Off-label prescribing of two or more antipsychotics for treatment-resistant psychosis carries inherent risks for both schizophrenia patients and their psychiatrists. You can reduce these risks by demonstrating that your patient will benefit more from combining antipsychotics than from monotherapy alternatives.
Until more empiric data become available, clinicians carry the burden of documenting individual patient response to justify combining antipsychotics. This article can help you identify and counsel possible candidates for this therapy, assess the risks and benefits, and defend your treatment choicesif necessary.
What Does ‘Combining’ Mean?
For this discussion, “combining antipsychotics” does not mean simultaneously using two or more antipsychotics to treat psychosis. Rather, it refers to using two or more antipsychotics for long-term control of psychotic symptoms. It does not apply to short-term tactics, such as overlapping antipsychotics when switching between them or combining a parenteral and an oral antipsychotic when treating an acute episode.
How long must a combination be used to qualify as long-term treatment? No standard exists, but a period >6 weeks exceeds normal short-term treatment.
How Safe Are Combinations?
Patient risk. Combination antipsychotics are used to treat 10% to 20% of schizophrenia patients in this country and >90% of those in some Asian countries, such as Japan.1 Statistics on the prevalence of combining antipsychotics seldom:
- distinguish between short- and long-term use
- identify when practitioners use combinations to treat co-existing symptoms such as insomnia, rather than for psychosis.
Clinicians, however, must define safety in terms of risks and benefits. Given that every medication has risks—some (such as allergic reactions) unique to the individual patient—adding another drug to a treatment regimen will always add risk. When considering more than one antipsychotic, ask yourself:
- Do benefits outweigh risks?
- Is a combination the least risky way to achieve these benefits?
How much does a practitioner’s perception of medicolegal risk influence treatment selection? No doubt, comfort level varies greatly. I have frequently met prescribers who use antipsychotic combinations instead of clozapine for fear of being sued should agranulocytosis occur.
Defining treatment-resistant schizophrenia
Most trials have used criteriafrom the seminal clozapine study to define “treatment resistant” schizophrenia:
- History of poor response to one or more antipsychotics.
- Demonstrated nonresponse to adequate dosage and duration of a nonclozapine antipsychotic before starting clozapine.2
This work defines treatment resistance as persistent positive symptoms despite treatment with ≥2 different antipsychotics other than clozapine.
Newer antipsychotics are different. The original clozapine studies found little likelihood that patients who had not responded to haloperidol would respond to chlorpromazine. Newer-generation antipsychotics are pharmacologically more heterogeneous than the first-generation agents, however, and failure to respond to one might not mean that none of the others will help.
When to start clozapine? Solid evidence is limited, but a consensus panel has recommended starting clozapine after two unsuccessful trials of newer-generation antipsychotics, with the option to try a third antipsychotic (first- or newer-generation) if clinically warranted.3
Symptoms vs function. In clinical practice, defining treatment resistance as persistent positive symptoms may exclude patients impaired by severe negative symptoms and/or disorganized thought processes. The treatment goal is to restore function, not just to reduce psychosis. As treatments evolve, we can expect more emphasis on a recovery model that addresses total patient well-being and combines psychosocial and pharmacologic interventions.
A Practical View
Medical risks. Treating patients with antipsychotic combinations may be associated with medical risks (Table 1). Patients are less likely to adhere to complex medication regimens than to simple ones. Thus, adding a second antipsychotic may decrease adherence to the first antipsychotic and to other medications, such as for hypertension, diabetes, etc.
Increased side-effect risk has been reported with antipsychotic combinations.4 Side effects include those expected from one or both drugs in the combination, especially extrapyramidal effects when conventional antipsychotics are included.4,5 Because the total antipsychotic dosage can be considerably higher than usual in patients receiving combinations,5 some of the increased side effect burden is probably related to high dosing, rather than to the combinations.
Pharmacodynamic or pharmacokinetic interactions or the loss of an agent’s advantages are infrequently reported, perhaps because prescribers are not looking for these effects or do not consider them worth reporting. Of particular concern is tardive dyskinesia (TD), which may develop when conventional antipsychotics are added to agents with very low propensity to cause TD—such as clozapine.