What oral risperidone dose should be restarted in a patient who discontinued paliperidone depot (long‑acting injectable) four weeks ago?

Restarting Oral Risperidone After Paliperidone Depot Discontinuation

Start risperidone at 2 mg once daily, as paliperidone (the active metabolite of risperidone) from the depot injection administered 4 weeks ago has likely cleared sufficiently to avoid overlap toxicity, and this represents the standard initial therapeutic dose for most adult patients with schizophrenia. 1

Rationale for 2 mg Starting Dose

• The FDA-approved initial dosing for risperidone in schizophrenia is 2 mg per day, which can be administered once or twice daily 1
• This dose represents the evidence-based starting point that balances efficacy with tolerability, as supported by clinical guidelines recommending 2 mg/day as the appropriate initial target dose for most patients 2
• Updated recommendations based on naturalistic studies and clinical experience suggest 4 mg/day as the eventual target dose for most patients, but emphasize starting lower with less-rapid titration than originally recommended 3

Pharmacokinetic Considerations at 4 Weeks Post-Depot

• Paliperidone depot injections maintain therapeutic levels for extended periods, but at 4 weeks post-injection, drug levels are declining toward the lower end of the therapeutic range
• Since paliperidone is the 9-OH metabolite of risperidone (the "active moiety"), restarting oral risperidone at standard initial doses is appropriate without risk of additive toxicity 4
• There is no need to start at sub-therapeutic doses (such as 0.5 mg) unless the patient has specific risk factors for sensitivity 1

Titration Strategy After Initiation

• After starting at 2 mg daily, increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day as tolerated, to reach the recommended maintenance dose of 4 to 8 mg per day 1
• In some patients, slower titration may be more appropriate to minimize extrapyramidal side effects, particularly if the patient experienced side effects with previous antipsychotic treatment 1, 3
• The effective dose range is 4 mg to 16 mg per day, though doses above 6 mg twice daily were not demonstrated to be more efficacious than lower doses and were associated with more extrapyramidal symptoms 1

Special Populations Requiring Dose Adjustment

Elderly patients or those with dementia: Start at 0.5 mg once daily at bedtime, then increase to 1 mg in two divided doses after 3 days, with further increases of 0.5 mg every three days as tolerated 5

Patients with severe renal or hepatic impairment: Use a lower starting dose of 0.5 mg twice daily, with increases to dosages above 1.5 mg twice daily at intervals of one week or longer 1

First-episode psychosis patients: Consider starting at lower doses (0.5-1 mg) with slower titration, as these patients may be more sensitive to antipsychotic effects and side effects 3

Monitoring Parameters

• Assess for extrapyramidal symptoms, particularly during the first 2 weeks when higher initial doses predict increased risk of EPS 4
• Monitor for orthostatic hypotension and sedation, especially during dose titration 2
• Evaluate clinical response using standardized rating scales, as nonresponders may paradoxically show higher plasma levels despite similar oral doses 4
• Consider therapeutic drug monitoring if clinical response is suboptimal or side effects emerge, given high inter-individual variability in risperidone metabolism 4

Common Pitfalls to Avoid

• Do not start at 6 mg/day: Original clinical trials suggested this dose, but it was based on chronically impaired, hospitalized, treatment-resistant patients and is now considered too high for most patients 3
• Do not assume immediate therapeutic effect: While rapid dose-loading protocols (reaching 3 mg twice daily within 24 hours) have been shown to be well-tolerated in acute inpatient settings, this aggressive approach is not necessary for patients transitioning from depot formulations 6
• Do not overlook the need for oral supplementation during depot initiation: This scenario is the reverse—transitioning from depot to oral—but highlights that depot formulations require time to reach steady state, just as they require time to clear 7