Elena Perrin

Tolerability of outpatient antipsychotic treatment: 36-month results from the European Schizophrenia Outpatient Health Outcomes (SOHO) study

SOHO is a 3-year, prospective, observational study of schizophrenia patients who started a new antipsychotic in 10 European countries. Cohorts of patients were defined according to the antipsychotic started at baseline: olanzapine, risperidone, quetiapine, amisulpride, clozapine, oral typical and depot typical antipsychotics. Tolerability in terms of rates of extrapyramidal symptoms (EPS), tardive dyskinesia (TD), anticholinergic use, loss of libido/impotence, amenorrhoea/galactorrhoea/gynaecomastia, and weight change was assessed in 4939 patients who started monotherapy. Logistic regression models related medication initiated at study entry to adverse events over follow-up, adjusting by baseline differences among treatment cohorts. Patients taking typical antipsychotics or risperidone were more likely to experience EPS and TD during follow-up than patients taking olanzapine. Patients taking olanzapine were less likely to have loss of libido/impotence during follow-up than patients in the risperidone, amisulpride, clozapine, oral typical and depot typical cohorts. Weight gain occurred in all groups, but was greater with olanzapine. In conclusion, antipsychotics have different tolerability profiles in terms of the adverse events we monitored. Results should be interpreted conservatively due to the observational study design.

Young Mania Rating Scale: how to interpret the numbers? Determination of a severity threshold and of the minimal clinically significant difference in the EMBLEM cohort

The aim of this analysis was to identify Young Mania Rating Scale (YMRS) meaningful benchmarks for clinicians (severity threshold, minimal clinically significant difference [MCSD]) using the Clinical Global Impressions Bipolar (CGI‐BP) mania scale, to provide a clinical perspective to randomized clinical trials (RCTs) results.

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.

Symptomatic remission and patient quality of life in an observational study of schizophrenia: Is there a relationship?

This analysis aimed to examine the association between remission and quality of life (QOL) in schizophrenia. In post-hoc analyses of the 3-year, prospective, observational Schizophrenia Outpatients Health Outcomes (SOHO) study, we compared the QOL of patients who achieved symptomatic and clinical remission with those who did not, and the factors associated. Symptomatic remission was defined as achieving a score of ≤3 on the Clinical Global Impression-Schizophrenia (CGI-SCH) scale, maintained for 6 months and without hospitalization. QOL was patient self-rated using the European-QOL. Of the 6516 patients analyzed, 38% were in symptomatic remission 12 months post-baseline and 52% at 36 months. Functional remission remained fairly constant from 12 months to 36 months (22.4% at both time points). At all visits from 12 to 36 months, patient QOL and social functioning were significantly higher for patients in symptomatic remission. QOL was higher in patients in functional remission. Patients with maintained symptomatic remission over the 3-year follow-up had a much greater improvement in QOL than patients with no symptomatic remission or symptomatic remission for part of the period. Factors associated with a better QOL also included paid employment, socially active, a higher CGI-SCH cognitive score, good compliance, and a better baseline QOL.

Assessing the infrequent oral supplementation of olanzapine long-acting injection in the treatment of schizophrenia.

OBJECTIVE Adding another antipsychotic to a treatment regimen was previously used in evaluating the medications efficacy. Supplementation of depot antipsychotics with oral antipsychotics is particularly meaningful because depot formulations are typically chosen for patients struggling with adherence to oral antipsychotics. This post-hoc analysis assessed supplementation of olanzapine long-acting injection (olanzapine-LAI) with oral olanzapine. SUBJECTS AND METHODS We used 12 months of data from an open-label, single-arm extension study of patients with schizophrenia or schizoaffective disorder (N=931) treated with olanzapine-LAI. The prevalence, duration, time to first supplementation, and best predictors of oral supplementation were assessed. RESULTS Oral supplementation occurred in 21% of patients for a median of 31 days with mean modal dose of 10.8 mg/day. Mean time to first supplementation was shorter for patients who were at least moderately ill at baseline compared to less ill patients (47 vs. 97 days, p<0.001). Best predictors of oral supplementation included a more severe illness profile at baseline, lower olanzapine-LAI dose prior to oral supplementation, supervised living arrangements, and being African-American. CONCLUSION Supplementation of olanzapine-LAI appears to be infrequent, of relatively short duration, and reserved for more severely ill patients who may require a targeted rescue medication due to signs of impending relapse.

A prospective, observational study of the safety and effectiveness of intramuscular psychotropic treatment in acutely agitated patients with schizophrenia and bipolar mania.

This naturalistic, observational pan-European study assessed the safety and early effectiveness of intramuscular (IM) psychotropic treatments in patients with acute agitation suffering from schizophrenia or bipolar mania. One thousand nine hundred and forty of 1945 patients completed the 24-hour observation period after initial IM treatment. Patients from 12 European countries were included (mean age 39 years; 58% male, 66% schizophrenia). IM treatment was at the physicians discretion. The primary objective was to describe the acute tolerability of IM psychotropic therapies in clinical practice, with particular emphasis on EPS. At baseline, 68% of the patients received IM monotherapy, with IM olanzapine most commonly prescribed (36%). During the first 24 hours, 190 (9.8%) patients experienced EPS. The occurrence of EPS was statistically significantly lower in patients treated with IM olanzapine compared to those treated with other IM psychotropic medications (mainly typical antipsychotics and benzodiazepines): acute dystonia: 1.1%, 95% CI 0.5-2.3 and 2.9%, CI 2.0-4.0; akathisia: 2.3%, CI 1.3-3.7 and 5.5%, CI 4.3-6.9; Parkinsonism: 2.9%, CI 1.8-4.4 and 7.8%, CI 6.4-9.4, respectively. Anticholinergic treatment was given to 12% IM olanzapine versus 31% non-olanzapine treated patients. Acute agitation after 24 hours was reduced by 1.68 (95% CI 1.46-1.91) points on the Clinical Global Impression of Severity (CGI-S) in IM olanzapine patients and 1.51 (95% CI 1.30-1.73) points in non-olanzapine patients. Additional psychotropic medication was required for 90% of the patients during the first 24 hours of treatment. Results provide naturalistic evidence for low EPS rates and improvement of agitation with IM psychotropic medications during acute states of patients suffering from acute mania or schizophrenia.

Reasons and Outcomes of Olanzapine Dose Adjustments in the Outpatient Treatment of Schizophrenia

INTRODUCTION Antipsychotic treatment dose adjustments may influence treatment outcomes in patients with schizophrenia. METHODS We analysed data from 4,247 outpatients with schizophrenia who started olanzapine monotherapy in the 3-year, prospective, observational SOHO study to determine factors associated with olanzapine dose adjustments and how these impact on treatment effectiveness and tolerability. RESULTS Regression analyses showed an association between changes in the Clinical Global Impression (CGI) and olanzapine dose changes: patients with a lack of effectiveness were more likely to have their dose increased, whereas patients with good treatment response were more likely to have a dose decrease. Improvement in tardive dyskinesia was associated with dose increase or no change (p=0.034) and worsening of sexual problems was associated with dose decrease (p=0.001). Conversely, an increase in olanzapine dose was associated with subsequent clinical improvement (CGI), but dose adjustment had no significant effects on tolerability outcomes. DISCUSSION These results indicate that psychiatrists tend to modify olanzapine dose according to treatment response. Dose increases seem to be associated with a better response to treatment and not with a worsening of side-effects.

Comparison of olanzapine and risperidone in the EMBLEM Study: translation of randomized controlled trial findings into clinical practice.

Data from the EMBLEM Study, a 2-year, prospective, observational study of health outcomes associated with acute treatment of patients experiencing a manic/mixed episode of bipolar disorder, was used to compare the effectiveness of olanzapine monotherapy versus risperidone monotherapy, and to investigate whether the treatment effects were similar to those reported in a 3-week, randomized controlled trial assessing the same treatments. Symptom severity measures included the Young Mania Rating Scale (YMRS), the 5-item Hamilton Depression Rating Scale, and the Clinical Global Impression-Bipolar Disorder Scale. A total of 245 EMBLEM inpatients were analyzed with YMRS ≥20: olanzapine (n=209), risperidone (n=36). Both the treatment groups had similar improvements in YMRS from baseline to 6 weeks, but there was a significantly greater improvement in 5-item Hamilton Depression Rating Scale in the olanzapine group. There was a similar improvement in Clinical Global Impression-Bipolar Disorder Scale in both the groups and the occurrence of treatment-emergent adverse events and weight gain did not differ between the treatment groups. The EMBLEM results partly support those of the randomized controlled trial, which suggests olanzapine and risperidone have similar improvements in mania but that olanzapine monotherapy may be more effective than risperidone monotherapy in the treatment of depressive symptoms associated with mania. Limitations include differences in study design, patient population, and length of follow-up.

Translation of Randomised Controlled Trial Findings into Clinical Practice: Comparison of Olanzapine and Valproate in the EMBLEM Study

OBJECTIVES The aim of this study was to compare the outcomes of olanzapine- and valproate-treated patients in an observational study of acute mania with the results of a randomised controlled trial (RCT) assessing the same treatments. METHODS EMBLEM (European Mania in Bipolar Evaluation of Medication) was a 2-year, prospective, observational study of health outcomes associated with the treatment of mania. Severity of mania and depression were assessed at baseline and 6 weeks using the YMRS and the 5-item version of the HAMD, respectively. RESULTS 621 patients were analysed (n=107 valproate, n=514 olanzapine). Both groups improved from baseline to 6 weeks in mean YMRS and HAMD-5 total scores, with greater mean improvements in the olanzapine compared with the valproate group. Olanzapine was associated with more weight gain and less gastrointestinal difficulties than valproate. DISCUSSION The EMBLEM results support those of the RCT, which suggest that olanzapine monotherapy seems to be more effective than valproate monotherapy in the treatment of acute mania.

Switching to olanzapine long-acting injection from either oral olanzapine or any other antipsychotic: comparative post hoc analyses

Background A considerable proportion of patients suffering from schizophrenia show suboptimal responses to oral antipsychotics due to inadequate adherence. Hence, they are likely to benefit from switching to a long-acting injectable formulation. These post hoc analyses assessed the clinical effects of switching to olanzapine long-acting injection (OLAI) from either oral olanzapine (OLZ) or other antipsychotics (non-OLZ). Methods Post hoc analyses were done based on two randomized studies (one short-term, one long-term) conducted in patients suffering from schizophrenia and treated with OLAI. The short-term study was an 8-week placebo-controlled, double-blind trial in acute patients, and the long-term study was a 2-year, oral olanzapine-controlled, open-label, follow-up of stabilized outpatients. Results These analyses used data from 62 OLAI-treated patients (12 switched from OLZ, 50 from non-OLZ) from the short-term study and 190 OLAI-treated patients (56 switched from OLZ, 134 from non-OLZ) from the long-term study. Kaplan–Meier survival analyses of time to all-cause discontinuation of OLAI treatment did not differ significantly between OLZ and non-OLZ patients in the short-term study (P=0.209) or long-term study (P=0.448). Similarly, the proportions of OLZ and non-OLZ patients that discontinued OLAI were not statistically different in the short-term (16.7% versus 36.0%, respectively; P=0.198) or long-term (57.1% versus 47.8% respectively; P=0.238) studies. In the short-term study, no significant differences were detected between the patient groups in mean change in Positive and Negative Syndrome Scale (PANSS) total score (−13.4 OLZ versus −20.8 non-OLZ; P=0.166). In the long-term study, mean change in PANSS total score (3.9 OLZ versus −3.6 non-OLZ; P=0.008) was significantly different between the non-OLZ and OLZ groups. Rates of treatment-emergent adverse events were similar in OLZ and non-OLZ groups per study. Conclusion These post hoc analyses suggest that no significant differences in clinical effectiveness were seen after switching from non-OLZ or OLZ to OLAI. However, these findings should be interpreted with care, due to small sample sizes and differences in patients’ clinical profiles.