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 ).

Pharmacist intervention to detect drug adverse events on admission to the emergency department: Two case reports of neuroleptic malignant syndrome.

WHAT IS KNOWN AND OBJECTIVE: Neuroleptic malignant syndrome (NMS) is a rare but severe adverse effect of antipsychotic drugs. CASE DESCRIPTION: We report two cases of NMS highlighted by clinical pharmacists in an emergency unit during summer. One of them was fatal. Medication reconciliation processes performed at admission identified treatment with loxapine for one of them and with loxapine and clozapine for the other. Interview of the patients highlighted clinical symptoms suggesting NMS, allowing the pharmacists to alert the medical team. WHAT IS NEW AND CONCLUSION: Adverse drug events may be severe and clinical pharmacists in emergency departments can help to detect them.

The Role of Inhaled Loxapine in the Treatment of Acute Agitation in Patients with Psychiatric Disorders: A Clinical Review.

Loxapine is a first generation antipsychotic, belonging to the dibenzoxazepine class. Recently, loxapine has been reformulated at a lower dose, producing an inhaled powder that can be directly administered to the lungs to treat the agitation associated with psychiatric disorders, such as schizophrenia and bipolar disorder. Thus, the aim of this narrative and clinical mini-review was to evaluate the efficacy and tolerability of inhaled loxapine in the treatment of acute agitation in patients with psychiatric disorders. The efficacy of inhaled loxapine has been evaluated in one Phase II trial on patients with schizophrenia, and in two Phase III trials in patients with schizophrenia and bipolar disorder. Moreover, there are two published case series on patients with borderline personality disorder and dual diagnosis patients. Inhaled loxapine has proven to be effective and generally well tolerated when administered to agitated patients with schizophrenia and bipolar disorder. Two case series have suggested that inhaled loxapine may also be useful to treat agitation in patients with borderline personality disorder and with dual diagnosis, but further studies are needed to clarify this point. However, the administration of inhaled loxapine requires at least some kind of patient collaboration, and is not recommended in the treatment of severe agitation in totally uncooperative patients. Moreover, the drug-related risk of bronchospasm must always be kept in mind when planning to use inhaled loxapine, leading to a careful patient assessment prior to, and after, administration. Also, the higher costs of inhaled loxapine, when compared to oral and intramuscular medications, should be taken into account when selecting it for the treatment of agitation.

Success of tardive electroconvulsive therapy sessions after loxapine-induced malignant syndrome in the context of very poor metabolisation.

We report the success of tardive electroconvulsive therapy in a case of loxapine malignant syndrome with catatonia. Loxapine and its metabolites were measured in biological samples by liquid chromatography coupled to tandem mass spectrometry. Genes were studied by sequencing and quantitative polymerase chain reaction (PCR). Plasmatic drug concentrations showed a supratherapeutic concentration of loxapine with a very low 8-hydroxyloxapine/loxapine ratio (range from 0.32 to 0.66, normal value>2 for 100mg) and a very long elimination half-life of loxapine (half-life>140h, normal value from 1 to 4hours). We tried to explain this kinetics by exploring the main pharmacogenes implicated in the metabolism of loxapine. No genetic abnormality for CYP1A2 was observed. The study of associated treatments showed the potential contribution of valproate. Pharmacokinetics and pharmacogenetics investigations revealed a blockade of the CYP1A2 metabolic pathway without genetic abnormalities, probably due to valproate co-medication. Toxicological monitoring of loxapine and its metabolites helped to explain the persistence of symptoms and to adapt the therapeutic management.

Rhabdomyolysis with Acute Renal Failure and Deep Vein Thrombosis Induced by Antipsychotic Drugs: A Case Report.

Atypical antipsychotics, the first line therapy for schizophrenia, have already been reported as causing rhabdomyolysis or isolated elevation in serum creatine kinase (SCK). This case report dealing with rhabdomyolysis in a 25-year-old man treated with antipsychotics is particularly unusual, due to the extremely high elevation in SCK and the ensuing acute renal failure. He was treated with loxapine 400 mg/day and risperidone 4 mg/day for 4 days and then loxapine was replaced by levomepromazine 300 mg/day. A series of laboratory examinations showed: SCK 43 650 UI/L, creatinine 392 µmol/L. An acute renal failure (acute tubular necrosis) after iatrogenic rhabdomyolysis was diagnosed, requiring hemodialysis. Furthermore, the patient also developed a deep vein thrombosis (DVT) attributed to his antipsychotic treatment. This case underlines the importance of taking rhabdomyolysis and DVT risk factors into account in patients treated with antipsychotics. Indeed, in this case we note that rhabdomyolysis was probably promoted by the interruption and the reintroduction of the treatment more than by possible dehydration, because no other risk factor could be identified.

Haloperidol versus first-generation antipsychotics for the treatment of schizophrenia and other psychotic disorders.

BACKGROUND: Haloperidol is worldwide one of the most frequently used antipsychotic drugs with a very high market share. Previous narrative, unsystematic reviews found no differences in terms of efficacy between the various first-generation ("conventional", "typical") antipsychotic agents. This established the unproven psychopharmacological assumption of a comparable efficacy between the first-generation antipsychotic compounds codified in textbooks and treatment guidelines. Because this assumption contrasts with the clinical impression, a high-quality systematic review appeared highly necessary. OBJECTIVES: To compare the efficacy, acceptability, and tolerability of haloperidol with other first-generation antipsychotics in schizophrenia and schizophrenia-like psychosis. SEARCH METHODS: In October 2011 and July 2012, we searched the Cochrane Schizophrenia Group's Trials Register, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. To identify further relevant publications, we screened the references of all included studies and contacted the manufacturers of haloperidol for further relevant trials and missing information on identified studies. Furthermore, we contacted the corresponding authors of all included trials for missing data. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared oral haloperidol with another oral first-generation antipsychotic drug (with the exception of the low-potency antipsychotics chlorpromazine, chlorprothixene, levopromazine, mesoridazine, perazine, prochlorpromazine, and thioridazine) in schizophrenia and schizophrenia-like psychosis. Clinically important response to treatment was defined as the primary outcome. Secondary outcomes were global state, mental state, behaviour, overall acceptability (measured by the number of participants leaving the study early due to any reason), overall efficacy (attrition due to inefficacy of treatment), overall tolerability (attrition due to adverse events), and specific adverse effects. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data from the included trials. The methodological quality of the included studies was assessed using The Cochrane Collaboration`s 'Risk of bias' tool.We analysed dichotomous outcomes with risk ratios (RR) and continuous outcomes with mean differences (MD), both with the associated 95% confidence intervals (CI). All analyses were based on a random-effects model and we preferably used data on an intention-to-treat basis where possible. MAIN RESULTS: The systematic review currently includes 63 randomised trials with 3675 participants. Bromperidol (n = 9), loxapine (n = 7), and trifluoperazine (n = 6) were the most frequently administered antipsychotics comparator to haloperidol. The included studies were published between 1962 and 1993, were characterised by small sample sizes (mean: 58 participants, range from 18 to 206) and the predefined outcomes were often incompletely reported. All results for the main outcomes were based on very low or low quality data. In many trials the mechanism of randomisation, allocation, and blinding was frequently not reported. In short-term studies (up to 12 weeks), there was no clear evidence of a difference between haloperidol and the pooled group of the other first-generation antipsychotic agents in terms of the primary outcome "clinically important response to treatment" (40 RCTs, n = 2132, RR 0.93 CI 0.87 to 1.00). In the medium-term trials, haloperidol may be less effective than the other first-generation antipsychotic group but this evidence is based on only one trial (1 RCT, n = 80, RR 0.51 CI 0.37 to 0.69).Based on limited evidence, haloperidol alleviated more positive symptoms of schizophrenia than the other antipsychotic drugs. There were no statistically significant between-group differences in global state, other mental state outcomes, behaviour, leaving the study early due to any reason, due to inefficacy, as well as due to adverse effects. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. AUTHORS' CONCLUSIONS: The findings of the meta-analytic calculations support the statements of previous narrative, unsystematic reviews suggesting comparable efficacy of first-generation antipsychotics. In efficacy-related outcomes, there was no clear evidence of a difference between the prototypal drug haloperidol and other, mainly high-potency first-generation antipsychotics. Additionally, we demonstrated that haloperidol is characterised by a similar risk profile compared to the other first-generation antipsychotic compounds. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. The results were limited by the low methodological quality in many of the included original studies. Data for the main results were low or very low quality. Therefore, future clinical trials with high methodological quality are required.

A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers.

OBJECTIVE: This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710). METHODS: Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart+oral placebo, two doses of inhaled placebo+oral placebo, or two doses of inhaled placebo+oral moxifloxacin (400 mg; positive control), with ≥3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazett-corrected QT duration and QTcI outliers. Pharmacokinetics and adverse events (AEs) were also assessed. RESULTS: Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE. CONCLUSIONS: Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.

Ioxapine (Adasuve) for inhalation. A dangerous gadget.

No comparative trials versus well-established drugs; worrisome risk of bronchospasm; unsuitable mode of administration for agitated, often uncooperative patients.

[Inhaled loxapine: A novel treatment for agitation in psychotic disorders]. / Loksapina podawana droga wziewna - nowa metoda leczenia pobudzenia w psychozach.

Psychomotor agitation is a widespread clinical problem both in patients with schizophrenia and BD. It is a highly hazardous condition, imposing significant risks in psychiatric emergency, as expressedby elevated ratios of adverse events and traumatic experiences (both for patients and medical staff). The available anti-agitation drugs have numerous disadvantages. The orally administered medications (even though preferable to:patients) take hours or even-days for the therapeutic effect to emerge .(and also there is a risk of exacerbating agitation in between). Although rapid onset of action (15-45 minutes) is a noteworthy merit of intramuscular drugs, such an invasive strategy is far too often bound to patients' anxiety, resistance, and traumatic experiences. The need for novel drug formulations (ideally, both integrating the benefits of injectable and orally administered tranquillizing medications, 'and free from their disadvantages) can be, therefore, clearly grasped. Development of.inhaled loxapine exemplifies the attempts to overcome the above-delineated obstacles. As suggested by the available research base, inhaled loxapine seems to be an effective anti-agitation drug in treatment of patients with schizoplhenia and BD (with the onset of action similar to the one observed in intramuscular antipsychotics). However, this formulation of loxapine is distinguished by its non-invasive route of administration, as accompanied by markedly, low risk of side effects or adverse events.

Alternative Approaches for Addressing Acute Agitation in Schizophrenia and Bipolar Disorder.

Importance: The prompt effective treatment of acute agitation among patients with schizophrenia or bipolar disorder can alleviate distressing symptoms for the patient and decrease the risk of escalation to aggression and the potential for serious harm to the patient, health care providers, and others.Observations: A commonly used approach for the management of acute agitation has been the intramuscular administration of antipsychotic medications and/or benzodiazepines. However, US Food and Drug Administration-approved treatments with alternative routes of delivery now include inhaled loxapine powder and, more recently, dexmedetomidine sublingual film. Two formulations of intranasal olanzapine for acute agitation are in development.Conclusions and Relevance: Intranasal formulations offer the potential for favorable pharmacokinetics and onset of action combined with ease of delivery obviating the need for injections and are thus consistent with patient-centered factors such as preference and self-administration. In this review, alternative methods of medication delivery are discussed, with an emphasis on the potential for intranasal administration to treat acute agitation in adult patients with schizophrenia or bipolar disorder.Prim Care Companion CNS Disord 2024;26(1):23nr03596. Author affiliations are listed at the end of this article.

Brain disposition and catalepsy after intranasal delivery of loxapine: role of metabolism in PK/PD of intranasal CNS drugs.

PURPOSE: To elucidate the role of metabolism in the pharmacokinetics and pharmacodynamics of intranasal loxapine in conscious animals. METHODS: At pre-determined time points after intranasal or oral loxapine administration, levels of loxapine, loxapine metabolites, and neurotransmitters in rat brain were quantified after catalepsy assessments (block test and paw test). Cataleptogenicity of loxapine was also compared with its metabolites. RESULTS: Intranasally administered loxapine was efficiently absorbed into systemic circulation followed by entering brain, with tmax ≤15 min in all brain regions. Oral route delivered minimal amounts of loxapine to plasma and brain. Brain AUC0-240min values of 7-hydroxy-loxapine were similar after intranasal and oral administration. Intranasal loxapine tended to induce less catalepsy than oral loxapine, although statistical significance was not reached. The catalepsy score was positively and significantly correlated with the striatal concentration of 7-hydroxy-loxapine, but not with loxapine. 7-hydroxy-loxapine was more cataleptogenic than loxapine, while the presence of loxapine tended to reduce rather than intensify 7-hydroxy-loxapine-induced catalepsy. The increases in striatal dopamine turnover were comparable after intranasal and oral loxapine administration. CONCLUSIONS: The metabolite 7-hydroxy-loxapine, but not loxapine, was the main contributor to the catalepsy observed after intranasal and oral loxapine treatment. Intranasal route could effectively deliver loxapine to brain.

Efficacy and Safety of Loxapine in Acute Agitation: A Systematic Review of Interventional Studies.

Objective: To assess the efficacy and safety of loxapine in acute agitation.Data Sources: PubMed, Cochrane database, EMBASE, PsycINFO, and ClinicalTrials.gov were searched to identify relevant articles published in English or French from inception to March 15, 2022. The term "Loxap*" was searched in titles and abstracts.Study Selection and Data Extraction: Interventional studies that compared the effectiveness of loxapine to any other intervention (including another administration route or dosage of loxapine, other drugs, and placebo) in acute agitation were included. From the 1,435 articles initially identified, and after the assessment of 73 full texts, 7 articles were selected, encompassing 1,276 participants. Two reviewers independently extracted data of interest using a predefined form.Results: Among included studies, 5 were double-blind, 2 were open-label, and all were randomized. The risk of bias was low for 2 studies, involving 658 participants. Four articles compared loxapine to placebo, and 3 compared it with haloperidol, aripiprazole, and droperidol. Loxapine was found to be more effective and faster regarding acute agitation control. Also, across included studies, loxapine was well-tolerated, with mildly or moderately severe adverse effects.Conclusions: Notwithstanding methodological limitations of the included studies, this systematic review provides reassuring results regarding the use of loxapine in acute agitation. However, further studies with methodological optimizations might be of interest.Prim Care Companion CNS Disord 2023;25(6):23r03552. Author affiliations are listed at the end of this article.

Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder.

OBJECTIVE: To describe the efficacy of inhaled loxapine for the treatment of agitation associated with schizophrenia or bipolar disorder using different examples of effect size (ES). DATA SOURCES: Psychopharmacologic Drug Advisory Committee briefing documents as prepared by the product manufacturer and by the US Food and Drug Administration. STUDY SELECTION: Phase III clinical trials. DATA EXTRACTION: Effect size for primary and secondary efficacy outcomes. DATA SYNTHESIS: Two similarly designed Phase III studies were completed with one conducted in patients with agitation associated with schizophrenia and one in patients with agitation associated with bipolar I disorder, manic or mixed episodes. In both studies, onset of anti-agitation effect was observed at 10 min (first time-point measured) for both the 5 mg and 10 mg doses, as evidenced by time to first statistically significant change from baseline on the Positive and Negative Syndrome Scale, Excited Component (PEC) as compared to placebo. Loxapine remained superior to placebo throughout the remainder of the study at all-time points measured. In the schizophrenia study, the ES difference from placebo on the PEC at 2 h was 0.45 for the 5 mg dose and 0.60 for the 10 mg dose (Cohen's d). ES differences for Clinical Global Impressions-Improvement (CGI-I) were similar. Prior to rounding up, the number needed to treat (NNT) for PEC response and CGI-I response vs. placebo were 4.1 and 4.6, respectively, for loxapine 5 mg and 3.2 and 3.2, respectively, for the 10 mg dose. For the outcome of requiring only one dose of study medication and no rescue medication, the NNT vs. placebo for the 5 mg dose was not statistically significant but was statistically significant for the 10 mg dose vs. placebo with a value of 7. When plotting the PEC responders over time NNT becomes more robust as time after dosing elapses, with the 10 mg dose reaching a NNT of 4 by 20 min. For the bipolar disorder study, the ES difference from placebo on the PEC at 2 h was 0.73 for the 5 mg dose and 0.94 for the 10 mg dose. ES differences for the CGI-I were somewhat higher. Prior to rounding up, NNT for response vs. placebo for PEC and CGI-I criteria were 2.9 and 2.6, respectively, for the loxapine 5 mg dose and 2.2 and 2.1, respectively, for the 10 mg dose. For the outcome of requiring only one dose of study medication and no rescue medication, the NNT vs. placebo for the 5 mg dose was 7 and for the 10 mg dose was 3. The NNT difference between 5 mg vs. 10 mg was statistically significant in favour of the 10 mg dose and had a value of 5. When plotting the PEC responders over time NNT becomes more robust as time after dosing elapses, with the 10 mg dose reaching a NNT of 3 by 20 min. Additional information regarding pulmonary safety demonstrated low rates of pulmonary adverse events among those subjects in the efficacy trials, however, in separate Phase I safety studies conducted in persons with asthma and COPD, respiratory symptoms and/or changes in flow parameters were common. CONCLUSIONS: Inhaled loxapine is a non-invasive treatment option for the management of agitation associated with schizophrenia or bipolar disorder. Effect sizes for inhaled loxapine vs. placebo are robust and on par with those observed with intramuscular antipsychotics and benzodiazepines. Onset of action is rapid. The magnitudes of the effect sizes were generally larger for the 10 mg dose vs. the 5 mg dose, and the overall data supports the 10 mg dose as the dominant choice. The efficacy profile of inhaled loxapine will need to be viewed within the context of its pulmonary safety profile. The advisers to the Food and Drug Administration recommended that inhaled loxapine be restricted to a single dose in 24 h and be subject to a Risk Evaluation and Mitigation Strategy programme.

[RÉALITÉ LT, a pharmacoepidemiological study of semiology and therapeutic strategy of patients with schizophrenia treated by antipsychotic loxapine in routine clinical practice]. / RÉALITÉ LT : Recherche Épidémiologique sur l'Activité de la Loxapine et ses Indications en Thérapeutique quotidiennE lors d'une utilisation à Long Terme. Étude pharmacoépidémiologique : sémiologie et stratégie thérapeutique d'une population de patients présentant des troubles schizophréniques traités par loxapine.

INTRODUCTION: Data concerning the clinical and therapeutic characteristics of patients with schizophrenia treated by antipsychotic in naturalistic conditions are useful. Two national pharmacoepidemiological studies were conducted in France, a retrospective survey RÉALITÉ and a prospective study RÉALITÉ LT, to examine the use of loxapine, first in acute and chronic psychotic states and second in long-term treatment prescribed for patients with schizophrenia. AIM OF STUDY: The aim of RÉALITÉ LT is to specify the clinical characteristics of schizophrenic patients treated by loxapine for at least 4 months and the description of the methods of use of this antipsychotic medication during a 6-month follow-up in "real life" conditions. DESIGN OF STUDY: RÉALITÉ LT is an epidemiologic, observational, longitudinal, prospective (during a half-year period), multicenter and national study of the prescription of loxapine in routine clinical practice. For this study, 645 patients with schizophrenia treated by loxapine were recruited, assessed by PANSS, CGI, GAF, MeDra-SOC-PT for side effects and Girerd questionnaire for compliance; statistical analysis used SAS 9.2. RESULTS: Six hundred and forty-five adult patients were included and assessed at inclusion, month 3 and 6. These patients were mostly male (69%), with an average age of 41, inactive (68%), lonely with no child (79%), under psychiatric care for more than 5 years (81%), less than one third were inpatients. The subtypes of schizophrenia were paranoid (59%), disorganised (21%), undifferentiated or residual (10%), the outcome of psychotic illness was episodic (50%) or continuous (33%). The daily mean dosage of loxapine was 168,4 mg/d, in antipsychotic loxapine monotherapy (27%) or in combination with other antipsychotics (63%); it was often associated with psychotropic medications (anxiolytic [72%], antidepressant [21%], normothymic [19%]). The stability of the dosage of loxapine during the 6 months follow-up (60%) was associated with strict loxapine monotherapy or antipsychotic monotherapy (loxapine associated with other psychotropic medication). Safety, side effects and compliance were compared with previous studies. DISCUSSION AND CONCLUSION: These results are discussed, comparing the two pharmacoepidemiological studies RÉALITÉ and RÉALITÉ LT, loxapine is used in compliance with the two indications (smpc) and French guidelines (HAS, Haute Autorité de santé).

[Dysphagia or dysphagias during neuroleptic medication?]. / Une ou des dysphagies lors d'un traitement par neuroleptiques ?

INTRODUCTION: Dysphagia is a common symptom in the general population, and even more among psychiatric patients, but rarely seen as a sign of seriousness. It is a cause of death by suffocation, and more or less serious complications, and therefore should be diagnosed and treated. Among psychiatric patients, organic and iatrogenic aetiologies, as well as risk factors are identified, which worsen this symptom when associated. It is now accepted that neuroleptics can aggravate or cause dysphagia. They act by several pathophysiological ways on the different components of swallowing, which can be identified by dynamic tests in the upper aerodigestive tract endoscopy. LITERATURE FINDINGS: This symptom is rarely reported by patients and often underestimated by caregivers. The frequency of swallowing disorders is not known. Dysphagia is a cause of complications and an increase in mortality rates among psychiatric patients. It has also been found that the average number of psychotropic drugs in patients who die by cafe coronary is significantly higher than in other patients. There are several phases in swallowing: oral, pharyngeal, and oesophageal. Swallowing disorders can affect each of these phases, or several at once: (a) Extrapyramidal syndrome: dysphagia is present in drug induced Parkinson's syndromes, but prevalence is not known. It is most often associated with another symptom of the extrapyramidal syndrome, but can also be isolated, making its diagnosis more difficult. Dysphagia is due to a slowing down in the oral and pharyngeal reflex, called bradykinesia; (b) Tardive dyskinesia: the oro-pharyngo-oesophageal dyskinesia is the most common type. Oesophageal dyskinesia causes asynchronous and random movements of the oesophagus, resulting in dysphagia. It appears mostly beyond 3 months of treatment with neuroleptics; (c) Acute laryngeal or oesophageal dystonia, associated or not with orofacial dystonia, is characterised by an impairment in the oesophageal muscle contraction and a hypertonia of the upper sphincter of the oesophagus; (d) Polyphagia or "binge eating", is frequent in psychotic patients; (e) Finally, there are risk factors for dysphagia: xerostomia, poor dental status, advanced age, neurological diseases, polypharmacy, sedative drugs, CNS depression, etc., which worsen the symptom. CASE REPORT: Mr J., aged 28, with no psychiatric history, is admitted to the Unit for Difficult Patients in Villejuif for behavioural disorder with homicide on the street. The patient was restrained by passers-by and suffers a head injury and a fracture of the transverse process of L1 vertebra. A cranial CT scan is performed in the emergency room, it is normal. The patient is not known to psychiatric services, and has never taken neuroleptics. Mr J. is homeless, known in his neighbourhood for "his noisy delirium on the street and repeated alcohol abuse." After being arrested by the police in this context, a first psychiatric examination is conducted. The medical certificate states that his condition is not compatible with custody. Mr J. remains mute; he has stereotyped gestures and strange attitudes. No delusion is verbalized. He receives vials of loxapine 50mg causing sedation. At his arrival in the department, Mr J. has the same clinical picture, with a rigid and inexpressive face, reluctance, major unconformity, poor speech. The search for drugs in urine is positive for cannabis. The diagnosis of schizophrenia is rapidly raised, motivating further prescription of loxapine 300 mg daily in combination with clonazepam 6 mg daily. From the earliest days, dysphagia to solids with choking and regurgitation is noted, aggravated by the increase of loxapine treatment of 450 mg / day to 700 mg / day, 7 days after admission. A physical examination is performed before the worsening of dysphagia, it is normal, and in particular, reveals no extrapyramidal syndrome. An anti-cholinergic corrector is introduced, without clinical improvement. A new physical examination is performed; it is normal except for sedation and a slight deviation of the uvula. Upper gastrointestinal endoscopy shows no anatomical lesion. No functional assessment of swallowing is done however. At this stage, the suspicion of neuroleptic induced dysphagia appears to be the most likely hypothesis. Treatment with loxapine is then stopped, resulting in a very rapid clinical improvement. Aripiprazole 15 mg / d is introduced. Dysphagia does not reoccur. DISCUSSION: Loxapine is an atypical antipsychotic, with a lower risk of neurological side effects than first generation of antipsychotics. These side effects are however numerous and from diverse pathophysiological mechanisms. Loxapine is an antagonist of dopamine and serotonin which is involved in the regulation of several neurotransmitters, explaining the multiple mechanisms involved in the onset of dysphagia: first, blocking dopamine D2 receptors in the striatum, causing motor side-effects of central origin, in addition to peripheral effects of the molecule, which impairs swallowing. In principle, the antagonist activity on serotonin 5-HT2A receptors increases dopaminergic activity in the striatum, reducing the risk of extrapyramidal symptoms and tardive dyskinesia, without avoiding them completely. In addition to these mechanisms, cholinergic blockade reduces oesophageal mobility and pharyngeal reflex. Moreover, the antihistamine, anti-cholinergic and adrenergic receptor blocking alpha-1 can cause sedation, which aggravates the symptom. Finally, the depression of the bulbar centres reduces the swallowing reflex and gag reflex altering the intake of food. CONCLUSIONS: The swallowing disorder caused by neuroleptics may occur regardless of the molecule or drug class to which it belongs. It can be found even in the absence of any other neurological signs. It is important to search for the aetiological diagnosis for treatment. At the crossroads of several specialties, swallowing disorders are difficult to diagnose and treat. They are frequently underestimated, partly because patients rarely complain. In our case report, the diagnosis was ascertained by the removal of the medication, without functional evidence, probably by a lack of collaboration between the physician and the endoscopist who had not performed any dynamic investigation of swallowing. This case illustrates the importance of knowing the different mechanisms underlying dysphagia in psychiatric patients, and good communication with gastroenterologists to establish a precise diagnosis of the disorder, and adapt the therapy.

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

BACKGROUND: There is a need for a rapid-acting, non-injection, acute treatment for agitation. AIMS: To evaluate inhaled loxapine for acute treatment of agitation in schizophrenia. METHOD: This phase III, randomised, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov number NCT00628589) enrolled 344 individuals who received one, two or three doses of inhaled loxapine (5 or 10 mg) or a placebo. Lorazepam rescue was permitted after dose two. The primary efficacy end-point was change from baseline in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) 2 h after dose one. The key secondary end-point was Clinical Global Impression-Improvement scale (CGI-I) score 2 h after dose one. RESULTS: Inhaled loxapine (5 and 10 mg) significantly reduced agitation compared with placebo as assessed by primary and key secondary end-points. Reduced PANSS-EC score was evident 10 min after dose one with both 5 and 10 mg doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications. CONCLUSIONS: Inhaled loxapine provided a rapid, well-tolerated acute treatment for agitation in people with schizophrenia.