ULTREON

Indications

• Schizophrenia
• Schizoaffective disorder

Dosage

Children: For children and adolescents

Adults: For adults, the initial dosage is typically 3 to 12 mg once daily, with adjustments made based on the clinical response and tolerability. For long-acting injectable formulations, the initial dose may range from 175 to 525 mg every 3 months, depending on previous treatment with paliperidone.

Mechanism of action

Paliperidone exerts its therapeutic activity primarily through antagonism of central dopamine Type 2 (D2) and serotonin Type 2 (5-HT2A) receptors. Although the exact mechanism of action is not fully understood, it is proposed that this dual receptor antagonism contributes to its efficacy in treating schizophrenia. Additionally, paliperidone may also interact with alpha-adrenergic and histamine (H1) receptors, influencing various therapeutic and adverse effects.

Pharmacodynamics

As an atypical antipsychotic, paliperidone is designed to address the symptoms of schizophrenia and schizoaffective disorder. It is chemically similar to risperidone, with a structure that includes a hydroxyl group modification. Its pharmacodynamic profile is characterized by a lower propensity to cause extrapyramidal symptoms compared to first-generation antipsychotics, potentially due to its receptor binding profile, which includes a greater affinity for serotonin receptors relative to dopamine receptors.

Pharmacokinetics

Paliperidone has a bioavailability of approximately 28% when administered orally. It is extensively metabolized in the liver, primarily via the CYP2D6 pathway, and has an elimination half-life of around 23 hours. The drug is excreted mainly through urine, and its pharmacokinetics can be influenced by factors such as renal impairment. In cases of renal impairment, dosage adjustments are necessary to avoid accumulation and potential toxicity.

Contra-indications

• Hypersensitivity to paliperidone or any component of the formulation
• Severe renal impairment (creatinine clearance < 10 mL/min)

Adverse effects

• Extrapyramidal symptoms
• Sedation
• Weight gain
• Hyperglycemia
• Hyperlipidemia
• QT prolongation
• Severe cutaneous adverse reactions (SCARs)
• Injection site necrosis (with intramuscular use)

Interactions

• Valproate: Moderate (increases exposure)
• Mitotane: Moderate (decreases exposure)
• Rifampicin: Moderate (decreases exposure)
• St. John's Wort: Unknown (decreases exposure)

Precautions

• Caution in patients with a history of seizures
• Caution in patients with diabetes mellitus
• Monitor for signs of tardive dyskinesia
• Gradual withdrawal is advised to prevent withdrawal syndrome
• Caution in hepatic impairment (no specific information available)

Pregnancy

Manufacturer advises avoiding use during pregnancy unless necessary, as safety has not been established.

Breast-feeding

Manufacturer advises avoiding use while breastfeeding, as paliperidone is present in breast milk.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablets: 1.5 mg, 3 mg, 6 mg, 9 mg
• Long-acting injection (TREVICTA): 175 mg, 263 mg, 350 mg, 525 mg

Indications

• Schizophrenia
• Bipolar disorder
• Acute and chronic psychosis
• Irritability associated with autistic disorder
• Manic episodes

Dosage

Adults: Initial dose: 2 mg daily in 1-2 divided doses

Mechanism of action

Risperidone primarily acts as an antagonist of the D2 dopaminergic receptors and 5-HT2A serotonergic receptors in the brain. By inhibiting D2 receptors, it reduces dopaminergic neurotransmission, which helps alleviate positive symptoms of schizophrenia like delusions and hallucinations. Its binding profile allows for rapid dissociation from D2 receptors, minimizing the risk of extrapyramidal symptoms. Additionally, through its high-affinity binding to 5-HT2A receptors, risperidone decreases serotonergic activity, addressing negative symptoms such as depression and reduced motivation.

Pharmacodynamics

Risperidone's pharmacodynamic profile is characterized by its ability to decrease dopaminergic and serotonergic activity in the central nervous system. This modulation results in the reduction of both positive and negative symptoms associated with schizophrenia and mood disorders. Its unique receptor binding properties, particularly its moderate affinity for D2 receptors compared to first-generation antipsychotics, contribute to a lower risk of extrapyramidal side effects, enhancing its therapeutic profile.

Pharmacokinetics

Risperidone is well-absorbed after oral administration, with peak plasma concentrations typically occurring within 1-2 hours. It undergoes extensive hepatic metabolism, primarily via the cytochrome P450 system, yielding active metabolites such as 9-hydroxyrisperidone. The drug exhibits a half-life of approximately 20 hours, with a longer duration of action due to its active metabolites. Renal excretion accounts for a significant route of elimination. Caution is advised in patients with hepatic or renal impairment, as dosage adjustments may be necessary.

Contra-indications

• Dehydration
• Dementia with Lewy bodies
• Prolactin-dependent tumors

Adverse effects

• Anemia
• Anxiety
• Appetite abnormalities
• Asthenia
• Chest discomfort
• Conjunctivitis
• Cough
• Depression
• Diarrhea
• Dyspnea
• Epistaxis
• Fall
• Fever
• Gastrointestinal discomfort
• Headache
• Hypertension
• Increased risk of infection
• Joint disorders
• Laryngeal pain
• Muscle spasms
• Nasal congestion
• Nausea
• Oedema
• Oral disorders
• Pain
• Sexual dysfunction
• Skin reactions
• Sleep disorders
• Urinary disorders
• Vision abnormalities

Interactions

• Bupropion - Moderate (increases exposure)
• Cinacalcet - Moderate (increases exposure)
• Cobicistat - Moderate (increases exposure)
• Idelalisib - Moderate (increases exposure)
• Levodopa - Moderate (decreases effects)
• Mitotane - Moderate (decreases exposure)
• Terbinafine - Moderate (increases exposure)
• Clarithromycin - Moderate (increases exposure)
• Rifampicin - Moderate (decreases exposure)
• Ropeginterferonalfa - Unknown (increases exposure)

Precautions

• Monitor for extrapyramidal symptoms due to D2 receptor occupancy
• Consider ECG in patients with a family history of sudden cardiac death

Pregnancy

Use only if potential benefit outweighs risk.

Breast-feeding

Use only if potential benefit outweighs risk-small amount present in milk.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Oral tablets
• Oral suspension
• Injection (Risperdal Consta)

Mechanism of action

Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. The exact mechanism of paliperidone's antipsychotic action, like that of other antipsychotic agents, has not been fully elucidated, but may involve antagonism of central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine [5-HT2A]) receptors.1 39 41 Antagonism at a1- and a2-adrenergic and histamine (H1) receptors may contribute to other therapeutic and adverse effects observed with the drug.1 2 39 Paliperidone possesses no affinity for cholinergic muscarinic and beta1- and beta2-adrenergic receptors. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. 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

Paliperidone is an atypical antipsychotic developed by Janssen Pharmaceutica. Chemically, paliperidone is primary active metabolite of the older antipsychotic risperidone (paliperidone is 9-hydroxyrisperidone). The mechanism of action is unknown but it is likely to act via a similar pathway to risperidone.

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 juven

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.