Evidence-Based Reviews

Managing first-episode psychosis: An early stage of schizophrenia with distinct treatment needs

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Minimize duration of untreated psychosis; aim for remission



The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery.1 However, relapse prevention is a major clinical challenge because >80% of patients will relapse within 5 years, and, on average, 40% to 50% of patients with a first-episode schizophrenia will relapse within 2 years depending on the definition used and patient characteristics.2 Although there are several explanations and contributing factors to relapses, non­adherence—partial or complete discontinuation of antipsychotics—is a primary risk factor, contributing to a 5-fold increase in relapse risk.3

As such, optimal antipsychotic selection, dosing, and monitoring play an important role in managing this illness. Patients with first-episode psychosis (FEP) are unusual in some ways, compared with patients with multiple episodes of psychosis and represent a different stage of schizophrenia.

In this 2-part series, we will discuss pharmacotherapy for FEP. This article focuses on antipsychotic selection, dosage, and duration of treat­ment among these patients. The second article, in the July 2015 issue, reviews the rationale and evidence for non-standard, first-line thera­pies, including long-acting injectable antipsychotics and clozapine.

Defining FEP
FEP refers to a patient who has presented, been evaluated, and received treatment for the first psychotic episode associated with a schizophre­nia spectrum diagnosis.4 FEP is part of a trajectory marked by tran­ sitional periods. The patient transitions from being “healthy” to a prodromal state characterized by: (1) nonpsychotic behav­ioral disturbances such as depression or obsessive-compulsive disorder, (2) attenu­ated psychotic symptoms not requiring treatment, then converting to (3) psychotic symptoms prompting initial presentation for antipsychotic pharmacotherapy, lead­ing to (4) a formal diagnosis of schizo­phreniform disorder and, subsequently, schizophrenia, requiring treatment to sta­bilize symptoms.

There are 2 critical periods along this continuum: prodromal stage and the dura­tion of untreated psychosis (DUP). The prodromal period is a retrospectively iden­tified time where the patient shows initial nonpsychotic disturbances (eg, cognitive and behavioral symptoms) before exhibit­ing clinical diagnostic criteria for a schizo­phrenia spectrum disorder. Approximately one-third of patients exhibiting these symptoms convert to psychosis within 1 year, and early treatment engagement at this stage has been shown to improve out­comes.5 The DUP is the time from when a patient has noticeable psychotic symptoms to initiation of drug treatment. The DUP is a consistent predictor of clinical out­come in schizophrenia, including negative symptoms, quality of life, and functional capacity.1

Antipsychotic selection
Treatment goals for FEP patients include:
• minimizing the DUP
• rapidly stabilizing psychosis
• achieving full symptomatic remission
• preventing relapse.

Several treatment guidelines for manag­ing schizophrenia offer variable recommen­dations for initial antipsychotic treatment in patients with first-episode schizophre­nia (Table 1).6-15 Most recom­mend second-generation antipsychotics (SGAs) over first-generation antipsy­chotics (FGAs)6,8,9,13,15 with specific recom­mendations on minimizing neurologic and metabolic adverse effects—to which FEP patients are susceptible—by avoid­ing high-potency and neurotoxic FGAs (eg, haloperidol and fluphenazine),7 clo­zapine,11,14 olanzapine,11 or ziprasidone.14 Two guidelines—the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network—do not state a preference for antipsychotic selection.10,12

The rationale for these recommendations is based on efficacy data, tolerability dif­ferences, FDA-approved indications, and recent FDA approvals with sparse post-marketing data. Of note, there are a lack of robust data for newer antipsychotics (eg, aripiprazole, paliperidone, iloperidone, asenapine, and lurasidone) in effectively and safely treating FEP; however, given the results of other antipsychotics studies, it is likely the efficacy and tolerability of these drugs can be extrapolated from experience with multi-episode patients.

Study design and demographics. Research studies of FEP share some simi­larities in study design; however, there is enough variability to make it difficult to compare studies and generalize find­ings (Table 2).16 The variability of DUP is a limitation when comparing studies because it is a significant predic­tor of clinical outcome. Patients who abuse substances—and often are more challeng­ing to treat17—typically are excluded from these trials, which could explain the high response rate documented in studies of first-episode schizophrenia.

In addition, some FEP patients included in clinical trials might not be truly antipsy­chotic naïve; an estimated 25% to 75% of patients in these studies are antipsychotic naïve. This is an important consideration when comparing data on adverse effects that occur early in treatment. Additionally, acknowledging the advantages and disad­vantages of how to handle missing data is critical because of the high dropout rate observed in these studies.18

Efficacy. There is a high response rate to antipsychotic therapy—ranging from 46% to 96%, depending on the study—in patients with first-episode schizophrenia.3 The response mainly is seen in reduction of positive symptoms because typically negative and cognitive symptoms do not respond to antipsychotics. One study reported only 29% of patients achieved both positive and negative symptom remis­sion.19 It is likely that secondary negative symptoms caused by social withdrawal, reduced speech, and avoidance improve when positive symptoms subside, but pri­mary negative symptoms endure.In general, there is a lack of evidence suggesting that 1 antipsychotic class or agent is more effective than another. Studies mainly assess effectiveness using the primary outcome measure of all-cause discontinuation, such as the Clinical Antipsychotic Trials of Intervention Effectiveness study.20 This outcome mea­sure is a mixture of patient preference, tol­erability, and efficacy that provides a more generalizable gauge on how well the treat­ment works in the clinic rather than tightly regulated settings such as clinical trials. A recent meta-analysis supports no differ­ences in efficacy among antipsychotics in early-episode psychosis.21

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