Kristen N. Gardner, PharmD PGY-2 Psychiatric Pharmacy Resident Western Missouri Psychiatric Pharmacy Residency Program Kansas City, Missouri
Henry A. Nasrallah, MD Sydney W. Souers Endowed Chair and Professor Department of Neurology and Psychiatry Saint Louis University School of Medicine St. Louis, Missouri
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. http://raiseetp.org.
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.
