Discovery of a Small Molecule Activator of Slack (Kcnt1) Potassium Channels That Significantly Reduces Scratching in Mouse Models of Histamine-Independent and Chronic Itch.

Various disorders are accompanied by histamine-independent itching, which is often resistant to the currently available therapies. Here, it is reported that the pharmacological activation of Slack (Kcnt1, KNa1.1), a potassium channel highly expressed in itch-sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack-activating antipsychotic drug, loxapine, a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles is designed that enables to validate Slack as a pharmacological target in vivo. One of these new Slack activators, compound 6, exhibits negligible dopamine D2 and D3 receptor binding, unlike loxapine. Notably, compound 6 displays potent on-target antipruritic activity in multiple mouse models of acute histamine-independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack.

Improving the pharmacotherapeutic treatment of agitation associated with bipolar disorder.

INTRODUCTION: Agitation is commonly encountered in people with bipolar disorder, particularly when experiencing a manic episode. The number of approved pharmacological agents to manage acute episodes of agitation in this population is limited. AREAS COVERED: A search was conducted using the US National Library of Medicine PubMed.gov resource for English-language papers of clinical trials and reviews/meta-analyses, using the text words 'bipolar disorder' AND 'agitation,' as well as any papers with both two text words in the title, without any date restrictions. EXPERT OPINION: Existing pharmacologic options approved by regulatory authorities for the treatment of acute episodes of agitation associated with bipolar disorder have similar degrees of efficacy but differ in their tolerability profiles and ease of use, giving clinicians an opportunity to individualize treatment. The goal is to treat mild-moderate agitation before it evolves into severe agitation, encouraging noninvasive pharmacologic treatment options. Inhaled loxapine and sublingual dexmedetomidine are newer options with rapid onset of action and may be preferable for patients willing to cooperate with treatment.

Fifty years of experience with loxapine for the rapid non-coercive tranquilization of acute behavioral disturbances in schizophrenia patients, and beyond.

INTRODUCTION: Acute behavioral disturbances in psychosis, including agitation, comprise a heterogeneous group of manifestations varying in intensity and duration they last for. They require rapid, non-coercive treatments ranging from verbal de-escalation to the calming effect of pharmacological agents. The treatment goals are reduction of patient suffering and prevention of disease deterioration. Stabilizing rather than sedating is preferred to ensure improved compliance and a stronger therapeutic alliance. Furthermore, animal pharmacology and clinical studies on agitation reveal the robust calming and anxiolytic properties of loxapine. AREAS COVERED: This review covers the pharmacological and clinical history of loxapine along with research developments. It emphasizes the advantages of its multiple formulations ranging from injectable forms and tablets to orally inhaled forms to attain rapid and fine-tuned tranquilization. EXPERT OPINION: Rapid tranquillization is achieved within 2-6 hours using liquid orally-consumed loxapine, and within an hour or less with its IM or orally inhaled forms. Loxapine has been adopted in the management of a wide range of acute disturbances, such as agitation in psychosis. In the context of personalized medicine, key cellular and molecular elements of the schizophrenia phenotype were recently shown to be improved with loxapine.

Inhaled loxapine for acute agitation in a psychiatric emergency service.

BACKGROUND: Rapid control of agitation in medical settings is necessary for safety and provision of care. Inhaled loxapine achieves peak plasma levels within 2 minutes of administration and is FDA-approved for managing acute agitation. METHODS: We examined the use of inhaled loxapine vs non-parenteral treatment as usual (TAU) in a psychiatric emergency service for consecutive patients with acute agitation or aggression. Data were collected retrospectively. T tests were used for continuous variables and Chi-square tests were used for categorical data. RESULTS: A total of 61 patients received inhaled loxapine and 29 received TAU. Time to outcome for patients receiving inhaled loxapine was 21 ± 21 minutes compared with 121 ± 206 minutes for TAU (t =-2.61; P = .014). At outcome, 89% of patients treated with loxapine experienced symptom resolution, compared with 69% of TAU (Chi-square = 17.4, P < .0001). Ten percent of patients receiving loxapine had no change in symptoms and 1% had worsening symptoms vs 14% in the TAU group who experienced no change in symptoms (z = 0.5, not significant), and 17% who described worsening symptoms (z = 6153.9, P < .0001). CONCLUSIONS: The rapid absorption of inhaled loxapine is associated with a 6-fold faster and more robust symptom control.

The Management of Psychomotor Agitation Associated with Schizophrenia or Bipolar Disorder: A Brief Review.

The early and correct assessment of psychomotor agitation (PMA) is essential to ensure prompt intervention by healthcare professionals to improve the patient's condition, protect healthcare staff, and facilitate future management. Proper training for recognizing and managing agitation in all care settings is desirable to improve patient outcomes. The best approach is one that is ethical, non-invasive, and respectful of the patient's dignity. When deemed necessary, pharmacological interventions must be administered rapidly and avoid producing an excessive state of sedation, except in cases of severe and imminent danger to the patient or others. The purpose of this brief review is to raise awareness about best practices for the management of PMA in emergency care situations and consider the role of new pharmacological interventions in patients with agitation associated with bipolar disorder or schizophrenia.

Agitation in schizophrenia: origins and evidence-based treatment.

PURPOSE OF REVIEW: Agitation associated with schizophrenia remains an important clinical concern and if not managed effectively, can escalate into aggressive behavior. This is a review of the recent biomedical literature on agitation in individuals with schizophrenia. RECENT FINDINGS: Themes in the recent literature include consideration of comorbidities such as cigarette smoking and cannabis use. Surveys reveal that pharmacological approaches to manage agitation have changed little, with haloperidol remaining in common use and intramuscular administration of antipsychotics and/or benzodiazepines being frequently administered to more severely agitated/aggressive individuals. Of note, ketamine has been recently adopted for use in severe agitation in medical emergency departments, but the risk of this medication for people with schizophrenia is unclear. At present, inhaled loxapine remains the only rapidly acting noninjectable FDA-approved treatment for agitation associated with schizophrenia. In development is an intranasal formulation for olanzapine (a well characterized atypical antipsychotic already approved to treat agitation) and a sublingual film for dexmedetomidine (an α2-adrenergic agonist used as an anesthetic and now being repurposed). SUMMARY: Comorbidities can contribute to agitation and can make an accurate differential diagnosis challenging. The ongoing development of rapidly acting novel formulations of antiagitation medications, if successful, may facilitate clinical treatment by providing additional options.

Haematologic malignancies associated with clozapine v. all other antipsychotic agents: a pharmacovigilance study in VigiBase®.

BACKGROUND: Clozapine is mainly used in patients with treatment-resistant schizophrenia and may lead to potentially severe haematologic adverse events, such as agranulocytosis. Whether clozapine might be associated with haematologic malignancies is unknown. We aimed to assess the association between haematologic malignancies and clozapine using Vigibase®, the WHO pharmacovigilance database. METHODS: We performed a disproportionality analysis to compute reporting odds-ratio adjusted for age, sex and concurrent reporting of antineoplastic/immunomodulating agents (aROR) for clozapine and structurally related drugs (loxapine, olanzapine and quetiapine) compared with other antipsychotic drugs. Cases were malignant lymphoma and leukaemia reports. Non-cases were all other reports including at least one antipsychotic report. RESULTS: Of the 140 226 clozapine-associated reports, 493 were malignant lymphoma cases, and 275 were leukaemia cases. Clozapine was significantly associated with malignant lymphoma (aROR 9.14, 95% CI 7.75-10.77) and leukaemia (aROR 3.54, 95% CI 2.97-4.22). Patients suffering from those haematologic malignancies were significantly younger in the clozapine treatment group than patients treated with other medicines (p < 0.001). The median time to onset (available for 212 cases) was 5.1 years (IQR 2.2-9.9) for malignant lymphoma and 2.5 years (IQR 0.6-7.4) for leukaemia. The aROR by quartile of dose of clozapine in patients with haematologic malignancies suggested a dose-dependent association. CONCLUSIONS: Clozapine was significantly associated with a pharmacovigilance signal of haematologic malignancies. The risk-benefit balance of clozapine should be carefully assessed in patients with risk factors of haematologic malignancies. Clozapine should be used at the lowest effective posology.

Management of Acute Agitation and Aggression in Children and Adolescents with Pro Re Nata Oral Immediate Release Antipsychotics in the Pediatric Emergency Department.

Background: Acute agitation in the pediatric emergency department (ED) has the potential to escalate into aggression and result in harm. Rapid and effective management may be warranted. Use of pro re nata (prn) oral immediate-release (IR) quetiapine, haloperidol, loxapine, and chlorpromazine has been observed in the pediatric ED at Surrey Memorial Hospital to manage this condition; however, evidence for oral prn antipsychotic use is limited in the pediatric population. Objectives: The primary objective is to characterize the dose of prn oral IR quetiapine used to manage acute agitation or aggression in a pediatric ED. Secondary objectives include characterizing the dose of prn oral IR haloperidol, loxapine, and chlorpromazine; and describing the 1-hour response rate, admission rate, length of stay (LOS), and adverse drug effects. Method: The medical records of pediatric patients who received at least one prn oral dose of IR quetiapine, haloperidol, loxapine, or chlorpromazine for acute agitation and aggression, without regard to the etiology of symptom presentation, between January 1, 2012 and December 31, 2016, were analyzed retrospectively. Results: Sixty-nine patients met the inclusion criteria. The mean dose of quetiapine was 32 mg/dose (0.54 mg/kg per dose); and the response rate was 53%. The mean haloperidol, loxapine, and chlorpromazine doses were 4 mg (0.07 mg/kg per dose), 13 mg (0.19 mg/kg per dose), and 29 mg/dose (0.53 mg/kg per dose) respectively; and the response rates were 36%, 30%, and 50%, respectively. Between 19% and 60% of patients were admitted, majority to the psychiatry ward. The median LOS in the ED was between 5 and 18 hours for nonadmitted patients. Extrapyramidal side effects (EPS) were reported with first-generation antipsychotics (FGA), but not with quetiapine. Conclusion: Quetiapine appears to be a viable agent for managing acute agitation and aggression in the pediatric ED with low rates of EPS. Further studies are encouraged to compare the effectiveness of quetiapine with FGA. A Clinical Trial Registration number is not applicable for this study.

Inhaled loxapine for agitation in patients with personality disorder: an initial approach.

Inhaled Loxapine (IL) has demonstrated efficacy in the treatment of agitation in schizophrenic and bipolar patients, although data in patients with Personality Disorder (PD) are scarce. To evaluate the effectiveness and safety of IL in the treatment of agitation in PD, data from 41 patients who presented at our unit with acute agitation and were treated with 9.1 mg of IL were collected retrospectively. The results showed that IL significantly decreased agitation within 10 minutes and its effect was greater at 20 minutes (Positive and Negative Syndrome Scale-excited component: from 22.78 ±â€¯4.39 at baseline to 11.14 ±â€¯4.17 at 20 minutes; p < 0.001; Agitation and Calmness Evaluation Scale: from 1.80 ±â€¯0.49 at baseline to 4.53 ±â€¯1.05 at 20 minutes; p < 0.01) without any severe adverse reactions registered. IL led to fast, safe and well-tolerated control of agitation in patients with PD.

Study Enrollment When "Preconsent" Is Utilized for a Randomized Clinical Trial of Two Treatments for Acute Agitation in the Emergency Department.

BACKGROUND: Acute agitation in the emergency department (ED) represents a danger to both patients and their caregivers. Medication is often needed, and few high-quality randomized trials have evaluated the optimal drugs for this vulnerable population. In the United States, as of 2017, randomized trials of drugs typically cannot be conducted under Waiver of Consent (46 CFR 45.116), and Exception From Informed Consent trials (21 CFR 50.24) are limited to life-threatening conditions, are onerous, and require filing an investigational new drug application with the FDA. We sought to conduct a randomized double-dummy trial of inhaled loxapine versus intramuscular haloperidol + lorazepam for acute agitation in the ED by obtaining consent in advance ("preconsent") in patients at risk of future agitation, allowing study drug administration up to 3 years later if the patient presented with acute agitation. OBJECTIVE: We sought to report the successful enrollment rate of patients preconsented at an earlier ED visit for this trial. METHODS: This was an analysis of patients age 18 to 64 with bipolar I disorder or schizophrenia preconsented for enrollment in the trial (clinicaltrials.gov, NCT02877108) conducted at a single urban academic center seeing approximately 60,000 patients per year. Eligible patients were assessed for capacity to consent by trained research associates, and informed consent was obtained at an ED visit for the possibility of administering drugs for agitation within the next 3 years. In the event the patient later presented to the ED and the attending physician deemed the patient required treatment for acute agitation, preconsent was confirmed and study drug would be administered. RESULTS: Over 67 days, 1,461 patients were screened in the ED, 269 had bipolar I or schizophrenia, 194 of whom had a contraindication to inhaled loxapine leaving 75 eligible patients; preconsent was obtained in 43 patients. Four additional patients who had not preconsented were consented for the trial in real time (three by surrogate, one patient had capacity while agitated) resulting in a total of 47 consented patients. Of these 47, a total of 12 were later removed from the study: 10 patients had unrecognized exclusion criteria for inhaled loxapine, one preconsented patient contacted the investigators at a later date and asked to be removed, and one surrogate revoked consent immediately after providing it. Only two patients were successfully enrolled, neither by preconsent: one was enrolled via a surrogate the day of enrollment, and the other was mildly agitated and had capacity to consent. The remaining patient with a valid surrogate consent did not receive study medication. CONCLUSIONS: Utilization of preconsent to enroll patients in a randomized trial of treatments for acute agitation in the ED requires substantial resources and may not be feasible.

Periodic catatonia with long-term treatment: a case report.

BACKGROUND: Periodic catatonia has long been a challenging diagnosis and there are no absolute guidelines for treatment when precipitating factors are also unclear. We report a schizophrenia patient with periodic catatonia with a 15-year treatment course. A possible correlation between decreased daylight exposure and periodic attacks has been observed. CASE PRESENTATION: We describe a 49-year-old woman with periodic catatonia associated with schizophrenia with 15 years of follow-up. The patient was treated with the antipsychotics risperidone, haloperidol, loxapine and quetiapine, but catatonia still relapsed once per year during the first few years of her disease course. The treatment was consequently been switched to clozapine due to fluctuated psychotic illness, and a longer duration of remittance was achieved. Lorazepam-diazepam protocol was used for rapid relief of catatonic symptoms, and was able to significantly shorten the duration of the symptoms. In addition, we observed a possible correlation between catatonic episodes and decreased daylight exposure during the 15-year duration. CONCLUSIONS: Successful treatment of acute periodic catatonia was achieved with a lorazepam-diazepam protocol, and the patient remained in remission for a longer duration under clozapine treatment. Besides, the possibility of decreased daylight exposure acting as a precipitating factor was observed during our 15 years of follow-up.

Older and Newer Strategies for the Pharmacological Management of Agitation in Patients with Bipolar Disorder or Schizophrenia.

BACKGROUND: The management of acute agitation in patients with bipolar disorder or schizophrenia is a multifaceted and dynamic task, which presents unique and complex challenges to healthcare providers. OBJECTIVE: To ascertain and describe which medications are best to use in patients with agitation, affected by bipolar disorder or schizophrenia. METHOD: Selective review of current literature and guidelines referred to the treatment of agitation in individuals affected with bipolar disorder or schizophrenia Results: When possible, the pharmacologic management of agitation should be preceded by a in-depth evaluation of the possible causes of the agitation. The use for of first and second-generation antipsychotic medications, of benzodiazepines and of the newer inhaled antipsychotic loxapine, is reviewed and commented. CONCLUSION: The mainstay of medication treatment of acute agitation should be based on a thotough assessment cause. If agitation is due to delirium or to another physial condition, an attempt to address the underlying causes should be always considered. When agitation is primarily due to schizophrenia or bipolar disorder, antipsychotics and/or benzodiazepines are usually the mainstay of treatment. Newer inhaled formulation of loxapine has shown ability to rapidly reduce the agitation in mild to moderate patients with schizophrenia or bipolar disorder, with a decrease in agitation that was evident since the first assessment, 10 minutes after the first dose.

Loxapine to control agitation during weaning from mechanical ventilation.

BACKGROUND: Weaning from mechanical ventilation (MV) may be impeded by the occurrence of agitation. Loxapine has the ability to control agitation without affecting spontaneous ventilation. The aim of this study was to establish whether loxapine would reduce MV weaning duration in agitated patients. METHODS: We performed a multicentre, double-blind, placebo-controlled, parallel group, randomised trial. Patients who were potential candidates for weaning but exhibited agitation (Richmond Agitation-Sedation Scale score ≥ 2) after sedation withdrawal were randomly assigned to receive either loxapine or placebo. In case of severe agitation, conventional sedation was immediately resumed. The primary endpoint was the time between first administration of loxapine or placebo and successful extubation. RESULTS: The trial was discontinued after 102 patients were enrolled because of an insufficient inclusion rate. Median times to successful extubation were 3.2 days in the loxapine group and 5 days in the placebo group (relative risk 1.2, 95% CI 0.75-1.88, p = 0.45). During the first 24 h, sedation was more frequently resumed in the placebo group (44% vs 17%, p = 0.01). CONCLUSIONS: In this prematurely stopped trial, loxapine did not significantly shorten weaning from MV. However, loxapine reduced the need for resuming sedation. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01193816 . Registered on 26 August 2010.

[New medical approach to out-of-hospital treatment of psychomotor agitation in psychiatric patients: a report of 14 cases]. / Nuevo abordaje farmacológico en la agitación psicomotriz en pacientes psiquiátricos tratados en el medio extrahospitalario. A propósito de 14 casos.

OBJECTIVES: This case series explored the usefulness of an inhaled dose of 9.1 mg of loxapine administered outside the hospital to treat psychomotor agitation related to schizophrenia, bipolar disorder, or schizoaffective disorder. The Clinical Global Impression Scale and the Positive and Negative Syndrome Scale (excitement component) were used to assess the effects of treatment in 14 patients. The treatment was useful in 12 patients, who showed significant improvement (P<.001) after inhalation. We conclude that inhaled loxapine is useful for treating out-of-hospital psychomotor agitation related to a psychiatric disorder. Mechanical restraint and parenteral medication can be avoided after use of this drug. Loxapine treatment shortens the agitation episode and attenuates the impact on the patient, facilitating ambulance transfer.

OBJETIVO: El presente artículo evalúa la utilidad de la dosis de 9,1 mg de loxapina inhalada, administrada en el medio extrahospitalario, en el tratamiento de la agitación psicomotriz asociada a esquizofrenia, trastorno bipolar y trastorno esquizoafectivo. Se emplearon la Escala de Impresión Clínica Global y la Escala de Síntomas Positivos y Negativos - Componente de Excitación. Se atendieron un total de catorce pacientes. En doce de ellos el tratamiento se mostró útil, con una diferencia significativa entre los momentos previos y posteriores al tratamiento (p < 0,001). Se concluye que la loxapina inhalada es una opción útil en el medio extrahospitalario para el control de la agitación psicomotriz de causa psiquiátrica. Evita la contención mecánica y la necesidad de terapia farmacológica por vía parenteral. El tratamiento permite acortar la duración del episodio y atenuar su repercusión en el paciente, sin producir sedación y facilitando su traslado en ambulancia.

Rationale and design of the PLACID study: a randomised trial comparing the efficacy and safety of inhaled loxapine versus IM aripiprazole in acutely agitated patients with schizophrenia or bipolar disorder.

BACKGROUND: The management of acute agitation manifesting in patients with schizophrenia or bipolar disorder requires swift pharmacological intervention to provide rapid symptomatic relief and prevent escalation to aggression and violence. Antipsychotic medications are widely used in this setting and the availability of an inhaled formulation with deep lung absorption of the antipsychotic loxapine has the potential to deliver a faster onset of therapeutic effect than the available intramuscular formulations of antipsychotics. METHODS: The efficacy of inhaled loxapine and the alternative antipsychotic aripiprazole delivered via intramuscular (IM) injection will be compared in the Phase IIIb PLACID study. Adults (18-65 years) with a confirmed diagnosis of schizophrenia or bipolar I disorder presenting with acute agitation will be randomly assigned to open-label treatment in a 1:1 ratio. Clinical evaluation will be conducted by raters blinded to treatment assignment. The primary efficacy endpoint is time to response (defined as a Clinical Global Impression of Improvement [CGI-I] score of 1 [very much improved] or 2 [much improved]). Secondary endpoints will include the percentage of responders at different time points after dosing; the proportion of patients who receive 1 or 2 doses of study drug; time to second dose; time to rescue medication; satisfaction with study drug (evaluated using Item 14 of the Treatment Satisfaction Questionnaire for Medication); and safety and tolerability. Approximately 360 patients will be recruited with an interim analysis conducted once 180 patients have completed the study to decide whether to stop for futility or continue with or without an increase in the sample size up to additional 288 patients. DISCUSSION: The PLACID trial will assess the efficacy and safety of inhaled loxapine with deep lung absorption compared with the IM antipsychotic, aripiprazole, in acutely agitated patients with schizophrenia or bipolar disorder. In the event that the median time to response of inhaled loxapine is significantly shorter than that of the intramuscular aripiprazole, the PLACID study has the potential to support the inhaled antipsychotic therapy as the standard of care in this setting. TRIAL REGISTRATION: The study protocol was registered with the European Clinical Trials Database on the 31 October 2014 (EudraCT number 2014-000456-29 ).

Dopamine antagonists for treatment resistance in autism spectrum disorders: review and focus on BDNF stimulators loxapine and amitriptyline.

INTRODUCTION: Drug development and repurposing are urgently needed for individuals with autism spectrum disorders (ASD) and psychiatric comorbidity, which often presents as aggression and self-injury. Areas covered: We review dopamine antagonists, including classical and atypical, as well as unconventional antipsychotics in ASD. The older antipsychotic loxapine is discussed in terms of preliminary albeit limited evidence in ASD. Emerging promise of amitriptyline in ASD is discussed, together with promising BDNF effects of loxapine and amitriptyline. Expert opinion: In ASD, pharmacotherapy and specifically dopamine antagonist drugs are often prescribed for challenging behaviors including aggression. The novel antipsychotics risperidone and aripiprazole have received most study in ASD and are FDA-approved for irritability in children with ASD over age 5 years; individuals with ASD are prone to weight gain, Type II diabetes and associated side effects. Low dose loxapine has properties of classical and novel antipsychotics but importantly appears more weight neutral, and with promising use in adolescents and adults with ASD. Amitriptyline appears effective in ASD for irritability, aggression, gastrointestinal problems, and insomnia, in children, adolescents and adults however our adult data on amitriptyline in ASD is still in preparation for publication. Both loxapine and amitriptyline may stimulate BDNF; further studies are warranted.

Simultaneous quantification of loxapine, loxapine N-oxide, amoxapine, 8-hydroxyloxapine and 7-hydroxyloxapine in human plasma using LC-MS/MS.

Loxapine is an antipsychotic medication used for the treatment of schizophrenia. In vivo, loxapine is metabolized to multiple metabolites. A high performance liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the determination of loxapine and 4 of its metabolites, loxapine N-oxide, amoxapine (N-desmethyl loxapine), 8-hydroxyloxapine and 7-hydroxyloxapine, in human plasma to support regulated clinical development. During method development, several technical challenges such as poor chromatography, separation of structural isomers, and inadequate sensitivity were met and overcome. The final method utilized micro-elution solid phase extraction (SPE) to extract plasma samples (100µL), and the resulting extracts were analyzed using reversed phase LC-MS/MS using a turbo-ionspray interface in positive ionization mode with selected reaction monitoring (SRM). The method was fully validated according to the current regulatory guidance for bioanalysis over the calibration curve range 0.0500-50.0ng/mL for all analytes using 1/x2-weighted linear regression analysis. Based on three separate runs, the between-run precision and inter-day precision for all five analytes at all concentrations, including the LLOQ (lower limit of quantitation) quality control at 0.0500ng/mL, varied from 0.0% to 13.8%, while the accuracy ranged from 86.4% to 109.3% of nominal. The extraction recoveries of loxapine and the four metabolites were above 80%. Various forms of short-term and long-term stability were established in both solutions and matrix, including the stability of loxapine and the four metabolites in human plasma for up to 260days of storage at -20°C. This method has been used to support a regulated clinical study, which included the successful execution of incurred sample reanalysis (ISR) testing. To the best of our knowledge, this is the first published methodology in which these five analytes were quantified with a single extraction and injection.

The effect of the medicine administration route on health-related quality of life: Results from a time trade-off survey in patients with bipolar disorder or schizophrenia in 2 Nordic countries.

BACKGROUND: Agitation episodes are common among patients with schizophrenia or bipolar disorder. Oral and intramuscular administration methods are commonly used in pharmacological treatment of acute agitation. Recently, an innovative inhalation product with loxapine(Adasuve®)has become available for treatment of acute agitation episodes associated with bipolar disorder or schizophrenia. The objective for the present study was to investigate the impact of the pharmacological treatment's administration methods on the health-related quality of life (HRQoL) in patients with bipolar disorder or schizophrenia in Denmark and Sweden using a time trade-off (TTO) approach. METHODS: The TTO methodology was used to examine the HRQoL impact of administration method of pharmacological treatment of acute agitation. Data were collected via an internet-based survey, using an existing panel of respondents with schizophrenia or bipolar disorder. RESULTS: Respondents considered living with schizophrenia/ bipolar disorder, having one yearly agitation episode treated with inhaler better than living with the same conditions and receiving treatment with tablet or injection. The utility value was 0.762 for inhalable treatment, 0.707 for injection and 0.734 for tablet treatment. CONCLUSIONS: Patients' preference for treatment delivery options showed that inhalation was associated with a significant utility gain when compared to injection or tablets. Inhalable loxapine may be a new tool for control of agitation episodes for strengthening the patient provider alliance when taking patient's preference for delivery method into consideration.

Inhaled loxapine for the urgent treatment of acute agitation associated with schizophrenia or bipolar disorder.

BACKGROUND: Acute agitation is a serious complication of schizophrenia and bipolar disorder, which may escalate quickly to aggressive behavior. Rapid treatment is therefore important to calm and stabilize the patient, reducing the potential for harm to the patient and others, and allowing further assessment. Current guidelines suggest that where pharmacologic intervention is indicated, medication should preferably be non-invasive, should have a rapid onset and should control aggressive behavior in the short term without compromising the physician-patient relationship in the long term. OBJECTIVES: This article presents an overview of a new inhaled formulation of the established antipsychotic loxapine, which aims to provide a more rapidly acting agent for the treatment of acute agitation without the disadvantages of intramuscular or intravenous injection. DISCUSSION: Inhaled loxapine is rapidly absorbed with intravenous-like pharmacokinetics, with a time to maximum plasma concentration of 2 minutes and a plasma half-life of approximately 6 hours. In phase III studies, loxapine reduced agitation within 10 minutes of inhalation; agitation was decreased at all subsequent assessments during a 24-hour evaluation period. Inhaled loxapine was generally well tolerated with no undue sedation. The most common adverse events were dysgeusia, mild sedation, and dizziness. Inhaled loxapine is contraindicated in patients with asthma, COPD or other pulmonary disease associated with bronchospasm. CONCLUSIONS: Inhaled loxapine rapidly reduces acute agitation in patients with schizophrenia or bipolar disorder and is generally well tolerated. The non-invasive route of delivery respects the patient's autonomy, reducing the perception of coercion or forced medication. Inhaled loxapine is therefore an effective and appropriate option for use in the emergency setting in patients with acute agitation.

Effectiveness of Inhaled Loxapine in Dual-Diagnosis Patients: A Case Series.

OBJECTIVES: Episodes of psychotic agitation are frequent in patients with dual diagnosis, that is, in patients with concomitant psychiatric and substance use disorders. Rapid intervention is needed to treat the agitation at a mild stage to prevent the escalation to aggressive behavior. Inhaled loxapine has been demonstrated to rapidly improve symptoms of mild-to-moderate agitation in adults with psychiatric disorders (schizophrenia and bipolar disorder), but data on patients with dual diagnosis are scarce. METHODS: This study is a retrospective review of data from a case series of patients with dual diagnosis, which were attended for symptoms of agitation while at the emergency room (n = 9), in the outpatient clinic (n = 4), or during hospitalization (n = 1) at 1 center in Spain. All patients received inhaled loxapine for treating the agitation episodes. RESULTS: Data from 14 patients with dual diagnosis were reviewed. All patients had 1 or more psychiatric disorders (schizophrenia, bipolar I disorder, drug-induced psychotic disorder, posttraumatic stress, borderline or antisocial personality disorder, depression, or anxiety) along with a variety of substance use disorders (alcohol, cocaine, cannabis, amphetamines, hypnotics and antianxiety drugs, caffeine, or street drugs). Overall, only 1 dose of inhaled loxapine (9.1 mg) was needed to calm each patient during an acute episode of agitation. CONCLUSIONS: Inhaled loxapine was rapid, effective, and well accepted in all dual-pathology patients presenting with acute agitation in the emergency setting. Inhaled loxapine facilitated both patient cooperation and an adequate management of his or her disease.