Should a Patient Be on More Than One Second-Generation Antipsychotic?
Routinely, no—one antipsychotic should be prescribed at a time, and antipsychotic polypharmacy should only be considered for patients who fail to respond to adequate monotherapy trials, particularly for clozapine augmentation in treatment-resistant cases, and only under close clinical monitoring. 1
Guideline Consensus Against Routine Polypharmacy
The WHO explicitly states that one antipsychotic should be prescribed at a time as routine practice. 1 The American Psychiatric Association endorses monotherapy exclusively and does not acknowledge situations warranting antipsychotic polypharmacy. 1, 2 NICE guidelines similarly advise against regular combined antipsychotic use except during brief medication transitions. 1, 2
When Polypharmacy May Be Considered
Antipsychotic combination treatment may be considered only in specific circumstances:
Treatment-resistant schizophrenia after documented failure of at least two adequate monotherapy trials with different antipsychotics at therapeutic doses for sufficient duration. 2
Clozapine augmentation is the most evidence-supported scenario—NICE specifically permits adding another antipsychotic when clozapine monotherapy proves ineffective. 1, 2 The World Federation of Societies of Biological Psychiatry notes that combining clozapine with another second-generation antipsychotic (possibly risperidone) might have advantages over monotherapy. 1
Negative symptom reduction—aripiprazole augmentation shows specific benefit for negative symptoms (standardized mean difference −0.41,95% CI −0.79 to −0.03, p = 0.036). 2
Critical Evidence Limitations
The evidence supporting polypharmacy is fundamentally weak. A 2021 meta-analysis found that antipsychotic augmentation appeared superior to monotherapy for total symptom reduction, but this benefit only emerged in open-label low-quality trials—not in double-blinded or high-quality studies. 2 Another meta-analysis of 42 antipsychotic combinations found no clear evidence recommending polypharmacy over monotherapy, with effect sizes inversely correlated with study quality. 2
Substantial Safety Concerns
Antipsychotic polypharmacy significantly increases adverse effect burden:
- Higher rates of extrapyramidal symptoms and Parkinsonian effects 2, 3
- Increased need for anticholinergic medications 2, 4
- Elevated risk of hyperprolactinemia and sexual dysfunction 2
- Greater sedation, hypersalivation, and cognitive impairment 2
- Increased metabolic complications including diabetes 2
Practical Algorithm If Polypharmacy Becomes Necessary
Before adding any second antipsychotic:
- Verify the current antipsychotic is at therapeutic dose and has been trialed for adequate duration 2
- Document failure of at least two adequate monotherapy trials with different antipsychotics 2
- Ensure this decision is made under supervision of mental health professionals with close clinical monitoring 1
If proceeding with polypharmacy:
- Select antipsychotics with differing side-effect profiles to avoid compounding adverse effects (e.g., do not combine two drugs that both cause significant sedation or metabolic effects) 1, 2
- Start with lower doses of each medication to minimize side effects 2
- Establish clear treatment goals with specific symptom targets and predetermined reassessment timelines 2
- Monitor regularly for extrapyramidal symptoms, metabolic parameters (glucose, lipids, weight), and cardiovascular effects 2
Common Pitfalls to Avoid
Do not use polypharmacy as a substitute for inadequate monotherapy trials. The most common error is adding a second antipsychotic before optimizing the first one. 2
Avoid combining antipsychotics with similar side-effect profiles, as this compounds adverse effects without clear benefit—for example, combining two highly sedating agents or two with significant metabolic effects. 1, 2
Do not continue polypharmacy indefinitely without reassessment. Establish specific timelines for evaluating whether the combination provides meaningful benefit over monotherapy. 2