior without an enduring pattern. On 22 August 2007, risperidone was approved as the only drug agent available for the treatment of schizophrenia in youths, ages 13–17; it was also approved that same day for the treatment of bipolar disorder in youths, ages 10–17, joining lithium. In December 2021, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended market authorization for Okedi, a long-acting depot injection of risperidone. Okedi was approved for the treatment of schizophrenia in adults for whom the tolerability and effectiveness of risperidone had already been established using an oral formulation. Long-acting depot injectable risperidone was approved for medical use in the European Union in February 2022. Lawsuits In April 2012, Johnson & Johnson (J&J) and its subsidiary Janssen Pharmaceuticals Inc. were fined $1.2 billion for downplaying multiple risks associated with risperidone. The verdict was later reversed by the Arkansas state supreme court. In August 2012, J&J agreed to pay $181 million to 36 US states to settle claims that it had promoted risperidone and paliperidone for off-label uses including for dementia, anger management, and anxiety. In November 2013, J&J was fined $2.2 billion for illegally marketing risperidone for use in people with dementia and paying kickbacks to prescribing physicians and nursing home pharmacies. In 2015, Steven Brill wrote an investigative journalism piece about J&J in The Huffington Post focused on J&J's marketing of risperidone. J&J has faced numerous civil lawsuits on behalf of children who were prescribed risperidone who grew breasts (a condition called gynecomastia); as of July 2016 there were about 1,500 cases in Pennsylvania state court in Philadelphia, and there had been a February 2015 verdict against J&J with $2.5 million awarded to a man from Alabama, a $1.75 million verdict against J&J that November, and in 2016 a $70 million verdict against J&J. In October 2019, a jury ordered J&J to pay $8 billion in punitive damages to a Pennsylvania man who had grown breasts during adolescence. This verdict amount chosen by the jury was reduced more than 1,000-fold by a judge in January 2020, with the new punitive damages being $6.8 million. A legal scholar commented that punitive damages which exceed the compensatory damages by a factor of 10 or more in cases of this type are usually found to be legally invalid. Risperidone is available as a tablet, an oral solution, and an ampule, which is a depot injection. ==References==