Savvy Psychopharmacology

Efficacy and safety of high-dose antipsychotic therapy

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Practice Points

Mr. K, age 21, is admitted to the psychiatry unit with agitation, disorganized behavior, and paranoia. Upon presentation, he has no known medical history or current medications. He is diagnosed with schizophrenia and subsequently tolerates but does not respond to adequate durations of treatment with fluphenazine, 20 mg/d; aripiprazole, 30 mg/d; and risperidone, 6 mg/d. Medication adherence is verified, but Mr. K is reluctant to try a fourth antipsychotic. The treatment team suspects that Mr. K may be a cytochrome P450 (CYP) 2D6 ultra-rapid metabolizer, so they obtain a serum risperidone level. The serum risperidone concentration is subtherapeutic (10 ng/mL). What should be considered next?

Several factors must be considered when a patient with psychosis does not experience significant symptomatic improvement with an adequate antipsychotic trial. This article focuses on high-dose second-generation antipsychotic (SGA) therapy in adults with psychosis. “High-dose” antipsychotic therapy is dosing that exceeds the standard maximum dosage for a given antipsychotic. Existing evidence on the use of high-dose SGAs consists of open-label studies and case reports, as well as a handful of randomized controlled trials (RCTs) with small sample sizes and high dropout rates. In some studies, the use of concomitant interventions (eg, duplicate antipsychotic therapy) limit the interpretation of data. High-dose first-generation antipsychotic therapy is discouraged because of a heightened risk of extrapyramidal symptoms (EPS).

Metabolic pathways and prescribing considerations for SGAs

Steps to take before increasing the dose

When considering prescribing high-dose antipsychotic therapy, first confirm that the patient has been adherent to the current medication regimen. Also, screen for factors that might impair drug absorption, such as bariatric surgery or noncompliance with administration precautions.1 For example, administration of lurasidone with less than 350 calories may considerably decrease absorption.2 Dosage requirements may vary based on ethnicity, gender, CYP polymorphisms, and pharmacokinetic drug interactions (Table 12-17).1,18,19 Causes of inadequate efficacy should be addressed before considering the use of high-dose antipsychotic therapy.1 Under certain circumstances, serum drug concentrations may be used to guide antipsychotic dosing (Table 22-17). Inadequate response despite a therapeutic serum concentration may indicate pharmacodynamic failure.1 Inadequate response in the context of subtherapeutic serum concentrations, good medication adherence, and compliance to administration precautions may be indicative of a genetic polymorphism or drug interaction.1 Changes in antipsychotic dosing or selection may be warranted, depending on associated risks and benefits.

Maximum daily dosages and estimated therapeutic ranges for SGAs

SGAs and high-dose administration

The SGA with the greatest evidence for high-dose administration is olanzapine, which is similar in structure and receptor pharma­cology to clozapine.20,21 The use of high-dose olanzapine is controversial. High-dose olanzapine has been compared to clozapine in patients with treatment-resistant schizophrenia (TRS) and schizoaffective disorder. Meltzer et al22 reported similar efficacy with clozapine, 300 to 900 mg/d, and olanzapine, 25 to 45 mg/d. In this study, high-dose olanzapine caused more weight gain when compared to clozapine. Olanzapine dosages of up to 100 mg/d have been prescribed for TRS; however, this is not common practice.23 A study comparing 10, 20, and 40 mg/d in patients with non-TRS or schizoaffective disorder showed no advantage with higher dosages.24

There is limited data on high-dose treatment with other SGAs.17 Orthostasis may limit iloperidone’s safety at high doses, and single doses of asenapine should not exceed 10 mg.25 Limited sublingual surface area and saliva saturation result in decreased bioavailability with higher asen­apine doses.25,26 In a small RCT of patients with stable schizophrenia or schizoaffective disorder, aripiprazole was relatively well-tolerated up to 75 mg/d, whereas akathisia and tachycardia occurred with 90 mg/d.27 Case reports have documented successful treatment with aripiprazole, 60 to 75 mg/d; however, dizziness and worsening psychosis, agitation, and confusion have been observed.28-31

There is a paucity of data on high-dose risperidone and paliperidone, possibly due to their potent dopamine-2 (D2) receptor antagonism and dose-related risk of EPS.1 At risperidone dosages >6 mg/d, the balance between D2 and serotonin-2A (5-HT2A) receptor potency is lost, which increases the potential for EPS.32 In one RCT, long-acting injectable (LAI) risperidone, up to 100 mg biweekly, was well-tolerated but no more effective for TRS than 50 mg biweekly.33 A case report suggested improvement of TRS in a patient administered risperidone LAI, 75 mg vs 37.5 mg biweekly, but it is unclear if a 50-mg dosage was tried.34 Another case report documented improvement in schizophrenia symptoms with risperidone LAI, 125 mg biweekly; however, anticholinergic therapy was required for EPS.35

Dose-dependent adverse effects, including EPS, sedation, anticholinergic effects, orthostasis, hyperprolactinemia, and QTc prolongation, may limit the safety of high-dose antipsychotic therapy.1,20,36 Two studies showed no correlation between QTc prolongation and ziprasidone dosages of up to 320 mg/d for psychosis.37,38 QTc prolongation was more likely at higher ziprasidone concentrations.37 Higher concentrations, but not higher dosages, also trended toward improvement in positive symptoms, and concentrations >100 ng/mL were associated with more negative symptoms.37 A case report described improvement in positive symptoms of schizoaffective disorder with ziprasidone, 320 mg/d, but activation, hostility, and depression worsened.39

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