This cross-study, post-hoc analysis indicates that patients with acutely exacerbated schizophrenia treated with olanzapine LAI dosages of 405 mg/4 weeks, 210 mg/2 weeks, and 300 mg/2 weeks had a similar magnitude of symptom reduction as patients treated with 10 ± 2.5 mg/day and 15 ± 2.5 mg/day of oral olanzapine and 15 ± 5 mg/day of oral haloperidol during 6 weeks of acute treatment. Using historical clinical data for oral olanzapine provided a helpful framework for understanding the relative efficacy and tolerability of the long-acting formulation of olanzapine.
Importantly, the 4 studies presented in this analysis were not conducted concurrently, and cross-study comparisons should be interpreted with caution. Therefore, effect size calculations were performed to allow a standardized comparison among the 4 studies. In general, an effect size above 0.5 standard deviations is considered “large” . Comparison of effect sizes among the 4 studies suggests that the magnitude of symptom reduction seen with the 3 doses of olanzapine LAI was “large” and generally similar to that of approximately 10 to 15 mg/day oral olanzapine or 15 mg/day oral haloperidol. The evaluation of assessment scores and relative effect sizes in this analysis demonstrate that despite clinical and research changes over the years, the response to treatment with olanzapine LAI as measured against placebo was comparable to results from earlier oral olanzapine clinical trials against placebo.
Onset of efficacy
The post-hoc exploration of early onset of action based on mean change in symptoms measured by the BPRS or PANSS total scales in each study suggests that speed of onset with olanzapine LAI may be at least as rapid as that of therapeutic doses of oral olanzapine and oral haloperidol. Patients in all 3 treatment groups in the olanzapine LAI study achieved statistically significant reduction in symptoms within 1 week of receiving their first injection, which was comparable to or better than results observed for oral olanzapine in studies 1, 2, and 3. Of note in the olanzapine LAI study, the clinical trial protocol did not allow supplementation with any oral antipsychotic medication, including oral olanzapine. The ability to begin to realize improvement of acute symptoms following the first injection, without the need for additional oral antipsychotic medication for symptom control during the initial weeks or months of treatment, may simplify the treatment plans for patients with acute symptoms.
Olanzapine plasma concentrations
Pharmacokinetic evaluation indicated that olanzapine plasma concentrations were in the therapeutic range as early as day 3 for the LAI study. Moreover, endpoint concentrations were generally similar across the 4 studies. These findings are consistent with the clinical observations. Interestingly, while all LAI patients had endpoint concentrations within the therapeutic range, some oral patients had concentrations below that range, suggesting that some oral patients may have failed to take their dose.
Safety and tolerability
Weight gain is very commonly reported during treatment with some atypical antipsychotics such as olanzapine. In this analysis weight gain was most similar between olanzapine LAI and oral olanzapine in oral study 1, with patients gaining a mean of 3.5 to 4 kg on the higher doses of olanzapine. Patients treated with olanzapine LAI or therapeutic doses of oral olanzapine gained significantly more weight than did those treated with haloperidol or placebo. A significantly greater percentage of patients treated with olanzapine LAI or therapeutic doses of oral olanzapine gained clinically significant amounts of weight than did those treated with haloperidol or placebo. Although these were all short-term studies, it is important to note that changes in metabolic parameters have also been reported during long-term treatment with olanzapine [21, 22]. Therefore, the potential consequences of weight gain should be considered prior to starting olanzapine treatment. Patients receiving olanzapine should have their weight monitored regularly.
With respect to the development of extrapyramidal symptoms, a significantly greater percentage of patients treated with haloperidol experienced treatment-emergent Parkinsonism or akathisia compared with those treated with olanzapine LAI, oral olanzapine, or placebo. The observed differences between the olanzapine LAI study and the oral studies may be due in part to historical context. At the time that the oral studies were conducted, patients were more likely to have been treated with typical antipsychotics previously, which may have influenced rates of extrapyramidal symptoms in the study despite the washout period. Also, rater expectations regarding extrapyramidal symptoms may have been different at that time, and inclusion of a haloperidol arm may have also biased rater expectations regarding extrapyramidal symptoms.
Post-injection delirium/sedation syndrome (PDSS)
Although no cases of PDSS occurred during the acute olanzapine LAI study, it is important to note that this is a risk for this depot formulation. During other olanzapine LAI clinical trials, adverse events related to delirium and/or excessive sedation (including coma) were identified in a small percentage of patients following injection. These events have been reported following <0.1% of injections of olanzapine LAI in <2% of patients . Because of the risk of PDSS, safety precautions—including a post-injection observation period— must occur at the time of each injection. Clinicians should consider these factors when weighing the overall risks and benefits of olanzapine LAI for each patient.
Study discontinuation rates
The low discontinuation rates in the olanzapine LAI study are encouraging considering that discontinuation rates are high in clinical studies of treatments for schizophrenia, but it is important to recognize that discontinuation rates in actual clinical use remain to be determined. Patients who have difficulty adhering to medication schedules are usually not participants in controlled clinical studies [24–26]. Additionally, these studies employed both inpatient and outpatient treatment settings which may have influenced the overall study discontinuation rates. Nevertheless, the present findings suggest possible improvement in treatment persistence for patients who receive a long-acting injection.
These findings are based on 4 separate studies, each analyzed separately, with a span of approximately 10 years between the oral olanzapine studies and the olanzapine LAI study. While effect size calculations help assess the magnitude of efficacy changes and comparison across baselines show similarities of symptoms, there are differences that must be considered when evaluating this information. Patient populations in these studies may have been different, particularly in their previous exposure to medications. Treatment paradigms at the time of the oral studies in the early 1990s were based on the use of first generation antipsychotic medications while current treatment includes the frequent use of second generation antipsychotic agents. It should also be noted that although the present analyses did not exclude any studies meeting our selection criteria, all studies were conducted by Lilly and did not include studies conducted by other sponsors.
It should also be noted that the present analyses are limited in their ability to provide comparisons of specific doses between oral and olanzapine LAI because of the differing length of time needed to reach steady state plasma concentrations for each olanzapine formulation. Olanzapine LAI does not reach steady-state concentrations of olanzapine for at least 3 months, while oral olanzapine should reach steady state levels within the first week of exposure. Therefore, the LAI results seen in the 6-week period examined in this work represent pre-steady state olanzapine levels, which are slightly lower than the levels which will ultimately be achieved over a longer period of time. For instance, while the 405 mg/4 week dose may ultimately correspond to a 15 mg/day oral dose, the short-term results presented here indicate that this dose may provide olanzapine concentrations more similar to a 10 mg/day dose in the first 8 weeks of treatment. This is consistent with the pharmacokinetic and clinical findings from a previous study . An additional consideration is that oral olanzapine studies 1 and 2 allowed semi-flexible dosing of the olanzapine target dose by ±2.5 mg/day while the olanzapine LAI study used strictly fixed doses and prohibited any oral antipsychotic supplementation.
An additional limitation is that only 2 of the 3 oral studies were placebo-controlled, and the 1-mg oral olanzapine reference dose did not perform like placebo with respect to safety measures and some small differences in treatment response. Therefore effect sizes vs. the 1-mg arm are not comparable with effect sizes vs. placebo.