Is augmentation of Risperidone (risperidone) with another agent useful in patients with schizophrenia who are not adequately responding to treatment?

Augmentation of Risperidone in Schizophrenia

Augmentation of risperidone with another antipsychotic can be useful in schizophrenia, particularly for patients who show partial response to risperidone monotherapy, though the evidence is mixed and guidelines generally recommend this approach primarily for clozapine-resistant cases rather than risperidone specifically.

Guideline Recommendations on Antipsychotic Polypharmacy

The most recent guidelines take a cautious but evolving stance on antipsychotic polypharmacy (APP):

• The American Psychiatric Association (2021) endorses monotherapy and does not acknowledge situations where APP would be routinely recommended 1
• The National Institute for Health and Care Excellence (2019) guides against regular combined antipsychotic medication, except for short periods when changing medication, but does allow adding an additional antipsychotic to augment clozapine treatment specifically if clozapine monotherapy has proven ineffective 1
• The World Federation of Societies of Biological Psychiatry recommends that APP should only be considered in certain individual circumstances 1

The key limitation is that guidelines focus primarily on clozapine augmentation, not risperidone augmentation specifically.

Real-World Evidence Supporting Augmentation

Despite conservative guideline recommendations, large-scale observational studies demonstrate potential benefits:

• A Hungarian nationwide study found that antipsychotic polypharmacy was associated with significantly lower mortality (HR 1.62 for monotherapy vs polypharmacy, 95% CI 1.12–2.34) and reduced hospitalization rates (HR 1.69,95% CI 1.43–1.99) compared to monotherapy switching strategies 1
• A Finnish nationwide cohort study (n=62,250) showed individuals had a 7–13% lower risk of psychiatric hospitalization when treated with APP instead of monotherapy 1
• A Japanese naturalistic study of 1,543 newly admitted acute-phase schizophrenia patients found that among 581 patients who did not respond to first or second monotherapy trials and received APP, 89.8% showed improvement on the Clinical Global Impression-Improvement Scale, with no higher rates of side effects 1

Specific Evidence for Risperidone Augmentation

The evidence specifically for augmenting risperidone (rather than augmenting with risperidone) is limited:

• A double-blind, placebo-controlled trial examining risperidone augmentation of clozapine in 24 outpatients showed a non-significant decrease in PANSS total score, though the PANSS disorganized thought subscale improved significantly (p=0.047) 2
• This trial does not support the routine addition of risperidone to clozapine, though larger trials are needed 2
• A pilot study of three cases combining clozapine and risperidone showed good clinical results with PANSS score reductions and no noticeable adverse effects 3

When to Consider Augmentation

Before considering augmentation of risperidone, you must establish true treatment resistance:

• Failure of at least two adequate treatment trials with different antipsychotic drugs is required to establish treatment resistance 1
• Each trial must use a therapeutic dose equivalent to at least 600mg chlorpromazine daily (risperidone 4-6mg/day falls within this range) for a minimum of 6 weeks 1
• Consider using a long-acting injectable formulation to rule out non-adherence as a confounding factor 1

Practical Algorithm for Risperidone Non-Response

If a patient shows inadequate response to optimized risperidone monotherapy:

1. First, verify adequate trial: Ensure risperidone dose is therapeutic (typically 4-8mg/day), duration is at least 6 weeks, and adherence is confirmed 1, 4

2. Second, consider switching rather than augmenting: There may be responders to olanzapine alone among early non-responders to risperidone, whereas there may be few responders to risperidone alone among early non-responders to olanzapine 5

3. Third, if switching fails, consider clozapine: Approximately 34% of patients with schizophrenia do not respond to non-clozapine antipsychotics and are deemed treatment-resistant, making clozapine the evidence-based next step 1

4. Fourth, if clozapine shows partial response, then consider augmentation: The strongest evidence for APP exists for augmenting clozapine, not risperidone 1

Most Effective Augmentation Combinations

If augmentation is pursued despite limited guideline support, the following combinations show the best outcomes:

• Clozapine combined with aripiprazole showed the lowest risk of psychiatric hospitalization (HR 0.86,95% CI 0.79–0.94 compared with clozapine monotherapy) 1
• Combinations with long-acting injectable formulations (excluding risperidone depot) were associated with better outcomes than oral-only combinations 1
• Clozapine monotherapy was the only monotherapy among the ten most effective treatments in the Finnish cohort; all others were polytherapy including either clozapine or long-acting injectables 1

Critical Pitfalls to Avoid

• Do not augment prematurely: At least 20% of individuals with schizophrenia do not receive clear benefit from monotherapy, but this does not justify immediate polypharmacy without adequate monotherapy trials 1
• Do not assume all augmentation is equal: APP may be superior during exacerbation of psychotic symptoms, but monotherapy may be superior for long-term sustained treatment 1
• Monitor for additive side effects: While the Japanese study found no higher rates of side effects with APP, this requires active monitoring for metabolic effects, extrapyramidal symptoms, and QTc prolongation 1
• Recognize that guidelines lag behind real-world evidence: Most guidelines are based on RCTs with stringent inclusion criteria that exclude many treatment-resistant patients, limiting their applicability to complex cases 1

Bottom Line

For risperidone specifically, the evidence supports switching to another antipsychotic (particularly olanzapine or clozapine) rather than augmentation as the preferred strategy for non-response. If augmentation is considered after multiple failed monotherapy trials, the strongest evidence exists for augmenting clozapine (not risperidone) with aripiprazole or using combinations involving long-acting injectables 1. The routine augmentation of risperidone with another agent lacks robust guideline support and should be reserved for exceptional circumstances where switching strategies have been exhausted 1, 2.