Original Article https://doi.org/10.9758/cpn.2022.20.3.482 pISSN 1738-1088 / eISSN 2093-4327 Clinical Psychopharmacology and Neuroscience 2022;20(3):482-490 Copyrightⓒ 2022, Korean College of Neuropsychopharmacology Inhaled Loxapine as a Rapid Treatment for Agitation in Patients with Personality Disorder: A Prospective Study on the Effects of Time Marc Ferrer1,2,3,4, Óscar Soto-Angona1, María Soler-Artigas2,3,5, Pol Ibáñez3, Christian Fadeuilhe1,2,3,4, 1,2,3,4 1 1 1 Raúl Felipe Palma-Álvarez , Raquefet Lidai , Sebastian Vargas-Cáceres , María Ángeles Torrecilla , Anna López1, Josep Antoni Ramos-Quiroga1,2,3,4 1 2 Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Catalonia, Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Catalonia, 3Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Barcelona, 4 5 Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain Objective: Agitation in patients diagnosed with personality disorders (PD) is one of the most frequent crises in emergency departments (ED). Although many medications have been tested, their effectiveness has been small or non-significant, and no specific drugs are supported by the available evidence. This study aimed to evaluate the efficacy of Inhaled loxapine (IL) as a therapeutic option for agitated patients with PD. Methods: A naturalistic, unicentric, prospective study was carried out. Thirty subjects diagnosed with PD and attending the ED with episodes of agitation were recruited most of whom were women diagnosed with Borderline Personality Disorder. Subjects were treated with a single dose of IL (9.1 mg). Efficacy was assessed with the Clinical Global Impression scale, the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) and the Agitation-Calmness Evaluation Scale (ACES). Patients were followed 60 minutes after administration to measure IL effect and its duration. Results: IL exhibited an overall efficacy in managing mild to severe agitation, with a quick onset of effect and persistence. ‘Effect of time’, where IL efficacy is maintained over time, is more marked in higher-severity agitation. No additional treatments were needed to improve agitation during the follow-up time. Conclusion: Results suggest that IL could be a safe and effective option to manage agitation in PD. KEY WORDS: Psychomotor agitation; Personality disorders; Loxapine; Antipsychotic agents. INTRODUCTION behaviour, coercive interventions (i.e., physical restraints) and longer admissions [6]. Agitation is an excessive motor activity associated with Agitation is common among patients diagnosed with a feeling of inner tension [1] which can progress to ag- personality disorders (PD), especially those exhibiting gressive and violent behaviours [2]. Its prevalence ranges pathological impulsivity-related personality traits asso- from 4.6% [3] to 10% [4] of all episodes consulting a ciated with low tolerance or poor skills to manage neg- Psychiatric Emergency Department (ED), while 20−50% ative emotions. Such clinical profile is commonly identifi- of visits to psychiatric emergency services show risk of ag- able both in Borderline Personality Disorder (BPD) and itation [5]. An inadequate treatment, especially a delayed Antisocial Personality Disorder (APD) [7]. As a matter of a intervention, has been linked to a greater risk of violent fact, 9−27% of agitated patients consulting in the ED are diagnosed with BPD, this being the third most prevalent Received: February 16, 2021 / Revised: May 26, 2021 diagnosis that causes agitation after schizophrenia and bi- Accepted: June 1, 2021 Address for correspondence: Óscar Soto-Angona polar disorder [3]. Department of Psychiatry, Hospital Universitari Vall d’Hebron, Since there is not enough evidence for specific treat- Passeig Vall d’Hebron 119-129, Barcelona 08035, Spain ment in agitated patients diagnosed with PD, general rec- E-mail: osoto@vhebron.net ORCID: https://orcid.org/0000-0003-0234-4280 ommendations, ranging from verbal interventions fo- This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 482 Inhaled Loxapine as Treatment for Agitation in Personality Disorder 483 cused on behaviour control (i.e., de-escalation) to phys- ited to a retrospective study [24] and a case series assess- ical restraint, are applied [8,9]. Administering medication ing the efficacy of IL for the agitation treatment of patients might be a useful way to calm the patient and ensure co- diagnosed with PD in different clinical settings [25]. operativeness, allowing for a proper assessment of the un- This study aimed to analyse the safety and efficacy of IL derpinning cause of agitation. In this sense, pharmaco- in the treatment of agitated patients with PD as their main logical treatment should aim at calming without sedating, diagnosis consulting in the ED, focusing on its potentiality allowing patients to participate in their own therapy [10]. as a rapid acting and well-tolerated agent. Using a pro- Regarding pharmacological interventions, oral and in- spective design allows to study the time effect of such tramuscular administration of benzodiazepines and anti- drug across the study period. psychotics are the most widely used choices. However, benzodiazepines can cause excessive sedation and hypo- METHODS tension and might also lead to paradoxical reactions [11,12], while antipsychotics might cause extrapyramidal Study Design and Informed Consent Statement symptoms and cardiac conduction abnormalities. This is This is a naturalistic, unicentric and prospective study- also the case of atypical antipsychotics, although these and was registered at the European Union Drug might show a better tolerability [13]. Antipsychotics have Regulating Authorities Clinical Trials Database (EudraCT) also shown a moderate effect on some relevant sympto- with EudraCT Number 2016-004884-38. Also, the study matic dimensions of PD, especially anger and (to a lesser was approved by The Spanish Agency of Medicines and extent) cognitive-perceptual symptoms [14]. Medical Devices (AEMPs) and was registered at the Although loxapine is classified as a typical anti- Spanish Clinical Studies Registry (REec) with the registry psychotic, its pharmacodynamicsis closer to that of atyp- number 17-0186. Approval was also recieved by the Vall ical antipsychotics [15]. Loxapine is widely used in some d’Hebron Research Institute Ethical Committee (Approval countries such as France as an intramuscular formulation code: FER-LOX-2016-01). All participants signed a writ- for acute agitation [16]. The possibility of having an in- ten informed consent before participating in the study. haled formulation that reaches the maximum blood con- centration (Cmax) 2 minutes after intake makes loxapine es- Participants pecially interesting to treat agitation, as it guarantees a Thirty adult patients were consecutively recruited for rapid onset of the effect [17]. Furthermore, it allows for a the study from December 2017 to June 2019 when they lower dose and hence fewer side effects. In comparison attended the Psychiatry ED for agitation as the highest pri- with the 9.1 mg of inhaled formulation, the amount of lox- ority goal treatment. apine to treat agitation when administered intramuscularly Inclusion criteria for this study included being aged be- might range from 200 up to 600 mg [18]. On the other tween 18 and 65 years, presenting moderate-severe agi- hand, patient cooperation is needed for the admin- tation according to Clinical Global Impression-Severity istration of inhaled loxapine (IL), hindering its use for se- (CGI-S) scoring (GCI-S ≥ 3 and ≤ 5), being diagnosed vere and disorganized agitation episodes [19]. Altogether, with PD according to the Diagnostic and Statistical IL appears to be a suitable treatment for agitation episodes Manual of Mental Disorder 5th edition (DSM-5), and un- of PD where patient cooperation is more feasible and the derstanding and signing the informed consent for the severity is lower than in schizophrenia and bipolar study. Exclusion criteria were not being pregnant (a preg- disorders. However, IL administration must be done ex- nancy test was performed if necessary to ensure this crite- clusively in hospital settings and supervised by healthcare rion), having no organic conditions that could cause psy- professionals [20]. chiatric symptoms or compromise the understanding of Despite that indications for IL include only agitation in the study information, not being diagnosed with any psy- patients diagnosed with schizophrenia and bipolar dis- chotic or bipolar disorder, and not showing signs of acute order [21,22], off-label use has been reported, especially intoxication. All patients recruited met all the inclusion for agitation in substance use disorders (SUD) and PD criteria and none of them met the exclusion criteria. [23]. Evidence focusing on its use on PD is scarce and lim- 484 M. Ferrer, et al. Measurements with the CGI-S scale, the PANSS-EC, and the ACES. CGI-S [26]: a 7-point scale that measures the clinical Clinical efficacy in agitated PD patients was assessed severity of the episode from the clinician’s point of view. through changes in the scores of PANSS-EC (main in- Severity ranges from 1 (normal) to 7 (extremely ill). dicator), ACES and CGI-I at two time points: 10 (T1) and Clinical Global Impression-Improvement (CGI-I) scale: 60 (T3) minutes after the administration. Safety assess- a 7-point scale that assesses clinical improvement from ments were performed, including blood pressure, heart the clinician’s point of view [27]. It rates clinical improve- rate and oxygen saturation at 10 (T1), 20 (T2) and 60 (T3) ment ranging from 1 (much improvement) to 7 (much minutes after drug administration. worsening). Excited Component of the Positive and Negative Statistical Analysis Syndrome scale (PANSS-EC) [28]: a 5-item scale (low im- A Wilcoxon signed-rank test was performed to assess pulse control, tension, hostility, lack of cooperation and differences in improvement (CGI-S scale) 10 and 60 mi- excitement), with a rating from 1 to 7 per item. Scores nutes after administration, as well as differences in the higher than 20 indicate severe agitation. PANSS and ACES scales. A total of 22 Wilcoxon tests were Agitation-Calmness Evaluation Scale (ACES) [29]: a sin- made, and a p value of 0.002 (0.05/22) was considered gle item that evaluates general agitation and sedation at significant after Bonferroni correction. To assess safety, a the moment of the assessment. It ranges from 1 (severe ag- Friedman rank test was performed on repeated measures itation) to 9 (unarousable). of oxygen saturation, cardiac frequency, and systolic and At the beginning of the study, a site initiation visit was diastolic arterial tension. carried out, in which all the research staff was informed To evaluate the effect of time on the different scales and about the study, trained to properly conduct the scales in- how this effect may vary on the scale, we performed a ser- volved and solve any further doubts. In addition, two ad- ies of mixed-effects logistic regression models. For each ditional meetings were scheduled during the study, in which the research staff refreshed the instructions. Spanish versions of all scales were used. Data was also Table 1. Clinical and socio-demographic characteristics of the study sample gathered by the treating clinician attending each patient Variable Participants (n = 30) in the ED. Age 39 ± 9.73 Gender Procedure Women 20 (66.7) Once a patient with PD in a state of agitation was ad- Personality disorder (PD) mitted to the Psychiatry ED, the most suitable treatment Borderline PD 23 (76.7) Antisocial PD 3 (10) was assessed by the clinician.. If patients did not respond Histrionic PD 4 (13.3) to standard verbal interventions (de-escalation), were suit- Comorbid disorders a able for treatment with IL 9.1 mg and agreed to partic- SUD 14 (46.6) ipate, informed consent was gathered and IL was admi- Affective disorders 10 (33.3) Eating disorders 2 (6.6) nisted by the clinician. Consecutive subject inclusion for ADHD 1 (3.3) the study was performed until a final sample size of n = 30 Dissociative disorder 1 (3.3) b was achieved. Seven patients declined to participate dur- Drug treatment Antidepressants 27 (90) ing the recruitment period. We ensured that the recruit- Antipsychotics 20 (66.6) ment procedures did not imply any modification in the Mood stabilizers 14 (46.6) medical treatment that the participants could receive in Benzodiazepines 17 (56.6) case they did not wish to participate. Other 2 (6.6) In all cases, baseline assessment (T0) was performed Values are presented as mean ± standard deviation ornumber (%). SUD, substance use disorders; ADHD, attention-deficit/hyperactivity within 30 minutes before the initial administration of the disorder. trial drug. Socio demographic information, as well as clin- a A patient can be diagnosed with different comorbid disorders; bA ical data, was gathered. Agitation severity was assessed patient can receive different drug treatments simultaneously. Inhaled Loxapine as Treatment for Agitation in Personality Disorder 485 value, the scale was dichotomised. We used a binary vari- characteristics, comorbidities and baseline treatment. able of whether individuals belonged to one group or an- SUD (n = 14, 46.6%) and affective disorders (n = 10, other as the dependent variable, and the variable time, 33.3%) where the most prevalent comorbid disorders. As measured in minutes, as the independent variable, in- for the baseline treatment, 90% of patients were taking an cluding a random intercept to account for the correlation antidepressant, whereas 66.6% were taking anti- of scores within patients. Scale values at the extremes of a psychotics, 56.6% benzodiazepines and 46.6% mood scale with less than 3 patients were combined with the stabilizers. value next to it in the scale. We also performed a sensi- Included patients showed a baseline mean CGI-S score tivity analysis, including age and sex as covariates in the of 4.63 (SD = 0.718), implying a consideration of model. ‘moderately to markedly ill’. The median score of CGI-I All statistical analyses were conducted using the SPSS was 2 (‘markedly improved’) at T1 and 1 (‘very much im- 19.0 version for Windows (IBM Co., Armonk, NY, USA) proved’) at T3. These results did not remain significant af- and R v3.6.3. ter Bonferroni correction (z = −2.985, p = 0.003). ACES scale results showed a significant increase from a median RESULTS of 2 (‘moderate agitation’) at baseline to 4 (‘normal state’) −6 at T1 (z = −4.713, p = 2 × 10 ), maintaining this state of Patients were aged between 19 and 57 (mean = 39, ‘normality’ at T3 (z = −4.866, p = 0.000001). PANSS-EC standard deviation [SD] = 9.73) and were mostly women scores had a median of 21.50 at baseline, decreasing to a (n = 20, 66.7%). Table 1 shows the main demographic median of 8 at T1 (z = −4.788, p = 2 × 10−6), and to a me- Table 2. Differences in the clinical assessment across the study period Scores Tool Time Time comparison z score p value Median (p25, p75) CGI-I T1 2 (1, 2) 0.0028 T3 1 (1, 1) T1 vs. T3 −2.985 a ACES T0 2 (2, 2) T0 vs. T1 −4.713 0.000002 T1 4 (4, 4.25) T1 vs. T3 −2.217 0.026617 T3 4 (4, 6) T0 vs. T3 −4.866 0.000001a a PANSS-EC T0 21.5 (19.5, 24.25) T0 vs. T1 −4.788 0.000002 a T1 8 (6, 14.25) T1 vs. T3 −4.121 0.000038 T3 5 (5, 7) T0 vs. T3 −4.787 0.000002a a PANSS-EC T T0 4 (5, 6) T0 vs. T1 −4.657 0.000181 a T1 2 (1, 3) T1 vs. T3 −3.745 0.000001 T3 1 (1, 1.25) T0 vs. T3 −4.824 0.000001a a PANSS-EC LIC T0 5 (4, 5.25) T0 vs. T1 −4.669 0.000003 a T1 2 (2, 3) T1 vs. T3 −4.327 0.000015 T3 1 (1, 2) T0 vs. T3 −4.815 0.000001a a PANSS-EC H T0 4 (3, 5) T0 vs. T1 −4.571 0.000005 a T1 1 (1, 2) T1 vs. T3 −2.588 0.000181 T3 1 (1, 1) T0 vs. T3 −4.65 0.000003a a PANSS-EC LoC T0 3 (2.75, 4) T0 vs. T1 −4.473 0.000008 T1 1 (1, 2) T1 vs. T3 −2.588 0.009654 T3 1 (1, 1) T0 vs. T3 −4.609 0.000004a a PANSS-EC E T0 5 (4, 6) T0 vs. T1 −4.820 0.000001 a T1 2 (1, 3) T1 vs. T3 −3.695 0.000220 T3 1 (1, 1.25) T0 vs. T3 −4.815 0.000181a CGI-I, Clinical Global Impresion-Improvement; ACES, Agitation-Calmness Evaluation scale; PANSS-EC, Positive and Negative Syndrome Scale-Excited Component; PANSS-EC T, PANSS-EC Tension item; PANSS-EC LIC, PANSS-EC Low Impulse Control item; PANSS-EC H, PANSS-EC Hostility item; PANSS-EC LoC, PANSS-EC Lack of Control item; PANSS-EC E, PANSS-EC Excitation item; T1, 10-minute assessment point; T3, 30-minute assessment point. a Significant after Bonferroni correction. 486 M. Ferrer, et al. −6 dian of 5 (z = −4.787, p = 2 × 10 ) at T3. All subscales tails, see Supplementary Table 1 [available online]). We showed a similar tendency towards a significant score de- also performed a sensitivity analysis to assess the effect of crease across time at the two assessment points after IL age and sex on the results. Overall, adjusting the model administration. Complete results are detailed in Table 2. for age and sex did not seem to alter the results. All the included subjects were discharged from the Psychiatric ED and no additional medication was needed DISCUSSION over the study period. No significant adverse effects were registered. A sig- Results of our study show that a single dose of IL can be nificant decrease of the basal arterial tension and cardiac a safe and effective treatment for agitation of patients with frequency was observed at T1, T2, and T3 assessment PD attending a psychiatric ED. IL had a rapid-onset and a points (p ＜ 0.001). Oxygen saturation remained stable lasting effect on improving agitation in patients with PD over the study period. The scores of systolic arterial ten- while maintaining a good safety profile and no incidence sion (SAT), diastolic arterial tension (DAT) and cardiac fre- of interactions or adverse reactions. Since agitated PD pa- quency remained at physiological levels (Table 3). tients represent roughly 9−27% of agitated emergency In all scales except for the ACES, time was significantly episodes [30] and no specific treatment is approved spe- associated (p ＜ 0.05) with a reduction in the score. For cifically for this particular group, IL may be an option for the ACES, on the other hand, increased over time. In addi- this treatment gap. tion, we observed that the odds of moving through the dif- Significant changes in ACES and PANSS-EC scores ferent values of the scale as time passed were not were observed early on at the 10 minutes assessment constant. Results suggest (for all scales except for the point, a very interesting fact considering a fast decrease of ACES) greater effects of time for higher values of the symptoms is the main goal of the pharmacological treat- scales, implying a faster change between higher values ment of agitation when non-pharmacological strategies than between lower values (see Fig. 1 and, for more de- do not work [6]. In this regard, the IL administration Table 3. Differences in hemodynamic parameters and oxygen saturation across the study period 2 Parameter Time Median (p25, p75) χ df p value SAT T-1 122 (110.75, 136) 30.28 4 ＜0.001 T0 123.5 (117, 136.5) T1 122.5 (108.75, 129) T2 121 (108, 129) T3 122.5 (108.75, 129) DAT T-1 86 (77.75, 91.75) 39.88 4 ＜0.001 T0 86 (78, 92.25) T1 78.50 (72, 85) T2 79 (71.75, 86.25) T3 78 (65.75, 82) CF T-1 83.5 (77.5, 100) 23.55 4 ＜0.001 T0 85 (77.75, 100) T1 79.50 (74.5, 88.25) T2 80 (70.50, 85) T3 79 (71, 85) O2SAT T-1 98 (97.75, 99) 0.99 3 0.80 T0 98 (97.5, 99) T1 98 (97.75, 99) T2 98 (97.75. 99) T3 98 (97.75, 99) T-1, assessment point during the patient’s admission in the Psychiatric Emergency Department; T0, baseline assessment point; T1,10-minute assessment point; T3, 30-minute assessment point; SAT, systolic arterial tension; DAT, diastolic arterial tension; O2SAT, oxygen saturation; CF, cardiac frequency. Inhaled Loxapine as Treatment for Agitation in Personality Disorder 487 Fig. 1. Odds ratios with 95% confidence intervals per scale and value are presented. A grey dashed line representing the line of best fit is also included for each scale. CGI-I, Clinical Global Impresion-Improvement; ACES, Agitation-Calmness Evaluation scale; PANSS-EC, Positive and Negative Syndrome Scale-Excited Component. mechanism (through inhalation directly delivered to the apeutic goal with a mild sedative effect. Therefore, IL alveoli) allows IV-like pharmacokinetics, producing a would be in line with the recommendations of treating ag- rapid onset of the effect while requiring a low total dose itation without sedating and would allow a higher im- [17]. This interpretation is reinforced by the fact that there plication of patients in their therapy [10]. Regarding safety were no significant differences in CGI points between T1 issues, oxygen saturation maintained high levels across (10 minutes after administration) and T2 (60 minutes). the study time with no episodes of bronchoconstriction, This is also suggested by the study of the effect of time: and heart rate and blood pressure remained within nor- changes in the assessment scores are observed over time, mal range. In addition to the absence of significant side ef- indicating that clinical improvement is maintained. fects, an indirect sign of the therapeutic effect can be in- Furthermore, this time effect is more marked in those agi- terpreted in the significant progressive reduction of heart tation episodes with higher severity, which could be due rate and blood pressure levels at the different assessment to a possible ‘ceiling effect’ in patients presenting less se- points [31,32]. These aspects are relevant since other vere agitations. Therefore, it appears that IL therapeutic ef- pharmacological treatments, sometimes from the same ficacy is persistent. Note that no additional doses or other family of antipsychotics, have exhibited a higher risk of medications were required, no physical restraint was nec- serious side effects and should be avoided if possible essary, and most of the patients were discharged without [11-13]. In summary, IL could be a safer, more tolerable needing to be admitted, altogether suggesting a potential and less invasive medication for agitation in PD patients benefit in the mid-term management of the crisis. than anxiolytics and antipsychotics, avoiding significant Based on the results showing a median value of 4 at the sedation and allowing also for a higher participation of ACES assessment (meaning ‘normal’) at the 60 minute the patient in his/her own treatment. time point together with an optimal calming effect ac- Despite IL has only been approved for agitation treat- cording to the observed improvements in the CGI and ment of patients diagnosed with schizophrenia or bipolar PANSS-EC, it could be argued that IL achieves the ther- disorder, other studies have evaluated its efficacy and se- 488 M. Ferrer, et al. curity in off-label usessuch as substance intoxications and comparing IL with other drugs and analysing the effect on dual disorders [19-21], which have showed similarly psychopathological dimensions of PD that could be on good results in tolerability and safety. It is important to the basis of agitation episodes, such as anger or cogni- note that the results of our study are in line with the recent tive-perceptual symptoms. Furthermore, given the lack of publication of Patrizi et al. [24] in agitated PD patients. significant side effects and with the aim of increasing the To our knowledge, this is the first prospective study that access to IL treatment, future studies should assess IL safe- aims to test IL efficacy and safety to treat agitation of pa- ty and efficacy when treating agitation of PD patients in tients diagnosed with PD in an ED setting. A prospective settings other than hospitals and without the supervision design has been chosen as it increases the reliability of the of healthcare professionals. association between the treatment and the observed ef- fect, it allows controlling variables such as time effect, and ■ Funding avoids recall bias. Furthermore, treating acute agitated pa- Over the course of this investigation, M. Soler Artigas tients in the ED adds the advantage that the data was gath- was a recipient of a contract from the Biomedical ered in a similar setting to the day-to-day environment Network Research Center on Mental Health (CIBERSAM), that clinicians face when dealing with agitation, allowing Madrid, Spain and was also a recipient of a Juan de la for a better external validity of these results. Cierva Incorporación contract from the Ministry of Some study limitations must be highlighted. First, as pa- Science, Innovation and Universities, Spain (IJC2018- tients with PD were consecutively included in the study 035346-I). due to the indication of treating agitation, and all patients were treated with IL, its efficacy could not be directly ■ Acknowledgments compared with other treatments. Nevertheless, since as to We would like to acknowledge Alex Ruè Jiménez, from date no specific recommendations for the treatment of ag- the Clinical Trials Unit of the Department of Psychiatry in itation in PD patients have been proposed, there is not a Vall d’Hebron Research Institute, for his help in proof- gold-standard drug to perform a direct comparison. reading and ensuring correct English use. Second, results of the mixed effect logistic regression models must be interpreted with caution, as there are not ■ Conflicts of Interest enough data to obtain robust estimates or even to estimate Marc Ferrer has received fees from Shire, Takeda, confidence intervals, even though our data appear to sup- Ferrer, Otsuka, Lundbeck, Janssen-Cilag, Eli-Lilly, Rubió, port a maintained efficacy trend over time, especially in Oryzon, Almirall to act as speaker or consultant. highest severity agitations. Third, a small sample size may Christian Fadeuilhe has received fees to give talks for make it difficult to determine if a particular outcome is a Shire, Takeda, Ferrer, Italfarmaco and Otsuka in the last 5 true finding, and in some cases a type II error may occur. years. Finally, the majority of the subjects included in the Raúl Felipe Palma-Álvarez has received fees to give sample were diagnosed with BPD, limiting the general- talks for Exeltis, Lundbeck, MSD, Mundipharma and ization of the study results to other PD. However, our find- Takeda. ings can be clinically relevant considering that BPD, to- Josep Antoni Ramos-Quiroga was on the speakers’ bu- gether with APD, are the PDs with the highest association reau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, with agitation [6]. Novartis, Shire, Takeda, Bial, Shionogui, Lundbeck, According to the results of our prospective, naturalistic Almirall, Braingaze, Sincrolab, Medice and Rubió in the study, IL could be a safe and effective option to treat agi- last 5 years. The Department of Psychiatry chaired by him tation of PD in hospital EDs, especially for those patients received unrestricted educational and research support diagnosed with BPD. The therapeutic target could be ach- from the following companies in the last 5 years: Eli-Lilly, ieved quickly, with patients’ participating in their own Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer, Oryzon, treatment, and the calming effect could be maintained Roche, Psious, and Rubió. over time. Our preliminary results should be replicated with randomized controlled trials with larger samples, Inhaled Loxapine as Treatment for Agitation in Personality Disorder 489 ness and underlying pathology. J Clin Psychiatry 2006;67 ■ Author Contributions Suppl 10:5-12. 5. Allen MH, Currier GW. Use of restraints and pharmacother- Marc Ferrer, Josep Antoni Ramos-Quiroga, and Pol apy in academic psychiatric emergency services. Gen Hosp Ibáñez designed the study and obtained the ethics Psychiatry 2004;26:42-49. approval. Óscar Soto-Angona, Raquefet Lidai, Christian 6. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Fadeuilhe, Raúl Felipe Palma-Álvarez, Sebastian Vargas- Vázquez G, et al. Assessment and management of agitation in Cáceres, María Ángeles Torrecilla, and Anna López, gath- psychiatry: expert consensus. World J Biol Psychiatry 2016; ered the clinical data and collaborated in the creation of 17:86-128. 7. Fossati A, Barratt ES, Carretta I, Leonardi B, Grazioli F, Maffei the dataset used for the study. Óscar Soto-Angona, Pol C. Predicting borderline and antisocial personality disorder Ibáñez, and María Soler-Artigas performed the statistical features in nonclinical subjects using measures of impulsivity analysis of the results obtained. Óscar Soto-Angona and and aggressiveness. Psychiatry Res 2004;125:161-170. Marc Ferrer conducted the bibliographic search, and 8. Borschmann R, Henderson C, Hogg J, Phillips R, Moran P. wrote the different versions of the manuscript. All authors Crisis interventions for people with borderline personality provided key suggestions and contributed to the dis- disorder. Cochrane Database Syst Rev 2012;(6):CD009353. 9. Martínez-Raga J, Amore M, Di Sciascio G, Florea RI, Garriga cussion, proofreading and correction of the final version M, Gonzalez G, et al. 1st International Experts' Meeting on of this work. All authors meet all four criteria for author- Agitation: conclusions regarding the current and ideal man- ship included in the ICMJE recommendations. agement paradigm of agitation. Front Psychiatry 2018;9:54. 10. Wilson MP, Pepper D, Currier GW, Holloman GH Jr, Feifel D. ■ ORCID The psychopharmacology of agitation: consensus statement Marc Ferrer https://orcid.org/0000-0002-1283-8578 of the american association for emergency psychiatry project Óscar Soto-Angona https://orcid.org/0000-0003-0234-4280 Beta psychopharmacology workgroup. West J Emerg Med 2012;13:26-34. 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