Treatment Of Agitation In Patients Research Articles

Role of citalopram in the treatment of agitation in Alzheimer's disease.

Neuropsychiatric symptoms (NPS) are common among individuals with Alzheimer's disease (AD), associated with excess morbidity and mortality, greater healthcare use, earlier institutionalization, and caregiver burden. Agitation presents as emotional distress, excessive psychomotor activity, aggressive behaviors, disruptive irritability and dishibition. There is an unmet need to find pharmacologic treatment for agitation in patients with AD that can be safely and effectively used as a concurrent treatment alongside psychosocial interventions. A recent, multicenter, randomized, placebo-controlled trial explored the efficacy of a 30-mg daily dose of citalopram for agitation in patients with AD and showed a significant decrease in agitation for citalopram compared with placebo. Both QTc prolongation and cognitive worsening, as measured by the Mini Mental State Examination, were observed in the citalopram group and present a concern to clinicians. Citalopram at a 20-mg daily dose should be considered as a possible first-line treatment in addition to psychosocial intervention.

Effect of smoking on the pharmacokinetics of inhaled loxapine.

Background:Loxapine inhalation powder delivered by a hand-held device as a thermally generated aerosol (ADASUVE) was recently approved in the United States and European Union for use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia. As smokers comprise a large subpopulation of these patients, and many antipsychotic drugs require dose adjustments for smokers, the objective of this study was to compare the pharmacokinetics of inhaled loxapine administered to smokers and nonsmokers.Methods:Pharmacokinetics and sedation pharmacodynamics using a visual analog scale were studied in 35 male and female adult subjects (18 nonsmokers and 17 smokers) following a single dose of 10 mg of inhaled loxapine. Blood samples were drawn at predose, 30 seconds, 1, 2, 3, 10, 30, and 60 minutes, and 2, 6, 12, and 24 hours after dosing. Loxapine and 8-OH-loxapine were analyzed using reverse-phase liquid chromatography coupled with a tandem mass spectrometer. Pharmacokinetic parameters assessed included Cmax, Tmax, AUCinf, and T1/2 for loxapine and 8-OH-loxapine. Geometric mean ratios (GMRs) were determined for smokers to nonsmokers.Results:Loxapine Cmax was similar in smokers and nonsmokers with a GMR of 99.0%. The median loxapine Tmax was 1.88 and 1.01 minutes for nonsmokers and smokers, respectively. Loxapine AUCinf and AUClast values in nonsmokers were comparable with smokers (GMRs of 85.3% and 86.7%, respectively). A slight decrease in the observed mean terminal half-life values was observed for smokers (6.52 hours for smokers and 7.30 hours for nonsmokers).Conclusions:Sedation profiles and visual analog scale scores at each time point were similar for nonsmokers and smokers. It was concluded that inhaled loxapine does not require dosage adjustment based on smoking behavior.

EPA-1508 – Efficacy of inhaled loxapine for the acute treatment of agitation in patients with schizophrenia or bipolar disorder: is it influenced by baseline agitation severity?

Agitation is a common problem in schizophrenia and bipolar disorder, often requiring drug therapy in an acute care setting. Experts in behavioral emergencies consider speed of onset as an important factor in choosing a treatment. One Phase 2 and two Phase 3 clinical trials were conducted to assess the efficacy of treating agitation with inhaled loxapine. To determine if baseline severity of agitation influenced patient outcome. All trials were multi-center, randomized, double blind, parallel group, placebo controlled. Two doses of inhaled loxapine, 10 mg and 5 mg, were tested. Study subjects were agitated patients with schizophrenia or bipolar disorder who provided informed consent. At baseline, subjects were required to have a minimum total score of 14 for the five items of the PANSS Excited Component (PEC). The primary endpoint was the change in the PEC total score at 2 hrs. This meta analysis compared the efficacy of inhaled loxapine across the 3 studies in subjects with PEC ≥ 20 (88 patients, more severely agitated; MSA) to those with PEC ≤15 (90 patients, less severely agitated; LSA). In the 10 mg dose group, the mean PEC change from baseline for the MSA group was 10.5 while for the LSA subjects was 6.6. This represents a 50% change from baseline for the MSA subjects and a 45% change for the LSA subjects. Inhaled loxapine has as good as or better effects in reducing agitation in more agitated patients as it does in less agitated patients.

Loxapine Inhalation Powder: A Review of its Use in the Acute Treatment of Agitation in Patients with Bipolar Disorder or Schizophrenia

Loxapine is a well-established, first-generation antipsychotic agent. Loxapine inhalation powder (Adasuve(®)) was recently approved in the USA and the EU for use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia. Inhaled loxapine is delivered by a hand-held, single-dose, single-use device that uses the Staccato(®) drug delivery system. With Adasuve(®), maximum plasma loxapine concentrations are reached in a median of 2min. In two randomized, double-blind, placebo-controlled, multicentre trials, inhaled loxapine 5 or 10mg significantly reduced agitation (assessed using Positive and Negative Syndrome Scale-Excited Component scores) in patients with bipolar I disorder or schizophrenia, with the onset of effect seen within 10min of administration. Inhaled loxapine was generally well tolerated in phase III trials (which excluded patients with clinically significant acute or chronic pulmonary disease), with the most commonly occurring adverse events including dysgeusia and sedation. Inhaled loxapine is contraindicated in patients with airways disease associated with bronchospasm or acute respiratory signs or symptoms. In conclusion, inhaled loxapine provides a novel new option for use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia, combining a rapid onset of effect with a noninvasive route of administration.

Pharmacological Treatment of Schizophrenia

We present the pharmacological treatment of schizophrenia based on a simple algorithm that starts with the most important decisions starting from the choice of an antipsychotic drug for an acutely ill patient and ends with maintenance treatment. It represents experts opinions, a formal guideline development process was not followed. Concerning acute treatment we present recommendations for the choice of drug in acutely patients, the treatment of agitated patients, persistent depression, negative symptoms and treatment resistance. Concerning maintenance treatment with antipsychotics we discuss indication, choice of drug, continuous versus intermittent treatment, duration of relapse prevention and dose.

A 3-Week, Open Label Study to Evaluate the Efficacy and Safety of Extended Release Quetiapine Fumarate in the Treatment of Agitation in Patients with Schizophrenia

Objective: To evaluate the efficacy of extended-release quetiapine fumarate (XR) monotherapy once daily, in the treatment of patients with acute episodes of schizophrenia and agitation.Method: Our study was a 3-week open-label study conducted in adult in- or outpatients with schizophrenia. Quetiapine XR was initiated at 300 mg on day 1,600 mg on day 2, and 400–800 mg (at the investigator's discretion) on day 3 and onwards. The primary endpoint was the change from baseline in the Positive and Negative Syndrome Scale Excited Component (PANSS- EC) score. Secondary endpoints included change from baseline in PANSS-Positive, PANSS-Negative, PANSS-General Psychopathological (PANSS-G) subscale scores, total PANSS score, PANSS aggression, hostility and depression cluster scores, CGI-Severity of illness (CGI-S) and the absolute CGI-Improvement (CGI-I) scales. Tolerability was assessed based on reported adverse events (AEs), the Simpson-Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS) scores, laboratory measurements and electrocardiograms (ECGs).Results: Of 40 patients enrolled, 35 completed the study. At day 21, statistically significant improvements versus baseline were seen for the primary and all secondary endpoints assessed. The incidence of AEs was low, and all were mild to moderate in severity. No extrapyramidal symptoms (EPS) as measured by the SAS and BARS were reported, indicating that the treatment was well tolerated. Hospitalization was required in one out-patient due to a relapse of psychosis, but was not considered to be treatment related.Conclusion: Once-daily quetiapine fumarate XR (400–800 mg/day) was effective in reducing agitation and a broad range of symptoms in acute schizophrenia. Treatment, including rapid dose escalation, was generally well tolerated in this study.

Efficacy and Safety of Loxapine for Inhalation in the Treatment of Agitation in Patients With Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial

Efficacy and Safety of Loxapine for Inhalation in the Treatment of Agitation in Patients With Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial

Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo‐controlled clinical trial with inhaled loxapine

The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder. A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo using the Staccato® system. Following baseline assessments, patients received Dose 1 and were evaluated for 24 hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The key secondary endpoint was the Clinical Global Impression-Improvement score at two hours after Dose 1. Additional endpoints included the changes from baseline in the PANSS-EC from 10 min through 24 hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests. For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10 min after Dose 1 with both 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 (dysgeusia was reported in 17% of patients receiving active drug versus 6% receiving placebo). Inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder.

Pain treatment of agitation in patients with dementia: a systematic review

Advancing age is associated with high prevalence of both dementia and pain. Dementia is frequently accompanied by distressing behavioral and psychological symptoms, including agitation and aggression, particularly in nursing home patients. The etiology of agitation is multifactorial. It has been suggested that un-diagnosed and untreated pain may contribute to agitation in people with dementia. If this is correct, individual pain treatment could be of benefit in ameliorating agitation and other behavioral changes in people with dementia. The objective of this paper is to conduct a systematic review of studies of whether pain medication can improve agitation in people with dementia. A systematic search of the PubMed and Cochrane databases for the period 1992-2010 was performed, using dementia, agitation, aggression, depression, behavioral disturbances, behavioral and psychological symptoms (BPSD), pain, pain assessment, pain treatment, pain management, and analgesics as search terms. Inclusion criteria were: prospective studies including patients with dementia, interventions focusing on pain reduction, inclusion of a control condition, and outcome measures including agitation or other related behavioral disturbances. Only three controlled trials were identified; all were cross-over trials, and two included small sample sizes (<50). Findings were inconsistent, and although some correlations were reported, these did not support the hypothesis that pain management reduced agitation. There is a profound dearth of rigorous studies of the effect of pain treatment in patients with dementia and agitation. The available studies do not support the hypothesis that pain management reduces agitation in nursing-home patients with dementia. Randomized, controlled parallel-group studies are needed.

Efficacy and Safety of Loxapine for Inhalation in the Treatment of Agitation in Patients With Schizophrenia

The objective of this study was to assess the efficacy and safety of inhaled loxapine in the treatment of agitation in patients with psychotic disorders. In this randomized, double-blind, placebo-controlled study, 129 agitated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) were randomized to receive in a clinical or hospital setting a single inhalation of 5 or 10 mg of loxapine or placebo administered using the Staccato loxapine for inhalation device. The inhalation device delivered thermally generated drug aerosol to the deep lung for rapid absorption. The primary efficacy measure was change on the Positive and Negative Syndrome Scale-excited component (PANSS-EC) 2 hours following treatment. Secondary outcomes included the Clinical Global Impressions-Improvement scale (CGI-I), Behavioral Activity Rating Scale (BARS), and time to first rescue medication. The study was conducted between September 2006 and January 2007. Differences were statistically significant (P < .05) between placebo and both 5-mg and 10-mg doses on the CGI-I and the CGI-I responder analyses at 2 hours and in time to first rescue medication, and they were statistically significant (P < .05) between placebo and 10-mg loxapine on the PANSS-EC 20 minutes after administration continuing through 2 hours and in change from baseline BARS. Three serious adverse events occurred at least 6 days after treatment, but none were judged related to study treatment. The most common adverse events were sedation and dysgeusia (22% and 17%, respectively, in the 10-mg group, and 14% and 9%, respectively, in the placebo group). Inhaled loxapine was generally safe and well tolerated and produced rapid improvement in agitated patients with psychotic disorders. Statistically significant differences in efficacy were found for the 10-mg dose compared with placebo, with results suggesting 5 mg may be effective. The delivery of loxapine by inhalation may provide a rapid, well-tolerated option for treating acute psychotic agitation that allows patients to avoid the aversive effects and loss of autonomy often associated with use of intramuscular medications. Further investigation of this new loxapine formulation is warranted. ClinicalTrials.gov identifier: NCT00369577.

P02-05 - Inhaled loxapine (AZ-004, staccato loxapine) for rapid and acute treatment of agitation in patients with schizophrenia or bipolar disorder

ObjectivesCurrent treatments for agitation in schizophrenia or bipolar disorder (BD) have limitations in onset of action, invasiveness and tolerability. AZ-004 (Staccato loxapine) is a rapidly acting inhaled treatment designed for acute treatment of agitation delivering drug aerosol to the deep lung for rapid systemic absorption with intravenous-like kinetics. The objective was to evaluate the efficacy and safety of AZ-004 in the acute treatment of agitation in schizophrenia and BD.MethodsTwo randomized, double-blind, placebo-controlled trials included consenting male and female adults, 18-65 years old with DSM-IV-defined schizophrenia (N=344) or BD type 1 or mixed (314) who presented with clinically relevant agitation. Patients received a single inhalation of 5 or 10mg AZ-004 or placebo in a clinical setting with up to 2 additional doses within 24 hours if required. The primary efficacy endpoint was the absolute change in Positive and Negative Syndrome Scale Excited Component score from baseline to 2 hours following treatment.ResultsIn each trial, both 5 and 10mg AZ-004 were significantly superior to placebo for the primary endpoint (P&lt; 0.001 for each dose in each trial). Significant improvements were noted for each AZ-004 dose versus placebo at all timepoints from 10 minutes through 24 hours. Clinical Global Impression-Improvement (CGI-I) at 2 hours post-dose and CGI-I responder analysis were statistically significant for each AZ-004 dose vs. placebo in both studies. Adverse events observed most often for all treatments were dysgeusia, dizziness, and sedation.ConclusionsAZ-004 produced rapid and significant improvement in treating agitation in BD or schizophrenia patients.

Low-Dose Divalproex in Agitated Patients with Alzheimer's Disease

Adequate treatment of behavioral disturbances in Alzheimer's disease is both important and difficult. This report describes a case series that examined the effectiveness and safety of low-dose divalproex in the treatment of agitated patients with Alzheimer's disease who were admitted to an inpatient geriatric psychiatry unit over a 1-year period. All patients had agitation due to probable Alzheimer's disease or mixed dementia and were prescribed divalproex monotherapy at low and completely flexible doses. Patients and nursing staff were blind to study enrollment. Clinical global impression scale scores, divalproex serum levels, and a variety of medical chart data were collected. Twenty patients met selection criteria and were included in the study. Of those, 13 patients (65%) were considered responders, while 4 patients (20%) required augmentation with other psychotropic medications; divalproex was discontinued in 1 patient. Adverse events occurred in 25% of patients. This case series suggests that low-dose divalproex may offer behavioral improvement and a reduced risk of side effects for some patients with agitation in Alzheimer's disease.

Priapism following Phenothiazine therapy: A Case Report and Review of the Literature

Chlorpromazine, a phenothiazine antipsychotic, is an old generation major tranquilizer that has remained relevant in the management of psychosis despite the advent of the newer atypical brands. Priapism, an uncommon urological condition may result from the alpha-adrenergic blocking action of antipsychotics. A 46 years old man developed priapism in the course of treatment with chlorpromazine. He was only able to achieve penile detumescence (subsidence or diminution of swelling or erection of the penis) after surgical intervention. Medical practitioners must regard this as a reminder of the possible risk of priapism with the use of chlorpromazine which remains a main line drug in the treatment of agitated patients in developing, low income countries. Caution must therefore be exercised particularly when combining drugs with high affinity for alpha-adrenergic blockade and patients\' vulnerability considered whenever possible Keywords: Priapism, phenothiazine Journal of Medicine and Biomedical Research Vol. 5 (1&2) 2007: pp. 72-74

Treatment of Agitation in Patients With Schizophrenia

Patients with acute agitation and schizophrenia require sensitive management by the medical staff. Nonpharmacologic de-escalation techniques are recommended prior to the selection and administration of antipsychotic agents. A variety of medication treatments with different routes of administration are available. Treatment selection for the agitated patient with schizophrenia involves weighing factors including, but not limited to, the medication's efficacy, side effects, and formulation, as well as the patient's medical history.

Is There an Alternative to Seclusion or Mechanical Restraint?

Sir: The treatment of agitated patients has been reviewed in the literature.1 We would like to comment on the use of restraints and seclusion for such patients. We agree that mechanical restraints or seclusion should be the last measure used in the majority of cases, but think that application of such methods is sometimes necessary. A decline in the use of seclusion or mechanical restraint due to administrative regulation might be dangerous and the reason for increased violence on psychiatric wards.2 Furthermore, some patients have been known to request placement in seclusion3 or to be mechanically restrained. Although significant literature exists, there is a lack of knowledge about patients' attitudes toward these methods independent of personal experiences.

Management of Acute Agitation in Patients With Bipolar Disorder

To investigate the efficacy and safety of intramuscular (IM) aripiprazole for the treatment of agitation in patients with bipolar I disorder, manic or mixed episodes. In total, 301 patients experiencing acute agitation were randomized to IM aripiprazole 9.75 mg per injection (n = 78), IM aripiprazole 15 mg per injection (n = 78), IM lorazepam 2 mg per injection (n = 70), or IM placebo (n = 75) in this double-blind multicenter study. Patients could receive up to 3 injections over 24 hours. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component score from baseline at 2 hours after first injection. Mean improvements in Positive and Negative Syndrome Scale Excited Component score at 2 hours were significantly greater with IM aripiprazole (9.75 mg, -8.7; 15 mg, -8.7) and IM lorazepam (-9.6) versus IM placebo (-5.8; P <or= 0.001). For all other efficacy measures, all 3 active treatments showed significantly greater improvements over IM placebo at 2 hours (P < 0.05), with similar improvements across the active treatments. Significant differences over IM placebo were seen by 45 to 60 minutes for several efficacy parameters. Both IM aripiprazole doses were well tolerated; the safety profile was similar to oral aripiprazole. Oversedation (Agitation-Calmness Evaluation Scale score of 8 or 9) during 2 hours after first injection was less frequent with IM aripiprazole 9.75 mg (6.7%) and IM placebo (6.8%) versus IM aripiprazole 15 mg (17.3%) and IM lorazepam (19.1%). IM aripiprazole 9.75 and 15 mg are effective and well tolerated for acute agitation in bipolar disorder, although the low incidence of oversedation suggests a risk-benefit profile for IM aripiprazole 9.75 mg.

P2-121: Safety & tolerability of memantine in the treatment of agitation in patients with Alzheimer’s disease: A pilot study in community dwelling patients presenting clinical & caregiver impressions

P2-121: Safety & tolerability of memantine in the treatment of agitation in patients with Alzheimer’s disease: A pilot study in community dwelling patients presenting clinical & caregiver impressions

Olanzapine versus Haloperidol in the Treatment of Agitation in Elderly Patients with Dementia: Results of a Randomized Controlled Double-Blind Trial

The goal of this study was to compare the efficacy and safety of olanzapine versus haloperidol in the treatment of agitation and aggression in patients with dementia. The subjects were 58 out-patients with dementia and agitation. After baseline assessments and, if necessary, a period of wash-out of a previous antipsychotic drug, they were randomly assigned to 5 weeks of double-blind treatment with either olanzapine or haloperidol. The first 2 weeks were used for dose titration. Subsequently, the patients received a fixed dose of either olanzapine (average dose 4.71 mg) or haloperidol (average dose 1.75 mg) from day 14 to day 35. Both olanzapine and haloperidol decreased agitation significantly (decrease in Cohen-Mansfield Agitation Inventory scores), but there was no significant difference between the two drugs. The two drugs had comparable effects on all secondary outcome measures. They were well tolerated and had a similar side-effect pattern. Our study could not demonstrate the superiority of olanzapine, compared to haloperidol, for the treatment of agitation in patients with dementia.

Best Clinical Practice With Ziprasidone IM: Update After 2 Years of Experience

Acute agitation is a common psychiatric emergency often treated with intramuscular (i.m.) medication when rapid control is necessary or the patient refuses to take an oral agent. Conventional i.m. antipsychotics are associated with side effects, particularly movement disorders, that may alarm patients and render them unreceptive to taking these medications again. Ziprasidone (Geodon) is the first second-generation, or atypical, antipsychotic to become available in an i.m. formulation. Ziprasidone IM was approved by the Food and Drug Administration in 2002 for the treatment of agitation in patients with schizophrenia. In October 2004, a roundtable panel of physicians with extensive experience in the management of acutely agitated patients met to review the first 2 years of experience with this agent. This monograph, a product of that meeting, discusses clinical experience to date with ziprasidone IM and offers recommendations on its use in various settings. In clinical trials, patients treated with ziprasidone IM demonstrated significant and rapid (within 15-30 minutes) reduction in agitation and improvement in psychotic symptoms, agitation, and hostility to an extent greater than or equal to that attained with haloperidol i.m. Tolerability of ziprasidone IM was superior to that of haloperidol IM, with a lower burden of movement disorders. Clinical trials have also shown that ziprasidone IM can be administered with benzodiazepines without adverse consequences. Transition from i.m. to oral ziprasidone has been well tolerated, with maintenance of symptom control. The most common adverse events associated with ziprasidone IM were insomnia, headache, and dizziness in fixed-dose trials and insomnia and hypertension in flexible-dose trials. No consistent pattern of escalating incidence of adverse events with escalating ziprasidone doses has been observed. Changes in QTc interval associated with ziprasidone at peak serum concentrations are modest and comparable to those seen with haloperidol IM. Results of randomized clinical trials of ziprasidone IM have been corroborated in studies in real-world treatment settings involving patients with extreme agitation or a recent history of alcohol or substance abuse. In these circumstances, clinically significant improvement was seen within 30 minutes of ziprasidone IM administration, without regard to the suspected underlying etiology of agitation. Agents with a good safety/tolerability profile, such as ziprasidone IM, may be more cost effective long term than older agents, due to reduced incidence of acute adverse effects (eg, acute dystonia) that often require extended periods of observation. Additional trials of ziprasidone IM in agitated patients in a variety of clinical setting are warranted to generate comparative risk/benefit data with conventional agents and other second-generation antipsychotics.

Regression to the Mean: Implications for Clinical Trials of Psychotropic Agents in Dementia

Effective drug development depends on understanding and optimizing results from controlled clinical trials. A recent double-blind, randomized, controlled trial of the treatment of agitation in patients with Alzheimer's disease (AD) found no difference among the four arms of the study: haloperidol, trazodone, behavioral therapy, placebo. The current analysis was undertaken to further investigate the issues bearing on this outcome and to identify better means of detecting psychotropic effects in trials involving patients with AD. This was post hoc analysis of a clinical trial data set. Patients in the placebo group were divided into responders (25% reduction in symptoms), worseners (25% worsening in baseline agitation scores), and those without a change in symptoms. Analysis of the trial outcomes demonstrated that the reduction observed in the placebo group was of the same magnitude as predicted by regression to the mean. Patients exhibiting greater improvement had more severe baseline behavioral disturbances. The relatively modest severity of agitation and the low medication doses achieved in the study may have further contributed to the failure to distinguish among treatment groups. Research design adjustments such as collection of both screening and baseline measures to determine eligibility may limit the effects of regression to the mean on trial outcomes and reduce this challenge to clinical trials.