Should High Dose or Very Long-Term Antipsychotic Monotherapy Be Considered Before Antipsychotic Polypharmacy?

Abstract

Standard doses of all antipsychotics target 60–80% occupancy of dopamine D2 receptors. However, many patients do not respond adequately in 2–6 weeks to standard doses of one or more antipsychotics given as sequential monotherapies, as suggested by contemporary treatment guidelines for schizophrenia. The reasons for such inadequate treatment responses are several, and include both pharmacokinetic and pharmacodynamic failures. That is, some patients at standard doses do not attain 60–80% D2 occupancy. Factors accounting for this include not only noncompliance, but also failure to absorb, rapid metabolism, CYP450 2D6 polymorphisms, and others. In addition, some patients at standard doses attain 60–80% D2 occupancy but do not respond adequately to this. Common problems among such patients are hostility, aggression, assaultiveness and violence as well as continued positive symptoms of psychosis. At least two approaches may be considered for such pharmacokinetic and pharmacodynamic failures: namely, high dose monotherapy, and very long treatment times when feasible. High doses of a single agent are actually better studied than antipsychotic polypharmacy with two or more antipsychotics, especially for certain agents, and provides an approach that is potentially simpler, safer and more effective for overcoming both pharmacokinetic and pharmacodynamic treatment failures, and allows a strategy to optimize antipsychotic treatment without polypharmacy. In addition, certain patients have very late onset improvements, measured in months or years, and very long term treatment data for antipsychotics in schizophrenia are beginning to emerge for patients who are not in urgent management situations as an alternative to antipsychotic polypharmacy.