Risperidone ISM (RISVAN®) – Rapid and Sustained-Release Injection for the Short and Long-Term Management of Schizophrenia

• D2 receptor occupancy (D2RO) is a key determinant of the clinical efficacy and safety of antipsychotic treatment in schizophrenia and represents the primary mechanism of action of risperidone. [Gomeni et al., 2013]
• Optimal antipsychotic response is associated with D2RO between 65% and 80%, with a significant increase in clinical response observed when D2RO exceeds 65%, minimising extrapyramidal side effects. [Gomeni et al., 2013]
• The kinetic hypothesis suggests that the binding and dissociation rates of atypical antipsychotics at D2 receptors and ligand rebinding influence their safety profile and EPS risk. [Sykes et al., 2017]
• The favourable tolerability of Risperidone ISM® in maintenance treatment may be linked to its optimised D2 receptor binding kinetics, contributing to its distinct pharmacokinetic profile [Llaudó et al., 2016]
• While other pharmacodynamic parameters may contribute to clinical improvement, D2RO remains the best-established correlate of response, particularly in relation to striatal occupancy and positive symptom reduction. [Gomeni et al., 2013]
• Steady-state administration of Risperidone ISM (75 mg and 100 mg) results in D2RO between 69% and 75%, maintaining therapeutic levels with minimal fluctuations. [Álamo, 2022] 
• Risperidone ISM achieves longer D2RO above 65% compared to monthly paliperidone palmitate (PP) and, in adherence simulations, demonstrates a higher average time above the 65% threshold than oral risperidone in real-world adherence scenarios. [Snoeck et al. 2023]

The Dopamine Hypothesis of Schizophrenia – Advances in Neurobiology and Clinical Application

• Utilises in-situ microimplants (ISM®) technology to enable immediate and sustained risperidone release. [Álamo, 2022]

• Upon injection, a solid polymeric matrix system containing risperidone microparticles forms in situ. [Álamo, 2022]

• Immediate drug release occurs within 2 hours, with therapeutic plasma concentrations reached within 12 hours. [Álamo, 2022], [API, 2025]

• The matrix undergoes slow biodegradation, ensuring sustained risperidone release over 28 days. [Walling et al., 2021], [Correll  et al., 2021]

• Risperidone ISM achieves therapeutic plasma concentrations comparable to oral risperidone within 12 hours of the first injection and maintains levels above the therapeutic threshold (7.5 ng/mL) throughout the dosing period. [Walling et al., 2021]

• Steady-state concentrations are reached after the first dose and are sustained across subsequent injections, ensuring consistent D2 receptor occupancy (>65%), which correlates with clinical efficacy. [Snoeck et al. 2023]

• A direct switch from oral risperidone is possible 24 hours after the last oral dose without requiring loading doses or oral supplementation, differentiating Risperidone ISM from other atypical LAIs such as paliperidone palmitate and aripiprazole LAI formulations. [Walling et al., 2021]

• The mean steady-state concentration (Cave: 38.63 ng/mL) remains within the range observed for oral risperidone, providing stable and predictable plasma levels essential for acute symptom control and long-term maintenance therapy. [Walling et al., 2021] 

• Risperidone ISM reaches steady-state levels without a washout period, dose adjustments, or oral supplementation, ensuring a pharmacokinetic profile comparable to oral risperidone. [Walling et al., 2021]

In the PRISMA-3 primary analysis study (n=390/438), Risperidone ISM offered rapid and progressive symptom reduction for patients admitted to the hospital due to relapse. [Filts et al., 2022]

Patients received once-monthly intramuscular injections of Risperidone ISM (75 or 100 mg) or placebo for 12 weeks. [Filts et al., 2022]

Results: 

• The PANSS total score (mean difference, 95% CI) improved significantly from baseline to day 85 with Risperidone ISM 75 and 100 mg (with placebo-adjusted differences of −13.0 (95% CI, −17.3 to −8.8); (p < 0.0001), and −13.3 (−17.6 to −8.9); (p < 0.0001), respectively). [Filts et al., 2022]
• CGI-S scores also improved significantly from baseline to day 85 for both doses of Risperidone ISM® compared with placebo −0.7 (−1.0 to −0.5); p < 0.0001. These improvements were observed as early as 8 days after the first injection for the 100 mg dose.  

In the 12-month open-label extension study (n=215), patients treated with monthly Risperidone ISM injections had a low overall relapse rate of 10.7% [95% CI: 6.9% to 15.6%]. [Filts et al., 2022]

Treatment-emergent adverse events (TEAEs) were mainly mild or moderate, and TEAEs leading to treatment discontinuation were attributed to Risperidone ISM® in 7 patients (3.2%). [Filts et al., 2022]

The most common treatment-related TEAEs were headache (12.1%), hyperprolactinemia (9.8%), asthenia (5.1%), weight increase (4.2%), insomnia (4.2%), and akathisia (3.7%). [Filts et al., 2022]

Risperidone ISM is not approved for use in elderly patients with dementia-related psychoses due to the increased mortality risk in this population. [API, 2025], [Correll, et al., 2020]

Careful titration with oral risperidone is recommended in patients with hepatic impairment.

The tolerability of an oral dose of at least 3 mg should be confirmed before initiating treatment with the lower 75 mg of Risperidone ISM. [API, 2025], [Correll, et al., 2020]

Risperidone ISM was PBS listed on Jan 1st 2025. [API, 2025]

It is available in 2 doses: 75mg and 100mg.

Initiation is every 4 weeks via either intramuscular deltoid or gluteal injection. [Walling et al., 2021], [Correll, et al., 2020]

Switching to Risperidone ISM : [API, 2025]

1. Patients with a history of previous response to Risperidone:

• If the patient is currently stabilised with oral risperidone, they can be switched directly to Risperidone ISM.
•  If they are stabilised with another oral antipsychotic, oral risperidone should be administered for at least 6 days before switching to Risperidone ISM.

2. Patients who have never received treatment with oral risperidone should be on oral risperidone for at least 14 days before administering Risperidone ISM . 

3. For patients currently on bi-monthly LAI of risperidone (Risperdal Consta) – Replace Risperdal Consta with Risperidone ISM  at the next scheduled dose. 

Australian Product Information for Risperidone ISM states : [API, 2025]

• For patients taking/previously on 3mg/day of oral risperidone, Risperidone ISM  75mg should be administered every 4 weeks. 
• For patients previously on ≥4mg/day of oral risperidone, Risperidone ISM  100 mg every 4 weeks should be administered. 
• For patients currently on 37.5 mg of bi-monthly risperidone LAI (Risperdal Consta), Risperidone ISM 75 mg should be administered every 4 weeks.
• For patients currently on 50 mg of bi-monthly risperidone LAI (Risperdal Consta), Risperidone ISM  100 mg should be administered every 4 weeks. 

Risperidone ISM (RISVAN®) is a four-weekly long-acting injectable providing immediate and sustained therapeutic levels without loading doses or oral supplementation.

It demonstrates rapid symptom improvement within 8 days and sustained efficacy in both acute and maintenance treatment.  

Its predictable pharmacokinetics, favourable safety profile, and initiation regimen support adherence and may reduce relapse and hospitalisations. 

 Its rapid onset of action, sustained therapeutic plasma levels, and well-characterised pharmacokinetics support its use in both acute exacerbations and long-term schizophrenia management. 

1. What is risperidone ISM?

Risperidone ISM, marketed as RISVAN®, is a once-monthly long-acting injectable antipsychotic used for the treatment of schizophrenia in adults. It is designed for patients who have already shown efficacy and tolerability with oral risperidone.

2.What does risperidone ISM mean?

ISM stands for in-situ microimplant technology. After intramuscular injection, the formulation creates a biodegradable matrix that releases risperidone rapidly and then sustains drug delivery over 28 days.

3. How is risperidone ISM different from other long-acting injectable antipsychotics?

A key difference is that risperidone ISM does not require oral supplementation, loading doses, dose titration, or a washout period. Therapeutic risperidone levels are achieved within 12 hours of the first injection, which may simplify initiation compared with some other second-generation LAI antipsychotics.

4. Does risperidone ISM require oral risperidone overlap?

No. Risperidone ISM can be started without oral risperidone overlap, provided the patient has established tolerability and response to oral risperidone. This is one of its main practical advantages in schizophrenia treatment.

5. How often is risperidone ISM given?

Risperidone ISM is administered once every four weeks as an intramuscular injection, either into the deltoid or gluteal muscle.

6. What doses of risperidone ISM are available?

Risperidone ISM is available as 75 mg and 100 mg once-monthly injections. The dose is generally selected according to the patient’s previous oral risperidone dose or prior risperidone LAI regimen.

7. How quickly does risperidone ISM work?

Risperidone ISM reaches therapeutic plasma concentrations within 12 hours of the first injection, with clinical studies showing symptom improvement as early as Day 8 in acute schizophrenia relapse.

8. Why are long-acting injectable antipsychotics important in schizophrenia?

Long-acting injectable antipsychotics can reduce the risk associated with missed oral doses, support adherence, and provide greater treatment continuity. This is clinically important because nonadherence in schizophrenia is strongly linked with relapse, hospital admission, and poorer long-term outcomes.

9. What are the common side effects of risperidone ISM?

Common treatment-related adverse effects include headache, hyperprolactinaemia, asthenia, weight increase, insomnia, and akathisia. Clinicians should monitor prolactin-related symptoms, metabolic parameters, extrapyramidal symptoms, weight, and overall tolerability.

10. Who may be suitable for risperidone ISM?

Risperidone ISM may be suitable for adults with schizophrenia who have responded to and tolerated oral risperidone, particularly where adherence, relapse prevention, cognitive impairment, repeated admissions, or treatment continuity are important clinical considerations.

11. Can patients switch directly from oral risperidone to risperidone ISM?

Yes. Patients stabilised on oral risperidone may be switched directly to risperidone ISM, usually 24 hours after the last oral dose, without requiring oral supplementation.

12. Can risperidone ISM be used in elderly patients with dementia-related psychosis?

No. Risperidone ISM is not approved for elderly patients with dementia-related psychosis because of the increased mortality risk associated with antipsychotic use in this population.

13. What should clinicians monitor when prescribing risperidone ISM?

Clinicians should monitor symptom response, relapse risk, injection tolerability, extrapyramidal symptoms, prolactin-related adverse effects, weight, metabolic parameters, sedation, akathisia, and adherence-related outcomes.

14. What is the clinical advantage of risperidone ISM in schizophrenia treatment?

The main clinical advantage is the combination of rapid onset, monthly dosing, sustained therapeutic exposure, and no need for oral supplementation, making it a practical LAI antipsychotic option for both acute stabilisation and long-term schizophrenia management.