Safety and efficacy of self-administered inhaled loxapine (ADASUVE) in agitated patients outside the hospital setting: protocol for a phase IV, single-arm, open-label trial.

INTRODUCTION: There is a need for fast-acting, non-injection antiagitation treatments that are well tolerated and can be used outside of healthcare facilities. In phase II/III trials, an inhaled formulation of loxapine (ADASUVE®), a well-established, first-generation antipsychotic agent, provided rapid control of mild to moderate agitation in the hospital setting. The present study was designed to investigate the safety and efficacy of inhaled loxapine when self-administered outside the hospital setting. METHODS AND ANALYSIS: This phase IV, multicentre, single-arm, open-label clinical trial is being conducted in five countries in Europe: Spain, Germany, Norway, Romania and Austria. The aim is to include approximately 500 patients with schizophrenia or bipolar disorder who previously received and responded well to inhaled loxapine in the hospital setting. Eligible patients will be followed up for 6 months from baseline. They will be given a 10 mg dose of inhaled loxapine to self-administer outside the hospital setting to treat an agitation episode, should one occur. Patients will also be given a short-acting beta-agonist bronchodilator for treatment of possible severe respiratory side effects. The primary endpoint is incidence of serious adverse events (AEs) and respiratory AEs of special interest related to use of inhaled loxapine outside the hospital setting. Secondary endpoints include incidence of other AEs, Clinical Global Impression-Improvement scores up to 2 hours after self-administration of inhaled loxapine, time to improvement of agitation, patient satisfaction with treatment, treatment outcomes according to agitation severity and concordance between the patient (or a family member/caregiver) and the physician in scoring of agitation severity and the decision to self-administer inhaled loxapine. ETHICS AND DISSEMINATION: The protocol received ethics committee approval in the participating countries between January and August 2016. The results of this study will be disseminated through one or more scientific papers. TRIAL REGISTRATION NUMBER: EudraCT2015-003331-36; NCT02525991; Pre-results.

Characterizing the experience of agitation in patients with bipolar disorder and schizophrenia.

BACKGROUND: Agitation is a common manifestation of bipolar disorder and schizophrenia which includes symptoms ranging from inner tension and unease to violence and aggression. Much of the existing literature has focused on agitation in the acute setting, with the patient experience poorly defined. Thus, the aim of this study was to characterize agitation and its management from a patient perspective, with the focus on those who reside in the community. METHODS: Surveys were completed across Germany, Spain and the UK by 583 community dwelling patients with schizophrenia or bipolar disorder who experienced episodes of agitation. Patients were recruited via either their physician or through patient support groups. The survey captured information on demographics, disease characteristics, frequency of agitation episodes and different pre-defined severity levels ranging from mild to severe, symptoms experienced during an episode, awareness of agitation and coping strategies employed by the patient. Statistics were descriptive in nature. RESULTS: The most commonly reported symptoms during an episode of agitation were feeling uneasy (n = 373, 64%), restless (n = 368, 63%) or nervous (n = 368, 63%). Patients experienced an average of 22.4 (SD 57.2) mild, 15.4 (SD 61.2) moderate, 6.8 (SD 63.3) moderate-intense and 2.9 (SD 24.4) severe episodes within the last 12 months; on average 2.7 (SD 6.8) required hospital attendance. Half of patients (n = 313) had attended hospital due to agitation. In total, 71% of patients (n = 412) were aware they were becoming agitated either always or sometimes and 61% of patients (n = 347) were aware of agitation triggers either always or sometimes. The majority of patients reported being able to sometimes control their agitation (56%, n = 329) but 16% (n = 94) stated that there is typically nothing they can do. To cope with episodes 55% (n = 125) of schizophrenia patients and 66% (n = 234) of bipolar disorder patients reported taking prescribed medication. CONCLUSION: Community based patients with schizophrenia and bipolar disorder reported frequently experiencing agitation episodes which they defined most commonly as feeling uneasy, restless or nervous. A range of coping strategies were reported but they were not always successful, highlighting an area of unmet need in this population.

A survey of caregiver burden in those providing informal care for patients with schizophrenia or bipolar disorder with agitation: results from a European study.

BACKGROUND: Agitation is a common feature of bipolar disorder and schizophrenia. Previous research indicates that specific symptoms impact caregiver burden in these conditions, but the impact of agitation on caregiver experience is poorly understood. The aim of this study was to characterise caregiver burden in providers of informal care for patients with bipolar disorder and schizophrenia who experience agitation. METHODS: In total, 297 matched patient and caregiver surveys were collected across the UK, Germany and Spain between October 2016 and January 2017. To be eligible, caregivers needed to provide informal care to a patient with a diagnosis of bipolar disorder or schizophrenia with agitation managed in a community setting and participating in the patient survey. The caregiver survey captured information on demographics and their role in managing the patient's agitation. Caregiver burden was assessed using the Involvement Evaluation Questionnaire. Descriptive analysis was conducted. RESULTS: Caregivers provided 38.3 h (SD ± 40.34) a week of support to the patient with 20% providing 50 h or more. Most caregivers reported that they recognised an episode of agitation all of the time (44%, n = 130) or sometimes (40%, n = 119). Verbal de-escalation techniques (talking (80%, n = 239) and soothing (73%, n = 218) were the most commonly reported strategies used by caregivers during an episode of agitation; 14% (n = 43) reported resorting to physically restraining the patient. Caregivers supervised rescue medication administration regularly (41%, n = 69) or occasionally (49%, n = 82). Mean Involvement Evaluation Questionnaire score was 32.2 (± 15.27), equivalent to 28.4 (± 13.56) in Germany, 35.6 (± 16.55) in Spain and 33.3 (± 15.15) in the UK. Involvement Evaluation Questionnaire scores were higher for caregivers who reported hostile (41.7 ± 17.07) lack of control (40.3 ± 16.35) and violent (39.5 ± 16.40) patient behaviours when agitated. Over excitement (31.8 ± 15.05), restless (32.6 ± 14.77) and tense (32.9 ± 15.64) behaviours were associated with a lower Involvement Evaluation Questionnaire score. CONCLUSIONS: Caregivers are active participants in the recognition and management of agitation episodes. The substantial burden reported by these caregivers is impacted by factors including the number of hours of care provided, patient behaviours and country. These may be viable targets for effective interventions to reduce caregiver burden.

State of Acute Agitation at Psychiatric Emergencies in Europe: The STAGE Study.

BACKGROUND: Agitation is an array of syndromes and types of behaviors that are common in patients with psychiatric disorders. In Europe, the estimation of prevalence of agitation has been difficult due to the lack of standard studies or systematic data collection done on this syndrome. OBJECTIVE: An observational, cross-sectional, multicenter study aimed to assess the prevalence of agitation episodes in psychiatric emergencies in different European countries. METHOD: For 1 week, all episodes of acute agitation that were attended to at the psychiatric emergency room (ER) or Acute Inpatient Unit (AIU) in the 27 participating centers were registered. The clinical characteristics and management of the agitation episode were also described. A descriptive analysis was performed. RESULTS: A total of 334 agitation episodes out of 7295 psychiatric emergencies were recorded, giving a prevalence rate of 4.6% (95% CI: 4.12-5.08). Of them, 172 [9.4% (95% CI: 8.2-10.9)] were attended at the ER and 162 [2.8% (95% CI: 2.4-3.3)] at AIU. Only data from 165 episodes of agitation (those with a signed informed consent form) was registered and described in this report. The most common psychiatric conditions associated with agitation were schizophrenia, bipolar disorder and personality disorder. The management of agitation included from non-invasive to more coercive measures (mechanical, physical restraint or seclusion) that were unavoidable in more than half of the agitation episodes (59.5%). CONCLUSION: The results show that agitation is a common symptom in the clinical practice, both in emergency and inpatient psychiatric departments. Further studies are warranted to better recognize (using a standardized definition) and characterize agitation episodes.