Savvy Psychopharmacology

When and how to use long-acting injectable antipsychotics

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Practice Points

• Long-acting injectable antipsychotics (LAIs) are an important therapeutic option for patients with schizophrenia that allows clinicians to tailor pharmacotherapy to each patient’s needs.

• When selecting a specific LAI, consider class similarities and individual antipsychotic differences.

• Although some LAIs are expensive, they potentially reduce the financial burden of schizophrenia and improve quality of life.

Long-acting injectable antipsychotics (LAIs) are a pharmacotherapeutic option to help clinicians individualize schizophrenia treatment. LAIs have been available since the 1960s, starting with fluphenazine and later haloperidol; however, second-generation antipsychotics were not available in the United States until 20071,2 and more are in development (Box).3,4


Long-acting injectable antipsychotics in development

Aripiprazole microsphere long-acting injectable (LAI) is a phase III investigational drug that at press time was being reviewed by the FDA. This formulation appears to be similar to risperidone LAI. The active antipsychotic differs in side effect profile and pharmacokinetics. Because the pharmaceutical science of microsphere construction allows many variations, it is not possible to determine the strengths and weaknesses of aripiprazole LAI compared with risperidone LAI microspheres at this time. The dosing intervals currently under investigation are 14 and 28 days.3

Iloperidone crystalline LAI is a phase II-III investigational drug. FDA registration documents and early publication and presentation data report that iloperidone LAI will be a crystalline salt structure pharmaceutically similar to paliperidone and olanzapine LAI formulations.4 The dosing interval under investigation is 28 days.

Up to one-half of patients with schizophrenia do not adhere to their medications.5 LAI use may mitigate relapse in acute schizophrenia that is caused by poor adherence to oral medications. LAIs may have a lower risk of dose-related adverse effects because of lower peak antipsychotic plasma levels and less variation between peak and trough plasma levels. LAIs may decrease the financial burden of schizophrenia and increase individual quality of life because patients spend fewer days hospitalized due to acute exacerbations.6

Some widely used schizophrenia treatment algorithms, such as the Harvard Schizophrenia Algorithm, neglect LAIs. Also, LAIs have not been well studied for maintenance treatment of bipolar disorder (BD) even though nonadherence is a substantial problem in these patients. Patients, families, and legal guardians may choose LAI antipsychotics over oral formulations to decrease the frequency and severity of psychotic relapse or for convenience because patients who receive LAIs do not need to take a medication every day.

Understanding the similarities and differences among LAIs7 and potential interpatient variability of each LAI allows prescribers to tailor the dosing regimen to the patient more safely and efficiently (Table).1,8-11 All LAI antipsychotic formulations rely on absorption pharmacokinetics (PK) rather than elimination PK, which generally is true for sustained-release oral formulations as well. Absorption half-life duration and absorption half-life variability are key concepts in LAI dosing.


Characteristics of long-acting injectable antipsychotics

AntipsychoticOral elimination half-lifeFormulationAbsorption half-lifeTime between injectionsClinically relevant PK/PD variabilityaOral overlapping taper necessary?Loading dose possible?
Fluphenazine1 dayDecanoate in organic oil14 days7 to 21 days+++YesNo
Haloperidol1 dayDecanoate in organic oil21 days28 days+/-NoYes
Olanzapine1.5 daysPamoate crystalline30 days14 to 28 days++MaybeNo
Risperidone1 dayMicrospheres5 days14 days++YesNo
Paliperidone1 dayPalmitate crystalline45 days28 days+NoYes
aMore + indicates greater variability among patients
PD: pharmacodynamics; PK: pharmacokinetics
Source: References 1,8-11

Clinical pearls

Before prescribing an LAI, check that your patient has no known contraindications to the active drug or delivery method. Peak-related adverse effects typically are not contraindications, although they may prompt you to start at a lower dose.

Ensure that your patient will have long-term outpatient access to the LAI and the entire treatment team—inpatient and outpatient—is committed to LAI treatment.

Do not rule out first-generation LAIs such as haloperidol and fluphenazine. The Clinical Antipsychotic Trials of Intervention Effectiveness study, Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, and other published data suggest older antipsychotics are not inferior to newer medications.12,13

Verify that your patient has had an oral trial of the active drug—ideally in the last 12 months—that resulted in at least partial positive response and no serious adverse drug effects (ADEs). Oral medications’ shorter duration of action may help identify ADEs before administering an LAI.1

Discontinue the oral medication as quickly as evidence, guidance, and good clinical judgment allow. Develop a plan to transition from oral to LAI that you will follow unless the patient develops intolerable ADEs or other problems. There is no evidence to suggest that patients who receive partial LAI therapy decompensate less frequently or less severely than those who take oral medication.


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