Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine

Lesem, Michael D.; Tran-Johnson, Tram K.; Riesenberg, Robert; Feifel, David; Allen, Michael; Fishman, Robert S.; Spyker, Daniel A.; Kehne, John H.; Cassella, James V.

doi:10.1192/bjp.bp.110.081513

Cited by 133 publications

(113 citation statements)

References 24 publications

(25 reference statements)

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“…The intramuscular form of loxapine is no longer marketed in the United States, but is frequently used in France for the acute treatment of agitation. 13 Intramuscular antipsychotics have a T max of 90 minutes and can take up to 60 minutes to reduce agitation, [14][15][16][17] and symptoms can escalate during this period. Moreover, intramuscular administration is often resisted by patients.…”

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confidence: 99%

Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens

Spyker

Riesenberg²,

Cassella

2015

The Journal of Clinical Pharma

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This randomized, double-blind, placebo-controlled, parallel-group study was to determine the pharmacokinetic characteristics, safety, and tolerability of multiple doses of inhaled loxapine aerosol in subjects on a stable, oral, chronic antipsychotic regimen. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Thirty-two subjects were randomized 1:1:1:1 to receive inhaled loxapine (total doses of 15, 20, or 30 mg) or inhaled placebo administered in 3 divided doses, given 4 hours apart. Following inhalation, the median T max was 2 minutes, and concentrations declined to about half C max approximately 5 minutes later across the 3 dose levels. The dose proportionality across data from this study combined with data from the single-dose study showed a slope (90%CI) of log AUC inf versus log dose of 0.818 (0.762-0.875) across the 8 doses (n ¼ 60 subjects) studied, indicating reasonable dose proportionality. The most common adverse events were cough (3 of 32, 9%), sedation (3 of 32, 9%), and dysgeusia (2 of 32, 6%). The inhalation of multiple doses of inhaled loxapine were well tolerated in study subjects and provided a safe, well-tolerated means for rapidly and reliably achieving therapeutic plasma concentrations of loxapine. ClinicalTrials. gov identifier: NCT00555412

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confidence: 99%

Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens

Spyker

Riesenberg²,

Cassella

2015

The Journal of Clinical Pharma

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“…Some independent variables might influence this result, including the inherent differences in the studies concerning the cohort size, population characteristics, and evaluation of adverse events. In the study of Lesem et al (2011), some patients were smokers (a comorbidity), and the clinical trial population included Hispanic and Asian minorities; these characteristics differ from those in a study by . Relatively few adverse events were reported, which were mild, subjective and typical (headache and dysgeusia), and the presence of heterogeneity is plausible.…”

Section: Discussionmentioning

confidence: 99%

“…The meta-analysis of two studies (Allen et al, 2011; Lesem et al, 2011) demonstrated potential evidence for the superiority of LOXi compared to a placebo regardless of the dosage for the treatment of chronic schizophrenic patients for agitation. The initial effects were observed 10 minutes after inhalation, and the intervention was more effective than the placebo for 2 hours following the treatment.…”

Section: Discussionmentioning

confidence: 99%

“…found no recorded cases of discontinuation of participation (Allen et al, 2011). Lesem et al (2011) found that a total of 6 patients discontinued treatment, as follows: 1 patient from the 5 mg LOXi group, 2 patients from the 10 mg LOXi group and 3 patients from the placebo group Note: For each adverse event subgroup, the study numbers were reported, as well as the number of participants and the value of the estimated effect (odds ratio) with the respective confidence interval (95% CI). p values < 0.05 were considered statistically significant and marked with an asterisk (*).…”

Section: Inhaled Loxapinementioning

confidence: 99%

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<b>New drugs for the treatment of agitation in schizophrenia: a systematic review and meta-analysis of inhaled loxapine and infused sodium nitroprusside

Tonin¹,

Piazza²,

Borba³

et al. 2017

Acta Sci. Health Sci.

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ABSTRACT. The use of novel drugs such as inhaled loxapine (LOXi) for schizophrenia and the off-label use of substances such as sodium nitroprusside (NIT) for the management of mental disorders require further investigation. We aimed to evaluate the efficacy and safety of LOXi and NIT for the treatment of agitation associated with schizophrenia. A systematic review of randomized controlled trials (RCTs) comparing the use of LOXi or NIT versus placebo or other antipsychotic agents was conducted, and we evaluated the efficacy (CGI-scale) and safety (adverse events) of the therapies. Altogether, 71 studies were identified, of which 2 (LOXi) were included in the meta-analysis, and 1 (NIT) was included in the systematic review only. The efficacy data showed superiority of LOXi against placebo, regardless of the dose (5 and 10 mg). No significant differences were observed concerning the safety results. Treatment with NIT showed favorable results, with significant reduction of the symptoms. The efficacy of these medications is difficult to assess because of the lack of RCTs. However, there is some information regarding the efficacy and safety of LOXi in the treatment of agitation in schizophrenic patients.Keywords: antipsychotic agents, mental disorders, evidence-based medicine.Novos fármacos para o tratamento da agitação na esquizofrenia: revisão sistemática e meta-análise da loxapina inalável e nitroprussiato de sódio RESUMO. Fármacos mais recentes como a loxapina inalável (LOXi) para o tratamento da esquizofrenia e o uso off-label de substâncias como o nitroprussiato de sódio (NIT) para o manejo de desordens mentais requerem mais investigações. O objetivo do estudo foi avaliar eficácia e segurança da LOXi e do NIT para tratamento da agitação na esquizofrenia. Foi realizada revisão sistemática de ensaios clínicos randomizados (ECR) comparando o uso de LOXi ou NIT versus placebo ou outros antipsicóticos. Foram avaliados desfechos de eficácia (escala CGI-I) e segurança (eventos adversos). Ao todo 71 estudos foram identificados, dos quais dois foram incluídos nas meta-análises (ambos da LOXi) e 1 sobre NIT foi incluído somente na revisão sistemática. Os dados de eficácia demonstraram superioridade da LOXi frente ao placebo, independente das doses avaliadas (5 ou 10 mg). Não foram observadas diferenças significativas entre os resultados de segurança com o controle. O único estudo incluído sobre o NIT mostrou resultados favoráveis, com redução significativa dos sintomas. Apesar da carência de ECR com esses fármacos dificultar a determinação e a reunião de informações, há potenciais evidências de eficácia e segurança da LOXi no tratamento da agitação em pacientes com esquizofrenia.Palavras-chave: antipsicóticos, transtornos mentais, medicina baseada em evidências.

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“…For example, following inhalation of loxapine, the median T max was 2 minutes. Phase II [50] and Phase III [51] studies in patients with schizophrenia or schizoaffective disorder demonstrated that inhaled loxapine (5 mg and 10 mg doses) was well tolerated and had dose-dependent anti-agitation effects without evidence of excessive sedation. The superior anti-agitation effects of inhaled loxapine compared with placebo were evident at 10 minutes after administration, and this early onset of action appears to be the most rapid anti-agitation effect ever reported in placebocontrolled trials [51].…”

Section: ) Inhalable Loxapinementioning

confidence: 99%

Pharmacological Treatment of Schizophrenia:

Fleischhacker

Miyamoto

2016

CNPT

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In the past decade, four main topics have shaped research and clinical practice. 1) In randomized controlled trials, researchers have investigated whether treating prodromal symptoms of schizophrenia helps to reduce the conversion risk to full-blown schizophrenia. Results are ambiguous and the discussion on whether or not an intervention at the stage is justified is ongoing. 2) Following the enhanced understanding of the pathophysiology of schizophrenia, also with respect to specific symptom domains, pharmacological targets beyond D 2 receptor antagonism have been explored. Much work and enthusiasm has revolved around nicotinergic and glutamatergic compounds, so far with mostly discouraging results. 3) Several new-generation antipsychotics have become available as long-acting formulations. All of them have demonstrated a significant positive impact on relapse rates in placebo controlled studies. Whether these compounds also have advantages over first-generation depots and/or oral antipsychotics is still debated. The development of an inhalable antipsychotic has complemented the treatment options for the management of acutely agitated patients. 4) Lastly, attempts from various perspectives, including genetics and neuroimaging, have investigated whether it is possible to predict treatment response and drug safety. Although some look promising, they have not yet reached a stage in which they can be applied to everyday clinical practice. What has become clear, though, is that early non response predicts late non response, leading to the recommendation to switch antipsychotics much earlier than stated in most treatment guidelines.

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Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine

Cited by 133 publications

References 24 publications

Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens

Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens

<b>New drugs for the treatment of agitation in schizophrenia: a systematic review and meta-analysis of inhaled loxapine and infused sodium nitroprusside

Pharmacological Treatment of Schizophrenia:

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