The most frequently reported AEs leading to discontinuation were schizophrenia [15 (1.6%) patients], weight increase [8 (0.9%) patients], and psychotic disorder [7 (0.8%) patients].
Olanzapine plasma concentrations
Steady-state olanzapine LAI plasma concentrations remained consistent over time, with no evidence of continuing accumulation over the course of 6 years of treatment (Fig. 2). The median dose-normalized olanzapine plasma concentration was 2.25 (ng/ml)/(mg/day), with a 10th–90th percentile range of 1.01–4.26 (ng/ml)/(mg/day).
Table 4 shows TEAEs reported by at least 5% of the patients. Overall, 670 (72.0%) patients reported at least one TEAE during the study. The five most commonly reported TEAEs were increased weight, anxiety, insomnia, somnolence, and nasopharyngitis. A total of 170 (18.3%) patients reported at least one SAE. The most frequently reported SAEs were schizophrenia (n=35), psychotic disorder (n=20), sedation (n=12), suicidal ideation (n=8), agitation (n=6), anxiety (n=6), depression (n=5), paranoia (n=5), and somnolence (n=5).
There were 11 deaths (Table 3), including one suicide, reported during the study. Of the 11 deaths, 10 were considered by the investigators to be unrelated to treatment with the study drug or to protocol procedures, and one patient’s death from myocardial infarction was considered to be possibly related to the study drug. The other causes of death were alcoholic cardiomyopathy, myocardial ischemia, mesenteric ischemia and septic shock, trauma as a result of a road traffic accident, pneumonia, leptospirosis, hypertrophic cardiomyopathy, renal cell carcinoma, and essential hypertension.
Overall, the incidence of injection-site AEs was low, reported in 36 (3.9%) patients. The most frequently reported injection-site AE was injection-site pain, reported in 18 (1.9%) patients. All other AEs were reported in less than 1% of patients.
During the course of the study, 36 PDSS events occurred in 35 patients; one patient experienced two events. These patients experienced temporary symptoms of delirium and/or excessive sedation following possible inadvertent intravascular injection of a portion of the dose of olanzapine LAI. Clinical presentation varied but was consistent with symptoms reported in cases of oral olanzapine overdose. There were no fatalities, and all patients recovered within 72 h of receiving the injection. Of the patients who experienced PDSS events, 25 (71.4%) continued to receive further injections of olanzapine LAI. In this study, PDSS events occurred in ∼0.08% of olanzapine LAI injections administered.
Mean changes in metabolic and hepatic laboratory analyte levels and prolactin levels are presented in Table 5. Overall, mean changes in these and all other laboratory analyte levels were small and not clinically significant. However, a number of patients experienced treatment-emergent abnormal changes. A total of 22.6% (n=97, N=430) of patients showed high prolactin levels (>1050.2 pmol/l for female patients; >814.6 pmol/l for male patients). Treatment-emergent significant changes from normal to high (≥6.993 mmol/l) fasting glucose levels were seen in 3.6% of patients, and changes from normal to impaired (≥5.55 and <6.993 mmol/l) glucose levels were seen in 29.7% of patients. For total cholesterol, 3.3% of patients showed changes from normal to high levels (≥6.21 mmol/l) and 21.2% from normal to borderline levels (≥5.17 and <6.21 mmol/l). For triglycerides, 16.1% of patients showed changes from normal to borderline levels (≥1.69 and <2.26 mmol/l), 9.3% showed changes from normal to high levels (≥2.26 mmol/l), and 0.4% showed changes from normal to extremely high levels (≥5.65 mmol/l).
Vital signs, weight, and electrocardiograms
Small, clinically insignificant mean changes were observed in vital signs (blood pressure, pulse, and temperature). A total of 83 (10.3%) patients experienced orthostatic hypotension [≥30 mmHg decrease in systolic blood pressure (supine to standing) during the study]. Other categorical changes in vital signs were assessed as not clinically significant. The baseline-to-endpoint mean change in weight was 2.10 kg (SD=7.81, P<0.001). During the study, 373 patients (40.6%) experienced an increase of at least 7% in baseline body weight, whereas 199 patients (21.7%) experienced a decrease of at least 7% in baseline body weight.
There was a small mean increase in the QT interval when corrected using the Fridericia method (QTcF), but this increase was not clinically significant (1.26 ms, P=0.022). Few patients experienced QTcF increases that were 60 ms or higher (<1%), and there were no clinically significant cardiac events observed with these changes.
Mean changes in the individual extrapyramidal scales were small [SAS: −0.15 (SD=1.53, P=0.005); BAS: 0.0 (SD=0.48, P=0.832); AIMS: −0.08 (SD=1.52, P=0.127)]. The percentage of patients with treatment-emergent parkinsonism was 8.1% at anytime during the study (2.6% at endpoint), with akathisia was 4.0% at anytime (1.5% at endpoint), and with dyskinesia was 3.3% at anytime (2% at endpoint). Two patients discontinued treatment after development of tardive dyskinesia, one patient discontinued because of symptoms of moderate dyskinesia, and one patient discontinued because of mild EPS. There were no reported cases of neuroleptic malignant syndrome.
Patients on average were ‘mildly ill’ (Leucht et al., 2005) at study entry with a mean PANSS total score of 54.54 (SD=17.69) and a CGI-S total score of 2.92 (SE=0.03). The baseline-to-endpoint mean change in PANSS total score was 0.30 (SD=16.4, P=0.590); the PANSS negative score was −0.08 (SD=5.14, P=0.637); the PANSS positive score was 0.21 (SD=4.69, P=0.190); and the PANSS general psychopathology total score was 0.19 (SD=8.51, P=0.510). A review of the individual item scores on the PANSS scale showed small mean changes from baseline to endpoint. There were statistically significant baseline-to-endpoint decreases for active social avoidance (−0.11, SD=1.08, P=0.003) and mannerisms and posturing (−0.09, SD=0.78, P<0.001), and baseline-to-endpoint increases for poor impulse control (0.11, SD=0.90, P<0.001) and suspiciousness (0.08, SD=1.10, P=0.038). There were small mean improvements in the CGI-S score over the duration of the study (mean change −0.17, from baseline to LOCF endpoint). These improvements were significant (P≤0.001) starting at week 3 and for all subsequent measured time points (Fig. 3).
Health outcomes/quality of life
The PSMQ was analyzed at endpoint for all patients. Overall, the majority of patients responding to this medication satisfaction questionnaire (N=931) indicated favorable responses for olanzapine LAI compared with previous oral therapy. For the current use of depot medication, 73.2% (n=629) of patients were either somewhat or very satisfied. For preference of olanzapine LAI versus previous oral medications, 66.8% (n=575) of patients preferred or much preferred olanzapine LAI. For side effects with olanzapine LAI versus previous oral therapy, 73.3% (n=630) of patients thought olanzapine LAI use resulted in less or much less side effects.
During the study period, 255 patients (27.4%) were hospitalized, with the majority of hospital days attributed to psychiatric care (13.01 days/patient-year) rather than to regular care (0.87 days/patient-year) or intensive care unit care (0.05 days/patient-year).
This 6-year open-label study represents the longest clinical trial to evaluate the safety and efficacy of olanzapine LAI in patients with schizophrenia, as well as in a small number of patients with schizoaffective disorder. The safety profile of olanzapine LAI was generally consistent with the known safety profile of oral olanzapine (Kantrowitz and Citrome, 2008), except for the incidence of injection-site-related AEs and PDSS events. The mean weight gain was 2.10 kg, which was statistically significant, and more than one-third of patients experienced potentially clinically significant weight gain (≥7% baseline body weight). Treatment-emergent significant changes in the levels of glucose, lipids, prolactin, and hepatic enzymes, as well as in other laboratory values and ECG readings, were consistent with the known safety profile of the olanzapine molecule. The rate of treatment-emergent parkinsonism, akathisia, and dyskinesia reported at anytime during the study is higher than that previously reported by a 6-month study (Beasley Jr et al., 2003) on oral olanzapine (0.9, 1.8, and 0.5%, respectively). However, this difference is more than likely due to the much longer term exposure seen in this study. The endpoint values for the same measures are lower than and similar to those previously reported on treatment with oral olanzapine. Only four patients discontinued the study because of possible EPS-related events. Pharmacokinetic analyses revealed no indication of systemic accumulation of olanzapine after 6 years of treatment, and the olanzapine concentrations delivered by the LAI formulation were within the expected therapeutic range that would be seen for patients treated with oral olanzapine (Bergstrom et al., 2000; Perry et al., 2001; Citrome et al., 2009).
The injection-site-related AEs occurred at a similar rate to those seen with other intramuscular injection products (Hamann et al., 1990; Jones et al., 1998). The PDSS events are thought to be related to the inadvertent intravascular injection of a portion of the olanzapine dose, resulting in symptoms consistent with an olanzapine overdose (Detke et al., 2010; McDonnell et al., 2010). A review of PDSS events reported that events occurred after 0.07% of injections (Detke et al., 2010). In the current study, PDSS events occurred after 0.08% of injections. All patients recovered from the events within 72 h. The majority of patients continued treatment with olanzapine LAI after experiencing their respective PDSS events. A regression analysis of pooled olanzapine LAI studies (Detke et al., 2010) indicated that lower body mass index (BMI) and/or higher age could increase the risk of a PDSS event. However, these events have occurred in patients at many different ages and BMIs, and thus the recommendation is that a PDSS event can potentially occur at any injection in any patient, suggesting the need to monitor all patients (regardless of risk factors) for its possible occurrence.
The efficacy analyses were carried out to evaluate maintenance of the treatment effect from previous studies. Although efficacy cannot be established in an open-label study, olanzapine LAI appeared to show sustained effectiveness in maintaining clinical stability for the duration of the study. Patients were, on average, mildly ill at study entry, and changes in PANSS total and subscale scores and CGI-S scores remained small throughout the study, indicating that patients, in general, were able to maintain their status.
For patients with schizophrenia, treatment with antipsychotics is typically necessary for the long term, but persistence on treatment is often poor, resulting in frequent relapses with potentially serious consequences (Robinson et al., 1999; Weiden et al., 2004). Reports indicate that up to 70% of patients with schizophrenia, in clinical trials, are partially noncompliant with treatment by 2 years (Thieda et al., 2003; Lieberman et al., 2005). In this long-term study, over 40% of patients treated with olanzapine LAI stayed on treatment until study completion, with a mean treatment duration of ∼3 years and the longest duration of ∼6 years. Although ideally all patients would remain on treatment, the completion rate is high considering the maximum possible duration of the study. Observational studies in the United States of America, Spain, Australia, and Belgium on risperidone LAI for a duration of 24 months have reported completion rates ranging from 39 to 63% (Lambert et al., 2011). A relatively high retention rate for olanzapine LAI treatment was observed despite the risk of PDSS events, as well as the requirement that all patients be observed at the healthcare facility for 3 h after the injection and be accompanied to their destination after leaving the facility.
Data from the present study also appear to indicate that not only will patients with schizophrenia stay on an injectable antipsychotic regimen for the long term, but that they may actually prefer this method of treatment. There have been perceptions reported in the literature that many patients do not want to take an injectable long-acting antipsychotic medication (Patel et al., 2003; Gray et al., 2009). However, other studies have shown that patients treated with a long-acting medication prefer to remain on that medication (Pereira and Pinto, 1997) or prefer the long-acting medication compared with a previous treatment (Wistedt, 1995). In keeping with those findings, a majority of patients in this study were satisfied with their treatment with olanzapine LAI. The level of satisfaction was similar to that reported by patients treated with oral antipsychotic medications (Gray et al., 2005; Bitter et al., 2010).
The current study includes patients treated for ∼6 years with olanzapine LAI, representing one of the longest long-acting injectable treatment studies of an atypical antipsychotic to date. These results provide data on safety and tolerability for patients on maintenance treatment with olanzapine LAI. The study design attempted to mimic real-world prescribing practices with few restrictions on the use of concomitant medications, including supplementation with oral olanzapine. The oral supplementation seen in this study indicates intermittent and infrequent use. A previous analysis of the interim data from this study indicated that the limited and targeted supplementation of olanzapine LAI with oral olanzapine functioned as a rescue medication, selectively aimed at more severely ill patients at baseline (Ascher-Svanum et al., 2011).
Limitations of this study include the open-label design and lack of comparators, making it difficult to draw conclusions with regard to relative safety and efficacy. Patients who entered this study were from three different feeder studies (acute study, maintenance study, and pharmacokinetic study), which may have led to varied patient characteristics at baseline. Although changes in total PANSS and CGI-S scores were observed to be small in this study, patients who experienced worsening of symptoms may have discontinued from the study before the maximum score was recorded, resulting in changes in these scores being understated. The majority of patients had previously been treated with olanzapine LAI before entering this study. Detection of any potential safety signals unique to the injectable formulation was limited, as oral olanzapine and other concomitant medications were permitted during the study.
In summary, these results provide long-term safety and tolerability information on a long-acting injectable antipsychotic. The safety profile of olanzapine LAI was generally consistent with the known safety profile of oral olanzapine with the exception of the AEs associated with the method of administration (e.g. injection site AEs and PDSS events). Of note, in this long-term study it was found that ∼40% of patients experienced potentially clinically significant weight gain. Efficacy results need to be interpreted cautiously because of the open-label study design. However, patients receiving olanzapine LAI showed very little change in PANSS total scores and CGI-S scores, suggesting that olanzapine LAI was effective in long-term maintenance of treatment effect. Further, pharmacokinetic analyses revealed no indication of long-term systemic accumulation of olanzapine, even after ∼6 years of treatment. Patient satisfaction with the injectable medication was high. Treatment with olanzapine LAI must be weighed against the known risks associated with olanzapine treatment in addition to the risk of PDSS events occurring after ∼0.07% of injections. However, for patients with schizophrenia who tolerate treatment with oral olanzapine but have difficulty adhering to oral treatment, olanzapine LAI represents an important treatment option.
The authors thank the principal investigators and their clinical staff, as well as the patients who generously agreed to participate in this clinical trial. They also thank Jody Arsenault, PhD (inVentiv Health Clinical), for her assistance with drafting the manuscript. In addition, they thank inVentiv Health Clinical for their help with editing and formatting.
This trial was funded by Eli Lilly and Company and/or any of its subsidiaries, Indianapolis, Indiana.
Conflicts of interest
All authors are full-time employees of Eli Lilly and Company and stockholders of Eli Lilly and Company.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders text revision 2000:4th ed..Washington, DC: American Psychiatric Association.
Ascher-Svanum H, Peng X, Montgomery W, Faries DE, Lawson AH, Witte MM, et al.. Assessing the infrequent oral supplementation of olanzapine long-acting injection
in the treatment of schizophrenia. Eur Psychiatry 2011; 26:313–319.
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry 1989; 154:672–676.
Beasley CM Jr, Sutton VK, Hamilton SH, Walker DJ, Dossenbach M, Taylor CC, et al.. Olanzapine Relapse Prevention Study Group. A double-blind, randomized, placebo-controlled trial of olanzapine in the prevention of psychotic relapse. J Clin Psychopharmacol 2003; 23:582–594.
Bergstrom R, Callaghan J, Cerimele J, Kurtz D, Hatcher BTran P, Bymaster F, Tye N, Herra J, Breier A, Tollefson G. Population pharmacokinetics and plasma concentrations of olanzapine. Olanzapine (Zyprexa): a novel antipsychotic 2000.Philadelphia: Lippincott, Williams, and Wilkins;232–252.
Bitter I, Treuer T, Dilbaz N, Oyffe I, Ciorabai EM, Gonzalez SL, et al.. Patients’ preference for olanzapine orodispersible tablet compared with conventional oral tablet in a multinational, randomized, crossover study. World J Biol Psychiatry 2010; 11:894–903.
Citrome L, Stauffer VL, Chen L, Kinon BJ, Kurtz DL, Jacobson JG, et al.. Olanzapine plasma concentrations after treatment with 10, 20, and 40 mg/day in patients with schizophrenia: an analysis of correlations with efficacy, weight gain, and prolactin concentration. J Clin Psychopharmacol 2009; 29:278–283.
Detke HC, McDonnell DP, Brunner E, Zhao F, Sorsaburu S, Stefaniak VJ, et al.. Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection
, I: analysis of cases. BMC Psychiatry 2010; 10:43.
Detke HC, Weiden PJ, Llorca PM, Choukour M, Watson SB, Brunner E, Ascher-Svanum H. Comparison of olanzapine long-acting injection
and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia. J Clin Psychopharmacol 2014[Epub ahead of print].
Gray R, Rofail D, Allen J, Newey T. A survey of patient satisfaction with and subjective experiences of treatment with antipsychotic medication. J Adv Nurs 2005; 52:31–37.
Gray R, Spilling R, Burgess D, Newey T. Antipsychotic long-acting injections in clinical practice: medication management and patient choice. Br J Psychiatry Suppl 2009; 195:S51–S56.
Guy W. ECDEU assessment manual for psychopharmacology, revised 1976.Bethesda, MD: US Department of Health, Education and Welfare.
Hamann GL, Egan TM, Wells BG, Grimmig JE. Injection site reactions after intramuscular administration of haloperidol decanoate 100 mg/ml. J Clin Psychiatry 1990; 51:502–504.
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al.. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatry 2013; 14:2–44.
Hogarty GE, Schooler NR, Ulrich R, Mussare F, Ferro P, Herron E. Fluphenazine and social therapy in the aftercare of schizophrenic patients. Relapse analyses of a two-year controlled study of fluphenazine decanoate and fluphenazine hydrochloride. Arch Gen Psychiatry 1979; 36:1283–1294.
Jones JC, Day JC, Taylor JR, Thomas CS. Investigation of depot neuroleptic injection site reactions. Psychiatric Bull 1998; 22:605–607.
Kalali A. Patient satisfaction with, and acceptability of, atypical antipsychotics. Curr Med Res Opin 1999; 15:135–137.
Kane JM. Review of treatments that can ameliorate nonadherence in patients with schizophrenia. J Clin Psychiatry 2006; 67Suppl 59–14.
Kane JM, Detke HC, Naber D, Sethuraman G, Lin DY, Bergstrom RF, et al.. Olanzapine long-acting injection
: a 24-week, randomized, double-blind trial of maintenance treatment in patients with schizophrenia. Am J Psychiatry 2010; 167:181–189.
Kantrowitz JT, Citrome L. Olanzapine: review of safety 2008. Expert Opin Drug Saf 2008; 7:761–769.
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13:261–276.
Kishimoto T, Robenzadeh A, Leucht C, Leucht S, Watanabe K, Mimura M, et al.. Long-acting injectable vs. oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull 2014; 40:192–213.
Lambert T, Olivares JM, Peuskens J, Desouza C, Kozma CM, Otten P, et al.. Effectiveness of injectable risperidone long-acting therapy for schizophrenia: data from the US Spain, Australia, and Belgium. Ann Gen Psychiatry 2011; 10:10.
Lauriello J, Lambert T, Andersen S, Lin D, Taylor CC, McDonnell D, et al.. An 8-week, double-blind, randomized, placebo-controlled study of olanzapine long-acting injection
in acutely ill patients with schizophrenia. J Clin Psychiatry 2008; 69:790–799.
Leucht C, Heres S, Kane JM, Kissling W, Davis JM, Leucht S. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of randomised long-term trials. Schizophr Res 2011; 127:83–92.
Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR. What does the PANSS mean? Schizophr Res 2005; 79:231–238.
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al.. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209–1223.
Macfadden W, Ma YW, Thomas Haskins J, Bossie CA, Alphs L. A prospective study comparing the long-term effectiveness of injectable risperidone long-acting therapy and oral aripiprazole in patients with schizophrenia. Psychiatry (Edgmont) 2010; 7:23–31.
McDonnell DP, Detke HC, Bergstrom RF, Kothare P, Johnson J, Stickelmeyer M, et al.. Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection
, II: investigations of mechanism. BMC Psychiatry 2010; 10:45.
Patel MX, Nikolaou V, David AS. Psychiatrists’ attitudes to maintenance medication for patients with schizophrenia. Psychol Med 2003; 33:83–89.
Pereira S, Pinto R. A survey of the attitudes of chronic psychiatric patients living in the community toward their medication. Acta Psychiatr Scand 1997; 95:464–468.
Perry PJ, Lund BC, Sanger T, Beasley C. Olanzapine plasma concentrations and clinical response: acute phase results of the North American Olanzapine Trial. J Clin Psychopharmacol 2001; 21:14–20.
Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geisler S, et al.. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder
. Arch Gen Psychiatry 1999; 56:241–247.
Rosenheck RA, Krystal JH, Lew R, Barnett PG, Fiore L, Valley D, et al.. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N Engl J Med 2011; 364:842–851.
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970; 212:11–19.
Thieda P, Beard S, Richter A, Kane J. An economic review of compliance with medication therapy in the treatment of schizophrenia. Psychiatr Serv 2003; 54:508–516.
Weiden PJ, Kozma C, Grogg A, Locklear J. Partial compliance and risk of rehospitalization among California Medicaid patients with schizophrenia. Psychiatr Serv 2004; 55:886–891.
Wistedt B. How does the psychiatric patient feel about depot treatment, compulsion or help? Nord J Psychiatry 1995; 49Suppl 3541–46.
Keywords:© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
antipsychotic agents; delayed-action preparation; long-acting injection; olanzapine pamoate; psychotic disorders; schizoaffective disorder