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

Barriers to LAIA use include:
• slow dosage titration and increased time to reach steady state drug level
• oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
• logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
• additional planning to coordinate care for scheduled injections
• higher expenses up front
• local injection site reactions
• dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
• limited availability of SGA depot formu­lations (4, to date, in the United States)
• frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
• skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
• guidelines do not explicitly recommend depot treatment in FEP
• treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
• improved symptom control^{38,40-43,46,48}
• adherence^43,44,48
• reduced relapse rates^37,43 and rehospitalizations^37,47
• lesser reductions in white matter brain volume⁴⁵
• no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Discussion and recommendations. Psychiatrists relying on subjective mea­sures of antipsychotic adherence may inac­curately assess whether patients meet this criterion for LAIA use.⁵³ LAIA could com­bat the high relapse rate in FEP, yet depot antipsychotics are prescribed infrequently for FEP patients (eg, for only 9.5% of par­ticipants in the RAISE-ETP study).²⁰ Most schizophrenia treatment guidelines do not discuss LAIA use specifically in FEP, although the AFPBN expert consensus guidelines published in 2013 do recom­mend SGA depot formulations in FEP.¹² SGA LAIA may be preferable, given its neuroprotective effects, in contrast to the neurotoxicity concerns of FGA LAIA.^54,55

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.