Managing first-episode psychosis: Rationale and evidence for nonstandard first-line treatments for schizophrenia

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

Overall, these studies demonstrate clo­zapine is as efficacious in this patient pop­ulation as chlorpromazine (no difference in remission at 1-year, although clozapine-treated patients remitted faster and stayed in remission longer)^60,61 or risperidone (no dif­ference in Positive and Negative Syndrome Scale scores).⁶²

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. https://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.