Why are some patients prescribed two antipsychotics?

Why Some Patients Are Prescribed Two Antipsychotics

Antipsychotic polypharmacy (APP) is primarily used for patients with treatment-resistant schizophrenia who do not respond adequately to monotherapy, including clozapine, or when clozapine is contraindicated. 1

Primary Indications for Antipsychotic Polypharmacy

• Insufficient treatment response to monotherapy - Approximately 20% of patients with schizophrenia do not experience a substantial response from antipsychotic monotherapy, necessitating alternative approaches 1

• Treatment-resistant schizophrenia - When patients have failed trials with at least two different antipsychotic monotherapies, including clozapine when appropriate 1

• Augmentation of clozapine - Adding a second antipsychotic (particularly a partial D2 agonist like aripiprazole) to clozapine when clozapine monotherapy has proven ineffective 1

• Targeting specific symptom domains - When one antipsychotic effectively treats certain symptoms but not others (e.g., combining medications to address both positive and negative symptoms) 1

Clinical Scenarios for Antipsychotic Polypharmacy

• Cross-titration periods - During the transition from one antipsychotic to another, patients may temporarily be on two medications 1

• Targeting comorbid symptoms - APP may be used to address specific comorbid symptoms such as anxiety, sleep disturbances, or impulsive behavior rather than adding other classes of medications 1

• Reducing side effects - Combining certain antipsychotics (particularly adding aripiprazole to another antipsychotic) may reduce side effects such as weight gain, dyslipidemia, hyperprolactinemia, and sexual dysfunction 1

• Decreasing the dose of any one medication - Using two antipsychotics at lower doses may help reduce dose-dependent side effects that would occur at higher monotherapy doses 1

Prevalence of Antipsychotic Polypharmacy

• APP is widely used despite guideline recommendations against it, with rates of:
  • 10-20% in outpatients with schizophrenia 1
  • Up to 40% in inpatients with schizophrenia 1
  • Higher prevalence in Europe (23%) and Asia (32-42.6%) compared to North America (16%) 1

Evidence and Guideline Recommendations

Most treatment guidelines recommend antipsychotic monotherapy as first-line treatment, but acknowledge specific situations where APP may be appropriate:

• The National Institute for Health and Care Excellence (NICE) recommends against regular combined antipsychotic medication except when changing medications or when augmenting clozapine in treatment-resistant cases 1

• The World Federation of Societies of Biological Psychiatry guidelines state that APP should only be considered in certain individual cases such as treatment-resistant schizophrenia, noting that combining clozapine with another second-generation antipsychotic might have advantages 1

• The Finnish Current Care Guideline acknowledges that some patients may benefit from two antipsychotics, particularly noting that combining aripiprazole with another antipsychotic may reduce negative symptoms 1

Risks and Considerations

• Increased side effect burden - APP is associated with more prolactin elevation, Parkinsonian side effects, anticholinergic use, hyperprolactinemia, sexual dysfunction, hypersalivation, sedation, cognitive impairment, and diabetes mellitus 1

• Drug-drug interactions - Combinations affecting the same metabolic pathways may have additive or reductive effects on plasma concentrations and side effects 1

• Adherence challenges - Multiple medications may reduce adherence compared to monotherapy 1

• Higher healthcare costs - APP generally incurs greater health service costs compared to monotherapy 1

• Risk of clinical deterioration when switching - Patients stable on two antipsychotics may experience symptom worsening when switched to monotherapy 2

Best Practices When Using Antipsychotic Polypharmacy

• Ensure adequate trials of monotherapy (including clozapine when appropriate) before considering APP 1

• Select antipsychotics with differing side-effect profiles to avoid compounding adverse effects 1

• Consider pharmacogenetic testing or blood drug concentration measurement to optimize dosing, especially for medications affected by CYP enzymes with genetic polymorphisms 1

• Monitor for drug-drug interactions and consider factors that affect metabolism (smoking status, caffeine consumption, eating schedule) 1

• Regularly reassess the need for continued polypharmacy and consider trials of dose reduction or discontinuation of one agent when clinically appropriate 1

• Consider long-acting injectable formulations to improve adherence when appropriate 1