It is marketed by Janssen Pharmaceuticals. An extended release formulation is available that uses the OROS extended release system to allow for once-daily dosing. Paliperidone palmitate is a long-acting injectable formulation of paliperidone palmitoyl ester.
It is on the World Health Organisation’s List of Essential Medicines.
Paliperidone (as Invega) was approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia in 2006. Paliperidone was approved by the FDA for the treatment of schizoaffective disorder in 2009. The long-acting injectable form of paliperidone, marketed as Invega Sustenna in US and Xeplion in Europe, was approved by the FDA on 31 July 2009. It is the only available brand in Bangladesh under the brand name “Palimax ER” manufactured & marketed by ACI Pharmaceuticals.
It was initially approved in Europe in 2007 for schizophrenia, the extended release form and use for schizoaffective disorder were approved in Europe in 2010, and extension to use in adolescents older than 15 years old was approved in 2014.
It is used for the treatment of schizophrenia and schizoaffective disorder.
Very Common (>10% incidence):
Somnolence (causes less sedation than most atypical antipsychotics).
Hyperprolactinaemia (seems to cause comparable prolactin elevation to its parent drug, risperidone).
Common (1-10% incidence):
Extrapyramidal side effects (EPSE; e.g. dystonia, akathisia, muscle rigidity, parkinsonism. It appears to produce similar EPSE to risperidone, asenapine and ziprasidone and more EPSE than olanzapine, clozapine, aripiprazole, quetiapine, amisulpride and sertindole).
Weight gain (tends to produce a moderate degree of weight gain, possibly related to its potent blockade of the 5-HT2C receptor).
QT interval prolongation (tends to produce less QT interval prolongation than most other atypical antipsychotics and approximately as much QT interval prolongation as aripiprazole and lurasidone).
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
In April 2014, it was reported that 21 Japanese people who had received shots of the long-acting injectable paliperidone to date had died, out of 10,700 individuals prescribed the drug.
Paliperidone is the primary active metabolite of the older antipsychotic risperidone. While its specific mechanism of action is unknown, it is believed paliperidone and risperidone act via similar, if not identical, pathways. Its efficacy is believed to result from central dopaminergic and serotonergic antagonism. Food is known to increase the absorption of Invega type ER OROS prolonged-release tablets. Food increased exposure of paliperidone by up to 50-60%, however, half-life was not significantly affected. The effect was probably due to a delay in the transit of the ER OROS formulation in the upper part of the GI channel, resulting in increased absorption.
The half-life is 23 hours.
Risperidone and its metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St John’s wort.
On 18 May 2015, a new formulation of paliperidone palmitate was approved by the FDA under the brand name Invega Trinza. A similar 3 -monthly injection of prolonged release suspension was approved in 2016 by the European Medicines Agency originally under the brand name Paliperidone Janssen, later renamed to Trevicta. On 01 September 2021, a newer formulation of paliperidone palmitate, Invega Hafyera, was approved by the FDA which is available as an injection every six months.
It is taken either by mouth or by injection into a muscle. The injectable version is long-acting and lasts for about two weeks.
Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, and high blood sugar levels. In older people with psychosis as a result of dementia, it may increase the risk of dying. It is unknown if it is safe for use in pregnancy. Its mechanism of action is not entirely clear, but is believed to be related to its action as a dopamine and serotonin antagonist.
Study of risperidone began in the late 1980s and it was approved for sale in the United States in 1993. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2018, it was the 159th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Risperidone is mainly used for the treatment of schizophrenia, bipolar disorder, and irritability associated with autism.
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.
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.
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 divalproex, 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.
Compared to placebo, risperidone treatment reduces certain problematic behaviours in autistic children, including aggression toward others, self-injury, challenging behaviour, and rapid mood changes. The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments. Weight gain is an important adverse effect. Some authors recommend limiting the use of risperidone and aripiprazole to those with the most challenging behavioural disturbances in order to minimise the risk of drug-induced adverse effects. Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.
Risperidone has shown promise in treating therapy-resistant obsessive-compulsive disorder, when serotonin reuptake inhibitors are not sufficient.
While antipsychotic medications such as risperidone have a slight benefit in people with dementia, they have been linked to higher incidences of death and stroke. Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not US Drug and Food Administration (FDA) approved.
Available forms of risperidone include tablet, oral dissolving tablet, oral solution, and powder and solvent for suspension for injection.
Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight. About 9 to 20% of people gained more than 7% of the baseline weight depending on the dose. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, and high blood sugar levels. In older people with psychosis as a result of dementia, it may increase the risk of dying.
While atypical antipsychotics appear to have a lower rate of movement problems as compared to typical antipsychotics, risperidone has a high risk of movement problems among the atypicals. Atypical antipsychotics however are associated with a greater amount of weight gain.
Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone.
If a person is taking both carbamazepine and risperidone, the dose of risperidone will likely need to be increased.
The new dose should not be more than twice the patient’s original dose.
CYP2D6 inhibitors, such as SSRI medications, may increase plasma levels of risperidone and those medications.
Since risperidone can cause hypotension, its use should be monitored closely when a patient is also taking antihypertensive medicines to avoid severe low blood pressure.
Risperidone and its metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St John’s wort.
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse. Some have argued the additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics. This has led some to suggest the withdrawal process might itself be schizomimetic, producing schizophrenia-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well as the public.
Older people with dementia-related psychosis are at a higher risk of death if they take risperidone compared to those who do not. Most deaths are related to heart problems or infections.
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, 5-HT2A, linked to its antipsychotic action and relief of some of the extrapyramidal side effects experienced with the typical neuroleptics.
It was recently 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:
This drug is an antagonist of the D1 (D1, and D5) as well as the D2 family (D2, D3 and D4) receptors, with 70-fold selectivity for the D2 family. This drug has “tight binding” properties, which means it has a long half-life and 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, 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.
Its action at these receptors may be responsible for its lower extrapyramidal side effect liability (via the 5-HT2A/2C receptors) and improved negative symptom control compared to typical antipsychotics such as haloperidol for instance. Its antagonistic actions at the 5-HT2C receptor may account, in part, for its weight gain liability.
Alpha α1 Adrenergic
This action accounts for its orthostatic hypotensive effects and perhaps some of the sedating effects of risperidone.
Alpha α2 Adrenergic
Perhaps greater positive, negative, affective and cognitive symptom control.
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. Though this medication possesses similar effects to other typical and atypical antipsychotics, it does not possess an affinity for the muscarinic acetylcholine receptors. In many respects, this medication can be useful as an “acetylcholine release-promoter” similar to gastrointestinal drugs such as metoclopramide and cisapride.
Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease. The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.
Society and Culture
Risperidone was approved by the 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 behaviour without an enduring pattern. On 22 August 2007, risperidone was approved as the only drug agent available for treatment of schizophrenia in youths, ages 13-17; it was also approved that same day for treatment of bipolar disorder in youths and children, ages 10-17, joining lithium.
Janssen’s patent on risperidone expired on 29 December 2003, opening the market for cheaper generic versions from other companies, and Janssen’s exclusive marketing rights expired on 29 June 2004 (the result of a paediatric extension). It is available under many brand names worldwide.
Risperidone is available as a tablet, an oral solution, and an ampule, which is a depot injection.
On 11 April 2012, Johnson & Johnson (J&J) and its subsidiary Janssen Pharmaceuticals Inc. were fined $1.2 billion by Judge Timothy Davis Fox of the Sixth Division of the Sixth Judicial Circuit of the US state of Arkansas. The jury found the companies had downplayed multiple risks associated with risperidone (Risperdal). The verdict was later reversed by the Arkansas State Supreme court.
In August 2012, Johnson & Johnson agreed to pay $181 million to 36 US states in order 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.
In 2015, Steven Brill posted a 15-part investigative journalism piece on J&J in The Huffington Post, called “America’s most admired lawbreaker”, which was 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 $1.75M verdict against J&J that November, and in 2016 a $70 million verdict against J&J. In October, 2019, a jury awarded a Pennsylvania man $8 billion in a verdict against J&J.
Brand names include Risperdal, Risperdal Consta, Risperdal M-Tab, Risperdal Quicklets, and Risperlet.