Rationale and Evidence for Nonstandard First-Line Treatments for Schizophrenia: Consider Long-Acting Injectable Antipsychotics; Use Clozapine as Second- or Third-Line Therapy Only

First-episode psychosis (FEP) in schizophrenia is characterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discontinuation and elevated relapse rates soon after maintenance treatment begins. (1,2) With subsequent episodes, time to response progressively increases and likelihood of response decreases. (3,4) To address these issues, this article--the second (a) of 2 parts (5)--describes the rationale and evidence for using nonstandard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider monotherapy exceeding FDA-approved maximum dosages, combination therapy, long-acting injectable antipsychotics (LAIA), or clozapine. Monotherapy beyond FDA-approved dosages Treatment guidelines for FEP recommend oral antipsychotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizophrenia. (6,16) Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient. (17) [ILLUSTRATION OMITTED] To control symptoms, higher dosages may be needed than those used in FEP clinical trials, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug-drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),18 or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns. In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dosages of olanzapine and risperidone after failing to respond to a standard dosage. (19) A study of data from the Recovery After an Initial Schizophrenia Episode Project's Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were prescribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage. (20) Of note, only olanzapine was prescribed at higher than FDA-approved dosages. Antipsychotic combination therapy Prescribing combinations of antipsychotics--antipsychotic polypharmacy (APP)-has a negative connotation because of limited efficacy and safety data, (21) and limited endorsement in schizophrenia treatment guidelines. (9,13) Caution with APP is warranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions. (9) APP has been shown to independently predict both shorter treatment duration and discontinuation before 1 year. (22) Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as: * to optimize neuroreceptor occupancy and targets (eg, attempting to achieve adequate D2 receptor blockade while minimizing side effects secondary to binding other receptors) * to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits) * to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another antipsychotic to which the patient has achieved a favorable response). (23) Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes. (23) For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP. …