Holland C. Detke

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases

BackgroundAn advance in the treatment of schizophrenia is the development of long-acting intramuscular formulations of antipsychotics, such as olanzapine long-acting injection (LAI). During clinical trials, a post-injection syndrome characterized by signs of delirium and/or excessive sedation was identified in a small percentage of patients following injection with olanzapine LAI.MethodsSafety data from all completed and ongoing trials of olanzapine LAI were reviewed for possible cases of this post-injection syndrome. Descriptive analyses were conducted to characterize incidence, clinical presentation, and outcome. Regression analyses were conducted to assess possible risk factors.ResultsBased on approximately 45,000 olanzapine LAI injections given to 2054 patients in clinical trials through 14 October 2008, post-injection delirium/sedation syndrome occurred in approximately 0.07% of injections or 1.4% of patients (30 cases in 29 patients). Symptomatology was consistent with olanzapine overdose (e.g., sedation, confusion, slurred speech, altered gait, or unconsciousness). However, no clinically significant decreases in vital signs were observed. Symptom onset ranged from immediate to 3 to 5 hours post injection, with a median onset time of 25 minutes post injection. All patients recovered within 1.5 to 72 hours, and the majority continued to receive further olanzapine LAI injections following the event. No clear risk factors were identified.ConclusionsPost-injection delirium/sedation syndrome can be readily identified based on symptom presentation, progression, and temporal relationship to the injection, and is consistent with olanzapine overdose following probable accidental intravascular injection of a portion of the olanzapine LAI dose. Although there is no specific antidote for olanzapine overdose, patients can be treated symptomatically as needed. Special precautions include use of proper injection technique and a post-injection observation period.Trial RegistrationClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Olanzapine for the treatment of borderline personality disorder: variable dose 12-week randomised double-blind placebo-controlled study

BACKGROUND Despite the prevalence and clinical significance of borderline personality disorder, its treatment remains understudied. AIMS To evaluate treatment with variably dosed olanzapine in individuals with borderline personality disorder. METHOD In this 12-week randomised, double-blind trial, individuals received olanzapine (2.5-20 mg/day; n=155) or placebo (n=159) (trial registry: NCT00091650). The primary efficacy measure was baseline to end-point change on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) using last-observation-carried-forward methodology. RESULTS Both olanzapine and placebo groups showed significant improvements but did not differ in magnitude at end-point (-6.56 v. -6.25, P=0.661). Response rates (50% reduction in ZAN-BPD) were 64.7% with olanzapine and 53.5% with placebo (P=0.062); however, time to response was significantly shorter for olanzapine (P=0.022). Weight gain was significantly greater (2.86 v. -0.35 kg, P<0.001), with higher incidence of treatment-emergent abnormal high levels of prolactin for the olanzapine group. CONCLUSIONS Individuals treated with olanzapine and placebo showed significant but not statistically different improvements on overall symptoms of borderline personality disorder. The types of adverse events observed with olanzapine treatment appeared similar to those observed previously in adult populations.

A Dose Comparison of Olanzapine for the Treatment of Borderline Personality Disorder: A 12-Week Randomized, Double-Blind, Placebo-Controlled Study

OBJECTIVE To examine the efficacy and safety of olanzapine at low and moderate doses for the treatment of borderline personality disorder. METHOD In this 12-week randomized double-blind placebo-controlled trial, 451 outpatients aged 18-65 years with DSM-IV borderline personality disorder received olanzapine 2.5 mg/d (n = 150), olanzapine 5-10 mg/d (n = 148), or placebo (n = 153). The trial was conducted from February 2004 through January 2006 at 59 community-based and academic study centers in 9 countries (United States, Italy, Poland, Romania, Turkey, Chile, Peru, Argentina, and Venezuela). The primary efficacy measure was mean change from baseline to last-observation-carried-forward endpoint on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) total score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Modified Overt Aggression Scale, the Global Assessment of Functioning, the Symptom Checklist-90-Revised, and the Sheehan Disability Scale. RESULTS An overall mean baseline ZAN-BPD total score of 17.2 (SD = 4.9) indicated moderate symptom severity. Only treatment with olanzapine 5-10 mg/d was associated with significantly greater mean change from baseline to endpoint in ZAN-BPD total score relative to placebo (-8.5 vs -6.8, respectively; P = .010; effect size = 0.29; 95% CI, 0.06-0.52). Response rates (response indicated by ≥ 50% decrease from baseline in ZAN-BPD total score) were significantly higher for olanzapine 5-10 mg/d (73.6%) versus olanzapine 2.5 mg/d (60.1%; P = .018) and versus placebo (57.8%; P = .006). Time to response was also significantly shorter for patients taking olanzapine 5-10 mg/d than for placebo-treated patients (P = .028). Treatment-emergent adverse events reported significantly more frequently among olanzapine-treated patients included somnolence, fatigue, increased appetite, and weight increase (all P values < .05). Mean weight change from baseline to endpoint was significantly greater for olanzapine-treated than for placebo-treated patients (olanzapine 2.5 mg/d: 2.09 kg; olanzapine 5-10 mg/d: 3.17 kg; placebo: 0.02 kg; P < .001). The overall completion rate for the 12-week double-blind treatment period was 65.2% (ie, 64.7% for olanzapine 2.5 mg/d, 69.6% for olanzapine 5-10 mg/d, and 61.4% for placebo). CONCLUSIONS Olanzapine 5-10 mg/d showed a clinically modest advantage over placebo in the treatment of overall borderline psychopathology. This advantage in effectiveness should be weighed against the risk of adverse events (particularly weight gain), which were consistent with the known safety profile of olanzapine. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00088036.

Dose correspondence between olanzapine long-acting injection and oral olanzapine: recommendations for switching.

Oral-to-depot dose correspondence was explored in a 24-week study of olanzapine long-acting injection (LAI). Patients with schizophrenia stabilized on oral olanzapine of 10, 15, or 20 mg/day (n=1065) were randomized to continue their oral treatment or switch directly to a fixed dose of olanzapine LAI [(mg/weeks) 45/4, 150/2, 405/4, or 300/2] without oral supplementation. Six-month relapse rates for each LAI-dose group stratified by earlier oral dose were analyzed using a Cox proportional hazard model assessing risk of relapse relative to each oral dose. Relapse rates for the therapeutic LAI doses (≥150 mg) varied depending on earlier oral dose, ranging from 1.5% (patients switched from 10 mg/day to 300 mg/2 weeks) to 18.8% (patients switched from 20 mg/day to 150 mg/2 weeks). Switching from 10 mg/day to 405 mg/4 weeks produced a comparable risk of relapse as remaining on that oral dose [Hazard ratio (HR)=1.03]. Switching from 15 or 20 mg/day to 300 mg/2 weeks produced comparable risk of relapse as remaining on those oral doses (HR=0.68 and 1.13, respectively). Pharmacokinetic modeling was conducted to evaluate the resulting dosing recommendations. Findings suggest that patients can be switched directly from oral to olanzapine LAI without the need for oral supplementation and with a low risk of relapse when initiated on an appropriate LAI dose.

Long-Term Safety and Tolerability of Open-Label Olanzapine Long-Acting Injection in the Treatment of Schizophrenia: 190-Week Interim Results

The primary objective of this ongoing study is to examine the long-term safety and tolerability of olanzapine long-acting injection (LAI). Current results are from a 190-week interim analysis. Patients were 18–75 years of age with schizophrenia (N = 909) or schizoaffective disorder (N = 22) previously enrolled in 1 of 3 randomized clinical trials of olanzapine LAI. In this open-label extension study, all patients received flexibly-dosed olanzapine LAI every 2–4 weeks. At time of analysis, rate of study discontinuation was 46.3%. The 18-month discontinuation rate was 34.2%. Adverse events in ≥5% of patients were increased weight, insomnia, anxiety somnolence, headache, and nasopharyngitis. There were 26 occurrences of post-injection delirium/sedation syndrome which all fully resolved within 72 hours. Mean weight change was +1.81 kg, with 32.1% of patients experiencing ≥7% weight gain. Mean Clinical Global Impressions-Severity scores remained stable throughout (2.9 at baseline to 2.8 at endpoint). Pharmacokinetic analyses indicated consistent olanzapine plasma concentrations over time, with no evidence of long-term accumulation. Safety profile was consistent with that of oral olanzapine, with the exception of findings specific to intramuscular injection. During the study period, there were 16 (1.7%) occurrences of treatment-emergent diabetes and 1 occurrence of treatment-emergent diabetic ketoacidosis. Percentages of patients with EPS scale-defined treatment-emergent akathisia, parkinsonism, and dyskinesia were 3.3%, 6.6%, and 3.0%, respectively.

Comparison of olanzapine long-acting injection and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia.

Abstract We compared long-term treatment effectiveness of monthly olanzapine long-acting injection (LAI) with that of oral olanzapine. Outpatients with 2 or more episodes of psychotic worsening in the past 24 months with Positive and Negative Syndrome Scale total score of lower than 70 were randomized to 405 mg/4 weeks of olanzapine LAI (n = 264) or 10 mg/d of oral olanzapine (n = 260) for 2 years of open-label treatment. Dosing thereafter was flexible (150-405 mg/4 weeks of LAI vs 5-20 mg/d of oral). Primary outcome was time to all-cause discontinuation. At baseline, patients were clinically stable (mean Positive and Negative Syndrome Scale total score of 57). Seventeen percent of patients had been psychiatrically hospitalized in the previous 6 months, and 4.6% were rated nonadherent in the month before study entry. The groups did not differ significantly in median time to all-cause discontinuation (645 days for LAI, 678 days for oral; P = 0.61), discontinuation rate (53.8% for LAI, 51.2% for oral; P = 0.60), or relapse rate (20.1% for LAI, 18.5% for oral; P = 0.66). Postbaseline psychiatric hospitalization rate was low for both groups (7.6% for LAI, 9.2% for oral), but mean hospitalization duration was significantly longer for oral patients (1.80 days [20 for those hospitalized] vs 0.43 days [6 for those hospitalized], P = 0.02). There were no clinically significant group differences in adverse events or safety measures. No post-injection delirium/sedation syndrome events occurred. In conclusion, olanzapine LAI and oral olanzapine were similarly effective and well tolerated for up to 2 years of treatment in patients with schizophrenia. Treatment discontinuation for olanzapine LAI was similar to that of oral olanzapine, despite the 3-hour post-injection observation period and other precautionary procedures related to risk of post-injection delirium/sedation syndrome.

Long-term safety and efficacy of olanzapine long-acting injection in patients with schizophrenia or schizoaffective disorder: a 6-year, multinational, single-arm, open-label study.

The objective of this study was to assess the long-term safety and efficacy of olanzapine long-acting injection (LAI). A 6-year, single-arm, open-label extension study of olanzapine LAI was conducted at 127 sites in 25 countries. Patients were 18–76 years of age, were diagnosed with schizophrenia or schizoaffective disorder (N=931), and had been previously enrolled in one of three clinical trials of olanzapine LAI. Patients received flexibly dosed (45-405 mg) olanzapine LAI every 2–4 weeks. The mean duration of exposure was ∼3 years. A total of 393 (42.2%) patients completed the study. The mean weight change was +2.1 kg (P<0.001), with 40.6% of patients experiencing 7% or higher weight gain. Treatment-emergent categorical changes occurred in fasting glucose, total cholesterol, and triglyceride levels. Pharmacokinetic analyses revealed no systemic accumulation of olanzapine after long-term treatment. There were 36 occurrences of post-injection delirium/sedation syndrome, all resolving within 72 h. The mean Positive and Negative Syndrome Scale total and subscale scores did not change significantly over the course of the study, indicating clinical stability. Olanzapine LAI appeared effective as a long-term maintenance treatment, with a safety profile generally consistent with the known profile of oral olanzapine, except for injection-related events (including post-injection delirium/sedation syndrome).

Comparison of metabolic changes in patients with schizophrenia during randomized treatment with intramuscular olanzapine long-acting injection versus oral olanzapine.

Metabolic changes were examined in patients with schizophrenia during treatment with either oral olanzapine or olanzapine long‐acting injection (LAI). Data were collected from patients who had been stabilized on oral olanzapine (10, 15, or 20 mg/day) for ≥4 weeks and then randomized to either continued olanzapine oral treatment (n = 322) or LAI (n = 599; 150 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) for up to 24 weeks. Mean and categorical changes in metabolic parameters were analyzed. Mean changes in weight, glucose, and most lipids were generally not significantly different between treatment groups. Weight changes over time followed similar patterns and were not significantly different at endpoint between the two treatment‐formulation groups. Low‐density lipoprotein cholesterol decreased significantly less among olanzapine LAI‐treated patients. Percentages of patients with potentially clinically significant changes in blood glucose and lipid concentrations were similar for the two treatments. Percentages of patients experiencing adverse events related to weight, diabetes, or dyslipidemia were also not significantly different between treatments. Metabolic changes in patients with schizophrenia appeared generally similar during treatment with oral olanzapine or olanzapine LAI. Copyright

Olanzapine long-acting injection: a review of first experiences of post-injection delirium/sedation syndrome in routine clinical practice

BackgroundOlanzapine long-acting injection (LAI) for the treatment of schizophrenia was associated with a cluster of symptoms termed post-injection delirium/sedation syndrome (PDSS) in a small percentage (~2%) of patients during clinical trials. The objective of this analysis was to evaluate the rate and clinical characteristics of PDSS since olanzapine LAI entered commercial use.MethodsCases of PDSS were identified from all reported adverse events during worldwide commercial use of olanzapine LAI through to 1 March 2014. Data sources included two ongoing post-marketing safety studies as well as spontaneously reported adverse events from routine clinical practice over a 5-year period (1 March 2009 to 1 March 2014).ResultsA total of 338 PDSS events were identified. Of these, 91% occurred within 1 hour of injection, and 52% of these occurred within 15 minutes. None of the PDSS events in this analysis were fatal, and most resolved within 72 hours. The most common symptoms (occurring in >30% of cases) were sedation (61%), confusion (56%), dysarthria (54%), somnolence (46%), dizziness (45%) and disorientation (35%). Overall, PDSS occurred with approximately 0.07% of injections and in 0.46–1.03% of patients (reporting and incidence rates from spontaneous reports and post-marketing safety studies, respectively).ConclusionsThe PDSS events reported during routine clinical use of olanzapine LAI are generally similar in incidence and presentation to those reported in clinical trials. Caution should be applied when interpreting spontaneously reported rates of adverse events, however, due to potential under-reporting. Implemented risk-minimisation activities may contribute substantially to the identification and appropriate management of patients with PDSS in clinical practice.

Open-label treatment with olanzapine for patients with borderline personality disorder.

Abstract This report presents efficacy and safety outcomes for patients with borderline personality disorder (BPD) treated with olanzapine for up to 24 weeks. In 2 concurrent studies, patients received open-label olanzapine for 12 weeks after 12 weeks of double-blind olanzapine or placebo. Open-label dosing started at 2.5 or 5 mg/d and could be increased up to 20 mg/d (study 1) or 15 mg/d (study 2). The primary efficacy measure was open-label baseline–to–endpoint change in Zanarini Rating Scale for BPD (ZAN-BPD) total score. Of 472 patients who completed the double-blind acute phase, 444 entered and 320 (72.1%) completed 12 weeks of open-label extension treatment. Mean ZAN-BPD total scores at the start of the acute phase were approximately 17, indicating moderate symptom severity. Mean ZAN-BPD total scores ranged from 7.8 to 10.5 at the start of the open-label treatment and decreased to 5.7 to 6.5, indicating mild symptom severity, by the end of the open-label treatment. Patients taking placebo during the acute phase showed increases in weight, prolactin level, and other laboratory values during open-label olanzapine treatment similar in magnitude to increases seen in olanzapine-treated patients during the acute phase. Patients proceeding from olanzapine during the acute phase to open-label olanzapine showed smaller changes in weight and laboratory values. In conclusion, these results suggest that continued therapy with olanzapine may sustain and build upon improvements seen with acute olanzapine treatment of patients with BPD. However, no medication is currently approved for treatment of BPD, and physicians should carefully weigh potential benefits and risks of antipsychotic treatment in this population.