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High-dose antipsychotics

Vol. 3, No. 10 / October 2004

Pierre et al and Preskorn (Current Psychiatry, August 2004) address an important treatment issue that has not been well investigated. Titrating an antipsychotic dosage too high and too soon is common in many settings, especially where treatment-resistant patients are numerous.1 But while I advise trainees to use the lowest effective antipsychotic dosage, several justifications exist for exceeding what is arbitrarily regarded as the “approved” dose range:

  • FDA registration trials of antipsychotics exclude treatment-resistant/refractory patients. Thus, the “approved” dose range applies only to those with good or adequate treatment response.
  • Smoking induces the cytochrome P-450 1A2 isoenzyme, which oxidizes olanzapine. Thus, heavy smokers—especially those who are rapid metabolizers—may need much higher olanzapine dosages to compensate for the rapid clearance.
  • The number of dopamine (D2) receptors varies among patients even at psychosis onset. Kapur et al 2 gave a fixed dose of haloperidol to 22 subjects with first-episode psychosis. Only a few developed extrapyramidal symptoms (ie, achieved >78% D2receptor occupancy). D2receptor occupancy ranged from 38% to 87%, suggesting that while some patients with relatively few D2 receptors may respond to lower dosages, others may need higher dosages to achieve response (<65% D2 receptor occupancy).
  • Different dosages may be needed at different phases of the illness. For example, much higher antipsychotic (or lithium) dosages are needed for acute mania than for maintenance.
  • A psychotropic may sometimes exert different neurochemical effects at high vs low dosages. For example, a typical antipsychotic’s serotonin antagonist effects may be more apparent at lower dosages, while the dopamine antagonist effect is more prominent at higher dosages.
  • In the United States, roughly 35% of persons with schizophrenia receive two or more concomitant antipsychotics. Although no controlled studies have shown that combination antipsychotic therapy is superior to monotherapy, many clinicians claim that some patients respond better to two atypicals than to one. This may be because of a net higher antipsychotic dosage, which may be therapeutic for treatment-resistant patients.

Use of antipsychotic dosages beyond the FDA-approved range is poorly studied and not evidence-based, but may be justified in some patients despite the higher risk of adverse events. Controlled trials addressing this issue are needed to help clinicians manage patients who perpetually fail to respond to approved dosage ranges. Treatment-resistant patients may be a biologically different subtype than responsive patients 3 and may need a different class of drug with another mechanism of action. Until that drug is discovered, empirical trials of higher antipsychotic dosages cannot be overlooked as a clinical option.

Henry A. Nasrallah, MD
Professor of psychiatry, neurology and neuroscience
University of Cincinnati College of Medicine


  1. Pierre JM, Wirshing DA, Cannell J, et al. High-dose quetiapine in treatment-refractory schizophrenia. Schizophr Res 2003;60(supp):299.
  2. Kapur S, Zipursky R, Jones C et al. Relationship between dopamine D 2 occupancy, clinical response, and side-effects: A double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000;157:514–20.
  3. Nasrallah HA, Garver DL, Zhu M. The apoptosis executioner caspase—3 levels are low in rapid-responders and elevated in treatment-refractory schizophrenia. Int J Neuropsychopharm 2004;7(supp):431.

The authors respond

Dr. Preskorn’s and Dr. Nasrallah’s commentaries temper the cautionary tone of our article, which reviewed the “evidence-basis” of high-dose antipsychotic therapy (HDAT). Our tone stems from a lack of controlled research establishing HDAT’s efficacy, a respect for potentially serious antipsychotic side effects, and our belief that clozapine—despite established efficacy in treatment-resistant schizophrenia—is underutilized.

Both colleagues outline several theoretical reasons why HDAT may help some treatment-resistant patients. As we noted, however, similar theories and clinical observations were used to defend rapid neuroleptization, which has been shown to be ineffective with an increased side-effect risk.

The observation that smoking can decrease olanzapine plasma levels is valid, yet existing olanzapine dosing guidelines are based on clinical trials involving subjects with schizophrenia who most likely were smokers.

While we agree that HDAT has theoretical appeal and may prove effective in some patients, we are concerned that clinicians are routinely escalating the dosage after only 1 to 2 weeks of nonresponse to recommended doses. Although high rates of treatment-refractory illness may justify this clinical practice, we find it alarming that clozapine use is so disproportionately low.

As proponents of evidence-based medicine, we note that the lack of data does not mean that HDAT is not effective, but we share the call for well-designed clinical trials to address this issue. Future research may indeed vindicate HDAT, but until then—while we do employ HDAT in some situations—we also typically proceed with clozapine before resorting to desperation measures.

Joseph M. Pierre, MD
Donna A. Wirshing, MD
William C. Wirshing, MD
Geffen School of Medicine
University of California-Los Angeles

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