RISABEX 1 mg/ml

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

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.