Olanzapine long-acting injection: When and for how long is oral supplementation required?

To the Editor

The olanzapine long-acting injection (OLAI) was introduced into the Australian market in December 2009. OLAI is a depot, given intramuscularly every two or four weeks, especially in the setting of non-compliance with oral olanzapine. Injectable depot antipsychotics improve compliance and adherence, reduce relapse and decrease rates of rehospitalisation (Vieta et al., 2008). Current guidelines for OLAI recommend 150, 210 or 300 mg every two weeks (corresponding to oral doses of 10, 15 and 20 mg respectively) or 405 mg every four weeks (Eli Lilly and Company, 2011).

The elimination half-life of OLAI is 26 days, as opposed to 29 h in the oral formulation (Frampton, 2010). The advantage of OLAI is the rapid establishment of therapeutic levels after initial depot administration without the need for oral supplementation (Lindenmayer, 2010). However, there are few guidelines to help clinicians negotiate the transition to OLAI in more complex cases. We present a case of oral olanzapine to OLAI depot conversion which required extended oral supplementation, and discuss the practical implications and challenges for clinicians.

Ms J is a 43-year-old woman with a 19-year history of bipolar affective disorder (BAD), which progressed to a rapid-cycling course. Over the last 2 years, Ms J had seven admissions to psychiatric facilities characterised by alternating mixed and manic episodes with psychosis. Several antipsychotic agents (both oral and depot) were trialled, with limited success, in conjunction with lithium carbonate 450 mg/day and sodium valproate 3400 mg/day, which formed part of her stable maintenance regime throughout her admission. A trial with clozapine resulted in intolerable side effects. Past records indicated that olanzapine 30 mg/day with lithium and valproate was clinically effective in supervised settings where compliance was guaranteed, which suggested Ms J might be a good candidate for OLAI. Ms J was initiated on 300 mg OLAI every two weeks, monitoring peak and trough serum levels on days 5 and 14 post-administration.

Ms J’s BAD briefly stabilised on OLAI, but she experienced breakthrough manic symptoms after 13 days. Peak serum olanzapine was 14 μg/ml (therapeutic range 20–50 μg/ml) resulting in oral olanzapine supplementation at 10 mg/day to settle her manic symptoms. Despite increasing OLAI to 405 mg every two weeks, Ms J’s clinical stability fluctuated. Ongoing serum olanzapine levels were frequently sub-therapeutic without oral supplementation, but therapeutic levels were maintained with OLAI (ranging between 25 and 51 μg/ml) with oral olanzapine supplementation at 10 mg/day.

During a period of oral olanzapine refusal while on OLAI 405 mg every two weeks, at week 10, peak serum olanzapine was 15 μg/ml indicating steady state had not been achieved. After 12 weeks, steady state without oral supplementation was reached (serum level 25 μg/ml). Ms J’s BAD remained in remission with her extended hospitalisation on OLAI 405 mg every two weeks with lithium and valproate at previous doses. OLAI therapy was ceased after several months due to considerable weight gain in the context of morbid obesity, sleep apnoea and diabetes mellitus.

Ascher-Svanum et al. (2011) found that supplemental oral olanzapine with OLAI was necessary for 8–12 weeks in 21% of 931 patients in clinical settings. Supplementation was required most frequently in the severely ill as a rescue therapy until steady state was attained. An alternate study suggested OLAI initiation without oral supplementation would suffice, however, patients selected for this study were stable on oral olanzapine without adherence problems (Kane et al., 2009). Ms J was a complex case, resembling patients in the study by Ascher-Svanum and colleagues (2011) necessitating prolonged oral supplementation.

This case exemplified the potential challenges in clinical practice when starting OLAI depot. The required dosage, frequency of administration and the need for oral supplementation and for how long, must be weighed up in each individual case based on clinical complexity. Illness factors, age, sex, smoking status and genotypic variation in genetic polymorphisms have been documented as affecting antipsychotic metabolism, distribution and elimination (Frampton, 2010).

The case we have described indicates that OLAI 405 mg every two weeks, although not generally recommended, can be safely administered and tolerated. It also highlights the importance of a conservative approach with oral supplementation until steady state is achieved, especially in patients with an unstable illness course. Serum olanzapine levels should be used to guide clinicians as to when to cease oral supplementation. This being a single case study with inherent limitations, we recommend that OLAI 405 mg administered every two weeks should only be given under close clinical supervision with serum level monitoring, as was possible in Ms J’s case. In light of two unexpected deaths of unidentified cause in patients on OLAI therapy to date, a cautious approach is presently recommended when initiating OLAI. Additional research in clinical settings with challenging cases like Ms J’s may shed further light on how best to proceed in the future with OLAI depot.