Clinical outcomes with olanzapine long-acting injection: impact of the 3-hour observation period on patient satisfaction and well-being.

BACKGROUND: The objective of the present analysis is to determine the impact of the 3-hour observation period for olanzapine long-acting injection (LAI) on patient satisfaction and well-being by comparing data collected before and after its implementation. METHODS: This is a post hoc analysis of patients treated with olanzapine LAI in 1) a 6-month fixed-dose randomized controlled trial and/or 2) a 6-year open-label safety study. This analysis was limited to patients with schizophrenia who were treated with olanzapine LAI consistent with the approved indication and dosing recommendations of the European Union Summary of Product Characteristics (N=966). Of the 966 patients, the analysis further focused only on those patients who received both 1) at least one injection before the implementation of the 3-hour observation period and 2) at least one injection after implementation of the 3-hour observation period (N=487). Patient satisfaction was assessed with the three-item Patient Satisfaction with Medication Questionnaire-Modified. Responses were averaged across all postbaseline visits occurring before (ie, without) the implementation of the 3-hour observation period and across all postbaseline visits occurring after (ie, with) the implementation of the 3-hour observation period. In addition, the rate of postinjection delirium/sedation syndrome events was calculated. RESULTS: There was no meaningful change after implementation of the 3-hour observation period in satisfaction (before: mean [SD] =4.0 [1.02] and after: mean [SD] =4.1 [0.82]), preference for olanzapine LAI over oral medication (before: mean [SD] =4.0 [0.90] and after: mean [SD] =4.1 [0.77]), or ratings of satisfaction regarding side effects (before: mean [SD] =1.9 [0.79] and after: mean [SD] =1.8 [0.60]). For the total population (N=966), postinjection delirium/sedation syndrome occurred in 26 (0.07%) of 38,010 injections. CONCLUSION: For patients with schizophrenia receiving treatment with olanzapine LAI, the 3-hour observation period had no impact on their satisfaction with the medication or on their subjective well-being.

The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research.

Atomoxetine is a noradrenergic reuptake inhibitor prescribed for attention-deficit/hyperactivity disorder (ADHD) that first gained approval in the USA in 2002 and has been authorized in 97 countries worldwide. The aim of this paper is to comprehensively review publications that addressed one or more of seven major safety topics relevant to atomoxetine treatment of children and adolescents (aged ≥6 years) diagnosed with ADHD. While the review focuses on children and adolescents, publications in which data from patients aged >18 years and from 6 to 18 years were analyzed in the same dataset were included. Using a predefined search strategy, including agreement of two reviewers when selecting papers, reduced the potential for bias. Using this process, we identified 70 eligible papers (clinical trials, epidemiological studies, and case reports) across the seven topics. We also referred to the European Summary of Product Characteristics (SPC) and US label. We found 15 papers about suicidality, three about aggression/hostility, seven about psychosis/mania, six about seizures, seven about hepatic effects, 29 about cardiovascular effects, and 28 about growth and development. The main findings (i.e., those from the largest and most well-conducted studies/analyses) are as follows. A large register-based study of pediatric and adult patients (6818 received atomoxetine) calculated a hazard ratio of 0.96 for suicide-related events during treatment with atomoxetine, and a meta-analysis of 23 placebo-controlled studies (N = 3883), published in 2014, found no completed suicides and no statistically significant association between atomoxetine and suicidality. The frequency of aggression/hostility was not statistically significantly higher with atomoxetine, e.g., experienced by 1.6 % (N = 21/1308) of atomoxetine-treated patients versus 1.1 % (N = 9/806) of placebo-treated patients in one meta-analysis. Symptoms of psychosis and mania were mainly observed in patients with comorbid bipolar disorder/depression. Based on spontaneous reports, during a 2-year period when 2.233 million adult and pediatric patients were exposed to atomoxetine, the reporting rate for seizures was 8 per 100,000 patients. In the manufacturer's database, atomoxetine was a "probable cause" of three hepatic adverse events (AEs) (all reversible hepatitis), and 133 hepatic AEs had possible confounding factors and were "possibly related" to atomoxetine, during 4 years when atomoxetine exposure had reached about 4.3 million patients. Rare cases of severe liver injury are described in the US label and European SPC; a case requiring liver transplantation is described in the US label. In a comprehensive review of a clinical trials database (N = 8417 received atomoxetine), most pediatric patients experienced modest increases in heart rate and blood pressure, and 8-12 % experienced more pronounced changes (≥20 bpm, ≥15 to 20 mmHg). However, in three long-term analyses (≥2 years), blood pressure was within age norms, and few patients discontinued due to cardiovascular AEs. As described in the European SPC, QT interval prolongation is uncommon, e.g., in an open-label study, 1.4 % of 711 children and adolescents had prolonged QTc intervals (≥450 ms in males, ≥470 ms in females) that were not clinically significant at ≥3 years of treatment with atomoxetine. The European SPC warns about potential QT interval prolongation in patients with a personal or family history, or if atomoxetine is administered with other drugs that potentially affect the QT interval. Decreases in growth (weight and height gain) occurred and were greatest in patients of above average weight and height, but appeared to recover over 2-5 years of atomoxetine treatment. In conclusion, suicidality, aggression/hostility, psychosis, seizures, liver injuries, and prolonged QT interval are uncommon or rare in children and adolescents treated with atomoxetine, based on data from the predefined search and from the European SPC. Overall, the data that we assessed from our search do not suggest that associations exist between atomoxetine and suicidality or seizures. The data also suggest that an association may not exist between atomoxetine and aggression/hostility. While atomoxetine may affect the cardiovascular system, the data suggest these effects are not clinically significant in most patients. Reductions in growth appear to be reversible in the long term.

Attention-deficit/hyperactivity disorder Under Treatment Outcomes Research (AUTOR): a European observational study in pediatric subjects.

The ADHD Under Treatment Observational Research (AUTOR) study was a European prospective, observational study that assessed factors associated with changes in ADHD severity, estimated change from baseline in quality of life (QoL), and characterized changes in ADHD symptoms over a 2-year period as a function of baseline treatment. The primary objective was to identify factors associated with worsening in ADHD severity during a 2-year follow-up period for subjects aged 6-17 years, who were receiving the same pharmacotherapy for 3-8 months before enrollment and had a Clinical Global Impression (CGI)-ADHD-Severity score of mild/lower and a CGI-ADHD-Improvement score of improved/very much improved. Multivariate logistic regression examined the association of factors with worsening in ADHD. Mixed-model repeated measures regression analyzed QoL in terms of change from baseline in CHIP-CE PRF scores. There were 704 subjects analyzed. Variables associated with worsening ADHD severity were parental occupation, poorer school outcomes, and use of psychoeducation; baseline treatment was not significant. Among the secondary objectives, initial use of atomoxetine (vs. stimulants) was associated with a significant improvement on the CHIP-CE PRF total score, with an adjusted treatment difference of -6.0 (95 % CI -7.9, -4.1) at 24 months. Additionally, the odds of stability (CGI-ADHD-S ≤ 3 over the 2-year period) were significantly lower for subjects initially responding to stimulants compared with atomoxetine (OR 0.5; 95 % CI 0.3, 0.8). ADHD symptom worsening was associated with initial use of psychoeducation, parental occupation, and poorer school outcomes. Response to initial treatment with atomoxetine was associated with improved QoL over 2 years.

A 6-year open-label study of the efficacy and safety of olanzapine long-acting injection in patients with schizophrenia: a post hoc analysis based on the European label recommendation.

PURPOSE: To assess the long-term efficacy and safety of olanzapine long-acting injection (LAI) in the treatment of schizophrenia, focusing on clinical trial data consistent with the approved indication and dosing recommendations in the European label and which forms the basis for treatment decisions made by clinicians in daily clinical practice. PATIENTS AND METHODS: This was a post hoc analysis of a 6-year open-label study of olanzapine LAI in patients (male or female, 18-75 years old) with schizophrenia entering this study following feeder studies of olanzapine LAI. Patients were flexibly dosed (45-405 mg, 2- to 4-week intervals), but those receiving oral olanzapine supplementation whose total olanzapine dose was >20 mg/day equivalent were excluded from this post hoc analysis. RESULTS: Data from 669 patients were analyzed (44.5% completed). Positive and Negative Syndrome Scale total scores did not change significantly from baseline to endpoint; Clinical Global Impression-Severity scores improved significantly. Mean weight change was +2.19 kg (P<0.001), with 40.8% of patients experiencing ≥7% weight gain. There were 24 occurrences of post-injection delirium/sedation syndrome (PDSS). CONCLUSION: Olanzapine LAI appeared to be effective in the long-term maintenance of schizophrenia, and the safety profile was consistent with that of oral olanzapine, except for injection-related events and PDSS events.

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

BACKGROUND: Olanzapine 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. METHODS: Cases 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). RESULTS: A 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). CONCLUSIONS: The 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.

The efficacy of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of clinical research.

Atomoxetine was first licensed to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in the US in 2002. The aim of this paper is to comprehensively review subsequent publications addressing the efficacy of atomoxetine in 6- to 18-year-olds with ADHD. We identified 125 eligible papers using a predefined search strategy. Overall, these papers demonstrate that atomoxetine is an effective treatment for the core ADHD symptoms (effect sizes 0.6-1.3, vs. placebo, at 6-18 weeks), and improves functional outcomes and quality of life, in various pediatric populations with ADHD (i.e., males/females, patients with co-morbidities, children/adolescents, and with/without prior exposure to other ADHD medications). Initial responses to atomoxetine may be apparent within 1 week of treatment, but can take longer (median 23 days in a 6-week study; n=72). Responses often build gradually over time, and may not be robust until after 3 months. A pooled analysis of six randomized placebo-controlled trials (n=618) indicated that responses at 4 weeks may predict response at 6-9 weeks, although another pooled analysis of open-label data (n=338) suggests that the probability of a robust response to atomoxetine [≥40% decrease in ADHD-Rating Scale (ADHD-RS) scores] may continue to increase beyond 6-9 weeks. Atomoxetine may demonstrate similar efficacy to methylphenidate, particularly immediate-release methylphenidate, although randomized controlled trials are generally limited by short durations (3-12 weeks). In conclusion, notwithstanding these positive findings, before initiating treatment with atomoxetine, it is important that the clinician sets appropriate expectations for the patient and their family with regard to the likelihood of a gradual response, which often builds over time.

Underdiagnosis of attention-deficit/hyperactivity disorder in adult patients: a review of the literature.

OBJECTIVE: To raise awareness of attention-deficit/hyperactivity disorder (ADHD) as an underdiagnosed, undertreated, often comorbid, and debilitating condition in adults. DATA SOURCES: PubMed was searched using combinations of keywords, including ADHD, adult, diagnosis, identify, prevalence, and comorbid, to find articles published between 1976 and 2013. STUDY SELECTION: In total, 99 articles were selected for inclusion on the basis of their relevance to the objective and importance to and representation of ADHD research, including international guidelines for adults with ADHD. RESULTS: In a large proportion of children with ADHD, symptoms persist into adulthood. However, although adults with ADHD often experience chaotic lifestyles, with impaired educational and vocational achievement and higher risks of substance abuse and imprisonment, many remain undiagnosed and/or untreated. ADHD is usually accompanied by other psychiatric comorbidities (such as major depressive disorder, anxiety disorder, and alcohol abuse). Indeed, adults with ADHD are more likely to present to a psychiatric clinic for treatment of their comorbid disorders than for ADHD, and their ADHD symptoms are often mistaken for those of their comorbidities. Untreated ADHD in adults with psychiatric comorbidities leads to poor clinical and functional outcomes for the patient even if comorbidities are treated. Effective treatment of adults' ADHD improves symptoms, emotional lability, and patient functioning, often leading to favorable outcomes (eg, safer driving, reduced criminality). A few medications have now been approved for use in adults with ADHD, while a multimodal approach involving psychotherapy has also shown promising results. Conclusions General psychiatrists should familiarize themselves with the symptoms of ADHD in adults in order to diagnose and manage ADHD and comorbidities appropriately in these patients.

Prognostic factors of improvement in health-related quality of life in atomoxetine-treated children and adolescents with attention-deficit/hyperactivity disorder, based on a pooled analysis.

The objective of this study is to identify prognostic factors of treatment response to atomoxetine in improvement of health-related quality of life (HR-QoL), measured by the Child Health and Illness Profile-Child Edition Parent Report Form (CHIP-CE PRF) Achievement and Risk Avoidance domains, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Pooled data from 3 placebo-controlled trials and separate data from 3 open-label trials of atomoxetine in children and adolescents with ADHD were analyzed using logistic regression methods. Based on baseline impairment in the Achievement and/or Risk Avoidance domains (CHIP-CE PRF < 40 points), 2 subsamples of subjects were included. Treatment outcome was categorized as <5 points or ≥5 points increase in the CHIP-CE PRF Achievement and Risk Avoidance domains. Data of 190 and 183 subjects from the pooled sample, and 422 and 355 subjects from the open-label trials were included in the analysis of Achievement and Risk Avoidance domains. Baseline CHIP-CE subdomain scores proved to be the most robust prognostic factors for treatment outcome in both domains, based on data from the pooled sample of double-blind studies and from the individual open-label studies (odds ratios [OR] 0.74-1.56, p < 0.05; OR < 1, indicating a worse baseline score associated with worse odds of responding). Initial treatment response (≥25 % reduction in ADHD Rating Scale scores in the first 4-6 weeks) was another robust prognostic factor, based on data from the open-label studies (OR 2.99-6.19, p < 0.05). Baseline impairment in HR-QoL and initial treatment response can be early prognostic factors of atomoxetine treatment outcome in HR-QoL in children and adolescents with ADHD.

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.

Fast vs. slow switching from stimulants to atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: To compare fast versus slow switching from stimulants to atomoxetine (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was a randomized, controlled, open-label study in 6-16-year-old ADHD patients, previously treated with stimulants and cross-titrated (fast switch, over 2 weeks, or slow switch, over 10 weeks) to ATX because of unsatisfactory response and/or adverse events. Study duration was 14 weeks with an ATX standard target dose of 1.2 mg/kg/day. Primary measure was the change from baseline in the investigator-rated ADHD-Rating Scale (ADHD-RS) at weeks 2 and 10. Secondary measures included Global Impression of Perceived Difficulties (GIPD) and Child Health and Illness Profile-Child Edition (CHIP-CE). RESULTS: The majority of the 111 patients were male (83.8%, n=93) and mean (SD) age was 11.5 (2.38) years. Mean baseline ADHD-RS total score was 36.0 in the fast and 38.0 in the slow group. Adjusted mean change after 2 weeks was -8.1 (-10.1; -6.1) in the fast and -8.0 (-9.9;-6.0) in the slow group (p=0.927), and after 10 weeks -15.0 (-17.4;-12.6) and -14.3 (-16.7;-12.0), respectively, (p=0.692). GIPD scores did not show differences between groups. Significant differences at week 10 were found in the CHIP-CE achievement domain favoring slow (p=0.036) and the comfort domain favoring fast cross-titration (p=0.030). No significant differences were found for adverse events, and differences for systolic blood pressure (BP) and weight were not considered clinically relevant. CONCLUSIONS: ADHD-RS and GIPD scores improved in both switching groups. No clinically relevant differences between fast and slow switching from stimulants to ATX were found.