What can be added to Abilify (aripiprazole) for a symptomatic adult patient with schizophrenia?

Adding Medication to Aripiprazole for Symptomatic Schizophrenia

Before adding another antipsychotic to aripiprazole, first optimize the aripiprazole dose to 15-25 mg/day, as doses below 10 mg/day show limited efficacy for core schizophrenia symptoms, and if symptoms persist after 6-8 weeks at therapeutic doses, add clozapine rather than another antipsychotic. 1

Primary Recommendation: Optimize Aripiprazole First

• Aripiprazole demonstrates optimal antipsychotic efficacy at doses between 10-25 mg/day for acute and maintenance treatment of schizophrenia, with doses below 10 mg/day showing significant efficacy only for agitation symptoms 1

• The recommended therapeutic range is 10-30 mg/day, but evidence suggests maximal benefit occurs at 15-25 mg/day without additional efficacy at 30 mg/day 1, 2

• Allow a full 6-8 week trial at therapeutic doses (15-25 mg/day) before concluding treatment failure 3

If Aripiprazole Monotherapy Fails: Add Clozapine

The Finnish Current Care Guideline specifically states that combining aripiprazole with another antipsychotic may reduce negative symptoms, making this a guideline-endorsed strategy when monotherapy proves insufficient 3

Evidence for Clozapine + Aripiprazole Combination

• The combination of clozapine with aripiprazole shows the lowest risk of psychiatric hospitalization (HR 0.86,95% CI 0.79-0.94) compared to clozapine monotherapy, representing the strongest evidence for any antipsychotic combination 4, 5

• For first-episode patients, this combination demonstrates even better outcomes (HR 0.78,95% CI 0.63-0.96) 5

• Aripiprazole augmentation specifically improves negative symptoms (standardized mean difference -0.41,95% CI -0.79 to -0.03, p = 0.036) when added to another antipsychotic 4, 5

• Aripiprazole may reduce clozapine-induced side effects including hyperprolactinemia, sexual dysfunction, weight gain, and dyslipidemia 4, 5

Implementation Algorithm for Clozapine Augmentation

• First, optimize clozapine monotherapy by achieving a plasma level of at least 350 ng/mL before adding aripiprazole 5

• If symptoms persist despite therapeutic clozapine levels, add aripiprazole 5-15 mg/day 5

• Monitor for metabolic parameters including BMI, waist circumference, blood pressure, fasting glucose, and lipid panel at baseline, 3 months, and annually 4

Guidelines on Antipsychotic Polypharmacy

• The American Psychiatric Association guidelines endorse monotherapy and do not acknowledge situations where antipsychotic polypharmacy would be recommended as first-line treatment 3

• NICE guidelines recommend against regular combined antipsychotic medication except for short periods (e.g., when changing medication), but allow adding an additional antipsychotic to augment clozapine treatment if clozapine monotherapy proves ineffective 3

• The World Federation of Societies of Biological Psychiatry recommends antipsychotic polypharmacy only in treatment-resistant schizophrenia, specifically noting that clozapine combined with another second-generation antipsychotic (possibly risperidone) might have advantages 3

Critical Warnings About Switching from Polypharmacy to Monotherapy

• Switching from antipsychotic polypharmacy to monotherapy carries significant risk of treatment discontinuation (risk ratio 2.28,95% CI 1.50-3.46), with approximately 20-33% of patients unable to tolerate the switch 4

• Discontinuation of antipsychotic medication significantly increases relapse risk in schizophrenia, with 70% of patients requiring long-term or lifetime medication 4

• One study found that 42% of patients switching from polypharmacy to monotherapy discontinued treatment versus only 13% continuing combination therapy 4

Aripiprazole's Favorable Safety Profile

• Aripiprazole has low propensity for weight gain, favorable metabolic profile, no association with hyperprolactinemia, and minimal QTc prolongation 6, 2, 7

• Aripiprazole may actually reduce prolactin levels and body weight when used as augmentation therapy 4

• Common adverse effects include insomnia (23%), headaches (15%), nausea, and agitation, typically transient and occurring at placebo-level incidence 6, 2

• Aripiprazole demonstrates placebo-level incidence of extrapyramidal symptoms with treatment-emergent tardive dyskinesia in only 0.2% of patients 6

Common Pitfalls to Avoid

• Never add a second antipsychotic without first optimizing aripiprazole to 15-25 mg/day and allowing 6-8 weeks for response 1, 3

• Avoid using aripiprazole at doses below 10 mg/day for core schizophrenia symptoms, as efficacy is limited to agitation at these doses 1

• Do not combine aripiprazole with typical antipsychotics like haloperidol, as this increases extrapyramidal symptoms without additional benefit 6

• If adding a second antipsychotic becomes necessary, clozapine has the strongest evidence base for combination with aripiprazole, not other second-generation agents 4, 5

• Recognize that antipsychotic polypharmacy should be time-limited when used for acute symptom control, with attempts to revert to monotherapy once stability is achieved 3