High-dose antipsychotics: Desperation or data-driven?
For patients on the brink of the neuroleptic threshold, risks of high-dose antipsychotics may outweigh any benefit.
Deutschman et al26 reviewed the charts of 31 patients who received ziprasidone, 240 to 320 mg/d, after an “incomplete” response to 160 mg/d. At the higher dosing:
- psychosis, affective symptoms, or anxiety improved in nearly one-half of patients
- 15% reported sedation, but most reported no side effects
- none developed QTc intervals >500 msec.
Caveats and precautions
These uncontrolled case reports and open-label studies do not “prove” efficacy or safety but reflect clinical practice. More than anything, they show that we need controlled trials to gauge high-dose antipsychotic therapy’s efficacy and safety and to curb our collective habit of relying on anecdotal experience and idiosyncratic beliefs.
Despite its side-effect profile, clozapine remains the treatment of choice for refractory schizophrenia. Given high-dose antipsychotic therapy’s uncertain efficacy and unknown risks, the evidence supports a clozapine trial before higher-than-recommended dosing is attempted.
Because educated guesswork plays a role in premarketing dosing studies, a medication’s optimal dose may be:
- overestimated (as with risperidone)
- underestimated (as perhaps with olanzapine and quetiapine).
Keep in mind some important caveats when you consider giving a patient high-dose antipsychotic therapy (Box).27 Of course, nonadherence is often the cause of apparent medication nonresponse. Increasing the dosage of a medication a patient is not taking rarely improves adherence. Interventions to enhance adherence—careful assessment, psychoeducation, and using longacting intramuscular medication—may be useful.
Related resources
- Marder SR, Essock SM, Miller AL, et al. The Mount Sinai Conference on the pharmacotherapy of schizophrenia. Schizophrenia Bull 2002;28:5-16.
- Practice guideline for the treatment of patients with schizophrenia (2nd ed). Am J Psychiatry 2004;161(suppl):1-56.
- Texas Medication Algorithm Project antipsychotic algorithm. https://www.mhmr.state.tx.us/centraloffice/medicaldirector/timascz1algo.pdf
Drug brand names
- Aripiprazole • Abilify
- Clozapine • Clozaril
- Divalproex • Depakote
- Fluphenazine • Prolixin
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosures
Dr. Pierre receives research support from Cephalon Inc., and is a consultant to and/or speaker for Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.
Dr. Donna Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, AstraZeneca Pharmaceuticals, and Abbott Laboratories.
Dr. William Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals.
