Share this article on:

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

Roncero, Carlos MD, PhD; Ros-Cucurull, Elena MD; Grau-López, Lara MD, PhD; Fadeuilhe, Christian MD; Casas, Miguel MD, PhD

doi: 10.1097/WNF.0000000000000153
Case Reports

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.

*Addiction and Dual Diagnosis Unit, Department of Psychiatry, Vall d'Hebron University Hospital-Public Health Agency, Barcelona (ASPB), CIBERSAM; and †Department of Psychiatry and Legal Medicine, Universidad Autónoma de Barcelona, Barcelona, Spain.

Address correspondence and reprint requests to Carlos Roncero, MD, PhD, CAS Drogodependencias Vall d'Hebron, Servicio de Psiquiatría, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain; E-mail:

Conflicts of Interest and Source of Funding: C.R. has received fees to give lectures for Janssen-Cilag, Bristol-Myers Squibb, Ferrer-Brainfarma, Pfizer, Reckitt Benckiser, Lundbeck, Otsuka, Servier, Lilly, GSK, Rovi, and Astra. He has received financial compensation for his participation as a member of the Janssen-Cilag, Lilly, and Shire board. He has carried out the PROTEUS project, which was funded by a grant from Reckitt-Benckisert/Indivior. E.R.C. has received fees to give lectures for Janssen-Cilag, Lundbeck, Otsuka, Servier, Rovi, Lilly, and Pfizer. She has received financial compensation for projects with Esteve and Pfizer. C.F. has no conflict of interest. M.C. has received fees to give lectures for Janssen-Cilag, Bristol-Myers Squibb, Ferrer-Brainfarma, Pfizer, Reckitt-Benckiser, Lundbeck, Otsuka, Servier, Lilly, Shire, GSK, Rovi, and Ferrer. He has received financial compensation for his participation as a member of the Janssen-Cilag, Lilly, Shire, Lundbeck, Otsuka, Ferrer, and Rovi board. L.G.L. has received fees to give talks for Janssen-Cilag, Lundbeck, Servier, Otsuka, and Pfizer. An unrestricted grant for medical writing assistance (A. Del Campo-Pivotal SL) was provided by Ferrer International.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Episodes of agitation are frequent in patients with dual diagnosis, and such patients generally experience greater consequences of and additional substance use disorder than those with a psychiatric disorder alone, including a greater exacerbation of psychiatric symptoms, medication nonadherence, increase in aggressive and violent behaviors, emergency room (ER) visits, and inpatient psychiatric placements.1,2 Dual diagnosis is particularly common in the emergency setting population but is often underrecognized and undertreated.3,4

Agitation may range from mild to severe, with rapid fluctuations, reaching extreme agitation in some cases that can derive into aggressive behavior in a relatively short period.5 Rapid intervention is needed to treat the psychotic agitation at a mild stage to prevent the escalation to an aggressive behavior but also to proceed with further investigations for each particular case and to properly treat such disorders.6 The management of agitation can include different measures from nonspecific sedating medication (benzodiazepines and/or antipsychotics) to behavioral management and psychological techniques such as de-escalation or physical restraint.7

Inhaled loxapine was effective in reducing mild-to-moderate agitation within 10 minutes in patients with schizophrenia or bipolar disorder.8–10 Pooled data from 2 phase III8–10 and 1 phase II8 studies observed a number needed to treat for achieving response (defined as a ≥40% reduction from baseline on the PANSS-EC scale score at 2 hours after dose administration) of 4 (95% confidence interval, 3–5) and 3 (95% confidence interval, 3–4) patients for inhaled loxapine versus placebo for agitation in schizophrenia and in bipolar disorder, respectively. The response rates are similar to those observed with the intramuscular administration of other antipsychotics.11 However, patients with comorbid alcohol and/or substance use may be underrepresented in the clinical trials, hence data on the use of inhaled loxapine for the agitation symptoms in these patients are limited.

Back to Top | Article Outline


In the reported case series, we describe our experience with inhaled loxapine for calming down psychotic agitation in 14 patients with dual diagnosis, who attended the ER (n = 9) or were evaluated preceding/during hospitalization (n = 5) at the Hospital of Vall d'Hebron in Barcelona (Spain) from June 2014 to May 2015.

All patients presented a diagnosis on axis I or II of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (Table 1). Four patients presented in a state of substance intoxication (Table 2). Most patients (11/74, 78.5%) received only 1 dose of inhaled loxapine, which was effective within minutes after administration. No other concomitant medication was needed during the acute episode of agitation, although 1 patient (no. 14) required physical contention and rescue medications (intramuscular [IM] haloperidol and levomepromazine) for a new crisis of agitation triggered by a surrounding factor. A second dose of inhaled loxapine was administered during the following 24 hours in 2 patients (nos. 9 and 2). Only mild dizziness was reported in one of them (patient 9) after the second dose. No respiratory adverse events or bronchospasm was reported for any patient.





Daily doses of inhaled loxapine were efficacious in 1 patient (no. 4) for the treatment of daily agitation episodes within the first 5 days of hospitalization. There was no interaction with the drug of abuse, depressants, or central nervous system stimulants.

Back to Top | Article Outline


To our knowledge, this case series constitutes the first reporting of inhaled loxapine use in patients with dual diagnosis outside the clinical trial setting. Inhaled loxapine was rapid, effective, and well accepted in patients with dual diagnosis presenting with acute agitation. In general, only 1 dose of inhaled loxapine was needed to calm the patients, with no concomitant medication required during the acute episode of agitation.

When a case of acute agitation or aggression is presented, the clinician may not have sufficient time to conduct a thorough evaluation and needs to use a medication that has a rapid calming effect, with no oversedation, and good safety profile to continue treating the patient as per required procedures. Until recently, the antipsychotic drug loxapine, as IM formulation, was the first choice in psychiatric emergencies as it helped to avoid the sedation effect associated with the use of hypnotics and sedatives. However, IM administration is not well received by most of the patients, which are usually reluctant to receive it. With the noninvasive route of administration and a quick calming effect, inhaled loxapine confers significant advantages in controlling the agitation.

Inhaled loxapine represents a valuable alternative to other currently used formulations for the reduction of agitation in dual-diagnosis patients. An inhaler is generally perceived as less coercive and therefore would engage the patient into a collaborative patient-medical therapeutic alliance.

In our case series, the comorbid psychiatric conditions were equally represented, with schizophrenia, bipolar I disorder, psychotic disorder, and posttraumatic stress disorder and borderline personality disorder as the most common disorders. All patients presented substance use disorders, with alcohol abuse (71.4%) and cocaine abuse (42.9%) as the most prevalent ones. Other authors have reported similar findings regarding the agitation episodes in patients with dual pathology.3,12,13 Moritz et al12 observed that 73% of the agitated patients presenting at the hospital ER report alcohol and/or drug use, which was the most frequently observed triggering factor (17%) in them. During a severe dual pathology program, it was noted that a considerable number of severe dual pathology cases first become noticed at an emergency mental health unit.13 The patient's cooperation while in the ER is essential for detecting undiagnosed dual-pathology cases or managing clinical decompensation episodes in these patients. The use of inhaled loxapine might be of a great help to attain this goal. Although our data refer to a limited number of cases, this case series represents the overall clinical practice and demonstrates the effectiveness of inhaled loxapine for agitation in dual patients who are seen at a hospital. Afterward, an adequate management of the comorbid disorders with the available integrated resources would be necessary to improve treatment adherence and outcome in patients with dual diagnosis.14,15

Back to Top | Article Outline


1. Buckley PF. Prevalence and consequences of the dual diagnosis of substance abuse and severe mental illness. J Clin Psychiatry 2006;67(suppl 7):5–9.
2. Macias Konstantopoulos WL, Dreifuss JA, McDermott KA, et al. Identifying patients with problematic drug use in the emergency department: results of a multisite study. Ann Emerg Med 2014;64(5):516–525.
3. Minassian A, Vilke GM, Wilson MP. Frequent emergency department visits are more prevalent in psychiatric, alcohol abuse, and dual diagnosis conditions than in chronic viral illnesses such as hepatitis and human immunodeficiency virus. J Emerg Med 2013;45(4):520–525.
4. Langås AM, Malt UF, Opjordsmoen S. Substance use disorders and comorbid mental disorders in first-time admitted patients from a catchment area. Eur Addict Res 2012;18(1):16–25.
5. Volavka J, Citrome L. Pathways to aggression in schizophrenia affect results of treatment. Schizophr Bull 2011;37(5):921–929.
6. Citrome L, Volavka J. The psychopharmacology of violence: making sensible decisions. CNS Spectr 2014;19(5):411–418.
7. Nordstrom K, Allen MH. Alternative delivery systems for agents to treat acute agitation: progress to date. Drugs 2013;73(16):1783–1792.
8. Allen MH, Feifel D, Lesem MD, et al. Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2011;72(10):1313–1321.
9. Kwentus J, Riesenberg RA, Marandi M, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord 2012;14(1):31–40.
10. Lesem MD, Tran-Johnson TK, Riesenberg RA, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry 2011;198(1):51–58.
11. Citrome L. Addressing the need for rapid treatment of agitation in schizophrenia and bipolar disorder: focus on inhaled loxapine as an alternative to injectable agents. Ther Clin Risk Manag 2013;9:235–245.
12. Moritz F, Bauer F, Boyer A, et al. Patients in a state of agitation at the admission service of a Rouen hospital emergency department. Presse Med 1999;28(30):1630–1634.
13. Haro Cortés G, Baquero Escribano A, Traver Toras F, et al. The importance of socio-legal interventions in the case management of a severe dual-pathology program: our 6 years' experience. Adicciones 2014;26(4):371–372.
14. Roncero C, Rodríguez-Cintas L, Barral C, et al. Treatment adherence to treatment in substance users referred from psychiatric emergency service to outpatient treatment. Actas Esp Psiquiatr 2012;40(2):63–69.
15. Szerman N, Vega P, Grau-López L, et al. Dual diagnosis resource needs in Spain: a national survey of professionals. J Dual Diagn 2014;10(2):84–90.

agitation; inhaled loxapine; dual diagnosis; substance use disorders; mental disorders

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.