Results were different in a randomized, double-blind, 16-week, crossover study,19 when 13 patients with inadequate response to neuroleptics, risperidone, or conventional-dose olanzapine then received olanzapine, 50 mg/d, or clozapine, 450 mg/d. No olanzapine-treated patients and 20% of clozapine-treated patients met criteria for treatment response (20% improvement in BPRS score and final BPRS score <35 or 1-point improvement on Clinical Global Impressions-Severity of Illness scale).
Thinking about high-dose antipsychotics? Consider these caveats first
Negative results don’t make headlines. Published clinical trials and case reports are subject to selective reporting of positive outcomes. Cases in which high-dose therapy proved ineffectivemay outnumber positive results but are less likely to be published.
Numbers don’t lie. Using high doses will almost always increase side effect risk and drug therapy costs, contributing to a poor risk-benefit ratio when efficacy remains unchanged. Resorting to an “if-it’s-not-working, double-it” strategy may seem reasonable, but two times zero is still zero.
Desperation warps perception. Clinicians tend to rely on observational experience. The desperation inherent in treating refractory patients, however, often creates a strong desire for improvement and therefore a potentially biased perception of outcome.
Likewise, patients may inaccurately portray themselves as improved to avoid disappointing their doctors. Controlled trials reduce these biases to better assess efficacy.
Antipsychotics work in 6 to 8 weeks. Improvements seen when pushing medications beyond recommended dosing may not be an effect of dose but of additional time on the medication. Antipsychotics usually take 6 to 8 weeks to produce maximal response, so high-dose therapy should not be started during this initial phase. This pace may not satisfy pressures for expedient stabilization and hospital discharge, but it is unrealistic to expect antipsychotics to work more quickly than they do.
Oversedation does not equal improvement. Patients who become excessively sedated from high-dose therapy or adjunctive medications may appear less psychotic but may not be so. The family or hospital staff may desire such sedation, but it can adversely affect the patient’s quality of life or medication adherence.
Polypharmacy clouds the issue. Many patients treated with high-dose antipsychotics are taking multiple agents, making it difficult to attribute improvement (or side effects) to any single one. A well-designed study of high-dose therapy would therefore:
- control for time
- examine concomitant medications’ effects
- determine whether “improvements” are related to sedation or reduced psychosis.
Medication may not need to change. When a patient decompensates, many forces pressure clinicians to change or add medications or increase dosages. Change may not be necessary, however, as nonadherence or substance abuse often trigger psychotic exacerbations. For example, Steingard et al27 added fluphenazine or placebo to antipsychotic regimens of newly hospitalized patients and found that increasing antipsychotic dosage did not improve outcome.
Subjects switching from clozapine to olanzapine tended to worsen, whereas those switching from olanzapine to clozapine tended to improve. Olanzapine-treated patients experienced more anticholinergic side effects and more weight gain than did clozapine-treated subjects.20
Conclusion. These mixed findings on high-dose olanzapine suggest questionable efficacy in patients with treatment-resistant schizophrenia and an uncertain risk of increased toxicity.
Quetiapine
Early placebo-controlled studies of quetiapine in schizophrenia concluded that statistically significant improvement begins at 150 mg/d and falls off after 600 mg/d.21 Although few high-dose quetiapine cases have been presented, clinical opinion holds that:
- most patients with chronic schizophrenia require 400 to 800 mg/d
- some treatment-refractory patients might benefit from >800 mg/d.
One patient responded to quetiapine, 1,600 mg/d, after not responding to olanzapine, 40 mg/d, and quetiapine, 800 mg/d. Constipation was the only reported side effect.22
Our group23 reported a series of 7 patients who responded (by clinician report) to quetiapine, 1,200 to 2,400 mg/d, after not responding to quetiapine, 800 mg/d, or to neuroleptics, risperidone, or olanzapine. Six responded to high-dose quetiapine and 1 to high-dose quetiapine plus risperidone, 2 mg/d; 4 received adjunctive dival-proex sodium, 1,500 to 3,000 mg/d. Psychopathology, violence, and behavioral disturbances were reduced throughout 5 to 14 months of monitoring. Side effects included sedation, orthostasis, and dysphagia.
When Nelson et al24 treated 13 subjects for 14 weeks with quetiapine, 1,000 to 1,400 mg/d, mean weight, glucose, total cholesterol, prolactin, and QTc interval duration did not change significantly. Heart rate increased significantly (though not to tachycardia), and headache, constipation, and lethargy were the most frequent side effects.
Summary. Although encouraging, these reports are preliminary, unpublished, and lack peer review. Controlled trials of high-dose quetiapine’s efficacy and safety are needed.
Ziprasidone and aripiprazole
No studies of high-dose ziprasidone or aripiprazole have been published. In premarketing trials:
- ziprasidone was studied at 200 mg/d and released with a maximum recommended dosage of 160 mg/d
- aripiprazole, 30 mg/d, was not more effective than 15 mg/d.25