Doses Of Haloperidol Research Articles

STOCKOUT: THE IMPACT OF NATIONAL HALOPERIDOL TABLET SHORTAGE TO PHYSICIAN PRESCRIPTION PATTERN AND PATIENT OUTCOMES

Introduction Drug shortages are common in the United States, and in 2019 alone there are 11 psychiatric medications out of a total of 270 drugs that are current listed as in shortage by the FDA. One of these medications is haloperidol, which has been in shortage since October 2018 for its low dosage tablet forms, only one out of two pharmaceutical companies recently restocked these forms as of September 2019. Consequently, patients are impacted due to compromised efficacy, possible medication or dosage errors, of which these lead to higher cost for substitute drug and increased risk of rehospitalization. In Canada, for example, those impacted by haloperidol decanoate shortage had higher rehospitalization rate after switching to a different long acting injectable (LAI) medication. As such, it is important for physicians to be aware of current drug shortages and be ready to address the concerns of patients and their caregivers. Methods We conducted a retrospective chart-review mirror study of the nine months before and after the shortage occurred in October 2018 in 37 patients who are on haloperidol followed in geriatric psychiatry outpatient clinic in Brooklyn, New York. Results The preponderance of subjects in this study were diagnosed with either primary psychotic disorders or dementia with behavioral disturbances. Twelve out of 37 (32%) patients who are prescribed haloperidol had to be switched to a higher dose or liquid form. All twelve patients were previously prescribed less than five milligrams of haloperidol daily. None of the patients had a psychiatric emergency visit or hospitalization in the last year prior to haloperidol shortage, but two of the 12 patients had poor medication adherence following the mandatory medication switch. For these two patients, one agreed to a switch to LAI form and the other decompensated and required a visit to the Comprehensive Psychiatric Emergency Program (CPEP). None of the 25 patients who were unaffected by the shortage had a change or decompensation. Conclusions Low dose haloperidol tablet shortage resulted in subsequent change in medication form in our cohort. Medication adherence became an issue following the switch with resultant emergency visit. These findings reflect the underreported impact of psychiatric drug shortages and specific measures should be taken to better coordinate drug supply chain to minimize negative impact to otherwise chronically stable patients. This research was funded by: This study is funded by the Department of Psychiatry, SUNY Downstate Medical Center

Pharmacogenomic response of low dose haloperidol in critically ill adults with delirium

PurposeTo characterize the pharmacogenomic response of low-dose haloperidol for delirium treatment in critically ill adults. Materials and methodsSingle-center, pilot study of a convenience sample of ICU adults with delirium treated with low-dose IV haloperidol. Patients were evaluated for delirium with the ICDSC every 8 h. Serum haloperidol concentrations were collected on ICU days 2–6, CYP2D6 and CYP3A4 genotypes were characterized and patients were categorized as extensive (EM), intermediate (IM) or poor metabolizers (PM). ResultsThe 22 patients (median age 67 [IQR 48,77] years; median APACHE III 81[IQR 54,181]; CYP2D6 [EM = 12, IM = 7, PM = 3], CYP3A [EM = 18, IM = 4]) received a median [IQR] daily haloperidol dose of 3.0 [2.4, 4.5] mg. After adjusting for age, SOFA, and ICU day, neither an association between CYP2D6 (IM p = .67/PM p = .25) or CYP3A4 (IM p = .44) metabolizer status and serum haloperidol concentrations was found. After adjusting for age, SOFA, and ICU day, neither an association between daily haloperidol dose (p = .77) or ICDSC score (p = .13) and serum haloperidol concentrations was found. No patient experienced QTc interval prolongation (≥500 ms). ConclusionsThis pilot study, the first to evaluate the pharmacogenomic response of low-dose haloperidol when used to treat delirium in the ICU, suggests CYP2D6/CYP3A4 metabolizer status does not affect the serum haloperidol concentrations.

Stencil Printing-A Novel Manufacturing Platform for Orodispersible Discs.

Stencil printing is a commonly used printing method, but it has not previously been used for production of pharmaceuticals. The aim of this study was to explore whether stencil printing of drug containing polymer inks could be used to manufacture flexible dosage forms with acceptable mass and content uniformity. Formulation development was supported by physicochemical characterization of the inks and final dosage forms. The printing of haloperidol (HAL) discs was performed using a prototype stencil printer. Ink development comprised of investigations of ink rheology in combination with printability assessment. The results show that stencil printing can be used to manufacture HAL doses in the therapeutic treatment range for 6–17 year-old children. The therapeutic HAL dose was achieved for the discs consisting of 16% of hydroxypropyl methylcellulose (HPMC) and 1% of lactic acid (LA). The formulation pH remained above pH 4 and the results imply that the drug was amorphous. Linear dose escalation was achieved by an increase in aperture area of the print pattern, while keeping the stencil thickness fixed. Disintegration times of the orodispersible discs printed with 250 and 500 µm thick stencils were below 30 s. In conclusion, stencil printing shows potential as a manufacturing method of pharmaceuticals.

Effect of the antipsychotic drug haloperidol on arrhythmias during acute myocardial infarction in a porcine model

Patients receiving psychiatric medication, like the antipsychotic drug haloperidol, are at an increased risk of sudden cardiac death (SCD). Haloperidol blocks the cardiac rapidly-activating delayed rectifier potassium current, thereby increasing electrical dispersion of repolarization which can potentially lead to arrhythmias. Whether these patients are also at a higher risk to develop SCD during an acute myocardial infarction (AMI) is unknown. AMI locally shortens action potential duration, which might further increase repolarization dispersion and increase the risk of arrhythmia in the presence of haloperidol compared to without. Our aim was to test whether treatment with haloperidol implies an increased risk of SCD when eventually experiencing AMI. Twenty-eight female Danish Landrace pigs were randomized into three groups: low dose haloperidol (0.1 mg/kg), high dose (1.0 mg/kg) or vehicle-control group. One hour after haloperidol/vehicle infusion, AMI was induced by balloon-occlusion of the mid-left anterior descending coronary artery and maintained for 120 min, followed by 60 min of reperfusion. VF occurred during occlusion in 7/11 pigs in the control group, 3/11 in the low dose (p = 0.198) and 2/6 in the high dose group (p = 0.335). High dose haloperidol significantly prolonged QT, and reduced heart rate, vascular resistance and blood pressure before and during AMI. Premature ventricular contractions in phase 1b during AMI were reduced with high dose haloperidol. AMI-induced arrhythmia was not aggravated in pigs with haloperidol treatment. Our results do not suggest that AMI is contributing to the excess mortality in patients treated with antipsychotic drugs seen in epidemiological studies.

Is Low-Dose Haloperidol Effective against Postoperative Nausea and Vomiting? A Randomized Controlled Trial

Background: Nausea and vomiting are undesirable outcomes during the postoperative period. Vomiting may cause life-threatening pulmonary aspiration, as the airway reflex may not be fully restored postoperatively due to the residual effects of anesthetic and analgesic medications. Objective: The aim of this study is to determine the effective dosage of haloperidol against nausea and vomiting, as well as its adverse effects. Materials and Methods: A total of 250 female patients between the ages of 19 and 70, who were admitted for laparoscopic abdominal hysterectomy, were included in this study. The patients were randomized into five groups: placebo (n = 50) (Group I), haloperidol 2 mg (n = 50) (Group II), haloperidol 1 mg (n = 50) (Group III), haloperidol 0.5 mg (n = 50) (Group IV), and haloperidol 0.25 mg (n = 50) (Group V). The patients’ duration of anesthesia, duration of surgery, and nausea/vomiting scores were recorded, along with the antiemetic agents used. The Aldrete’s recovery scale was used as the postoperative recovery criteria. Data from the following variables were recorded for all patients at postoperative minute 30 and hours 1, 2, 3, 4, 6, 12, and 24: heart rate, systolic arterial pressure, diastolic arterial pressure, level of sedation, visual analog scale values, antiemetic need, patient satisfaction, side effects. Results: It was determined that 0.5, 1, and 2 mg doses of haloperidol were effective in preventing nausea and vomiting, and there was no difference in effectiveness between the 0.25 mg dose group and placebo. Conclusion: Haloperidol was found to be an effective agent against nausea and vomiting at a dose of 0.5 mg and can be administered at the doses of 0.5 mg to 2 mg.

Paw-Print Analysis of Contrast-Enhanced Recordings (PrAnCER): A Low-Cost, Open-Access Automated Gait Analysis System for Assessing Motor Deficits.

Gait analysis is used to quantify changes in motor function in many rodent models of disease. Despite the importance of assessing gait and motor function in many areas of research, the available commercial options have several limitations such as high cost and lack of accessible, open code. To address these issues, we developed PrAnCER, Paw-Print Analysis of Contrast-Enhanced Recordings, for automated quantification of gait. The contrast-enhanced recordings are produced by using a translucent floor that obscures objects not in contact with the surface, effectively isolating the rat's paw prints as it walks. Using these videos, our simple software program reliably measures a variety of spatiotemporal gait parameters. To demonstrate that PrAnCER can accurately detect changes in motor function, we employed a haloperidol model of Parkinson's disease (PD). We tested rats at two doses of haloperidol: high dose (0.30 mg/kg) and low dose (0.15 mg/kg). Haloperidol significantly increased stance duration and hind paw contact area in the low dose condition, as might be expected in a PD model. In the high dose condition, we found a similar increase in contact area but also an unexpected increase in stride length. With further research, we found that this increased stride length is consistent with the bracing-escape phenomenon commonly observed at higher doses of haloperidol. Thus, PrAnCER was able to detect both expected and unexpected changes in rodent gait patterns. Additionally, we confirmed that PrAnCER is consistent and accurate when compared with manual scoring of gait parameters.

Effects of Pramipexole on Learning and Memory Processes in Naïve and Haloperidol-challenged Rats in Active Avoidance Test.

Parkinson's disease (PD) is the second most common neurode-generative disease, usually detected by its motor symptoms. The non-motor symptoms, including cognitive deficits, have been of great interest to researchers in the last few decades. To assess the effect of pramipexole on learning and memory in naïve and haloperidol-challenged rats. Male Wistar rats divided into 9 groups (n=8): naïve - saline, pramipexole 0.5; 1 and 3 mg/kg bw; Haloperidol groups - saline, haloperidol, haloperidol + pramipexole 0.5; 1 and 3 mg/kg bw. Two-way active avoidance test (TWAA) and activity cage were performed. The studied parameters were: number of conditioned and unconditioned responses, vertical and horizontal movements. Statistical analysis was done using SPSS 19. The naïve experimental groups significantly increased the number of conditioned responses during the tests for short- and long-term memory, compared with the saline groups (p<0.05). During the short-memory test only the animals with the lowest dose of PMX significantly increased the number of unconditioned responses whereas during the long-term memory test all experimental groups increased the number of escapes in comparison with the saline groups (p<0.05). Challenge dose of haloperidol attenuates learning and memory in pramipexol treated rats. Only the highest dose of pramipexol showed significant increase in conditioned and unconditioned responses compared with the haloperidol group (p<0.05). Pramipexole improves learning and memory in naïve rats by enhancing dopaminergic neurotransmission. This is probably not the only mechanism involved. This is confirmed by the decrease in learning and memory ability in rats with haloperidol-challenge.

Combinations of haloperidol and morphine produce maximal levels of anti‐hyperalgesic or potentiation effects in rats with neuropathic pain

Neuropathic pain (NP) is a chronic disorder that result from an injury or dysfunction at central or peripheral nervous system, promoting alterations in control and modulation of nociceptive signalling pathways. The haloperidol is a butyrophenone prototype, that recently some authors have described as anti‐nociceptive drug mediated by sigma‐1 receptors antagonism. Besides, morphine is a prototype analgesic opioid drug currently used in the NP treatment.ObjectiveTo detect the optimal combinations generated by therapy of haloperidol with morphine in NP induced by chronic constriction injury (CCI).MethodsThe anti‐hyperalgesic effects of haloperidol (0.017–0.100 mg/Kg, s.c.) and morphine (0.01–3.16 mg/Kg, s.c.) were determined after single‐doses, both in monotherapy and combined, using the von Frey test. Evaluations were done until 10 days post‐surgery at 30, 60, 90, 120 and 180 minutes after drugs administration and data were processed using Surface of Synergic Interaction analysis (SSI).ResultsHaloperidol and morphine showed a dose‐dependent anti‐hyperalgesic effects. From 16 combinations studied, six were potentiation, while remaining 10 combinations resulted in an additive effect or limited by the maximum effect of the individual doses. The combination morphine (0.0316 mg/Kg) and haloperidol (0.01778 mg/Kg) showed the maximum potentiation effect (p&lt;0.001). In turn, the combination of maximum anti‐hyperalgesic efficacy (p&lt;0.01) was morphine (1.0 mg/Kg) and haloperidol (0.1 mg/Kg). Interestingly, was detected that is required a haloperidol single dose tenfold higher than haloperidol dose employed by the combination of maximum potentiation for reach similar antinociceptive effect.ConclusionsThis study showed that haloperidol and morphine in combination can produce addition and potentiation effects in neuropathic pain, and the SSI analysis allowed to detect the optimal combinations to produce maximum efficacy or maximum potentiation of anti‐hyperalgesic effects.Support or Funding InformationDepartment of Pharmacobiology, Cinvestav‐Unidad Coapa, C.P. 14330, Tlálpan, Mexico City, Mexico.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

DIAGNOSIS DOES MATTER: MEDICATION DOSING IN END-OF-LIFE CARE FOR PERSONS WITH DEMENTIA

Introduction • Background: We provide end-of-life care to veterans with various diagnoses both in acute and long-term care settings. During our practice we noticed differences in dose requirements of various medications used to control symptoms based on primary terminal diagnoses. Literature review did not show any evidence suggesting correlation of doses of medications and primary terminal diagnoses in end-of-life care. Objective To review medication use, doses, symptoms and diagnoses to establish whether terminal diagnosis would impact the amount of medications required for symptom management in end-of-life care. Methods We conducted a retrospective chart review of patients who died in the Topeka VA Medical Center inpatient setting from January 1, 2018 to May 31, 2018. Various clinical events were reviewed during the last 48 hours of life of these deceased patients. Results There were 20 patients who died during the review period; 19 (95%) of them were men. Average age was 74.45 years (range 66 to 95). Out of the total, 5 (25%), 5 (25%) and 4 (20%) of patients had terminal diagnosis of dementia, malignancy and thought disorder respectively. Thirteen (65%) died in acute medical setting and the rest of them died in long-term care setting. None of these patients had a change in care setting during last 48 hours of life. All of these patients experienced pain, anxiety and terminal delirium during last 48 hours of their life, based on clinical assessment. Opiates, lorazepam and haloperidol were used to manage these symptoms during end-of-life care. All of these patients required parenteral (intravenous or subcutaneous) use of medications for symptom control during the last 48 hours of life. Data showed differences in dose requirements of medications based on the primary terminal diagnosis. During the last 48 hours of life, patients with primary terminal diagnosis of dementia required 146.8 mg of parenteral morphine equivalent (PME), 40.9 mg of lorazepam and 68.5 mg of haloperidol in comparison to 42 mg, 11.7 mg and 14.9 mg of respective medications for patients without primary terminal diagnosis of dementia. During the same period, patients with primary terminal diagnosis of thought disorders required 53.6 mg of haloperidol compared to 19 mg for other patients. The PME requirement for patients with and without malignancy as primary terminal diagnosis was 67.8 mg and 68.4 mg respectively. Conclusions During the last 48 hours of their life, patients with primary terminal diagnosis of dementia required 3 times more morphine, 4 times more lorazepam and 4 times more haloperidol than patients without primary terminal diagnosis of dementia for management of end-of-life symptoms. During the last 48 hours of their life, patients with primary terminal diagnosis of thought disorder required 2.5 times more haloperidol than patients without primary terminal diagnosis of thought disorder. During the last 48 hours of their life, patients with primary terminal diagnosis of malignancy required almost the same doses of morphine equivalent as patients without primary terminal diagnosis of malignancy. Limitations: - Very small sample size - Retrospective review of charts - Single site - Short period of study Implications for Future Research: Our data suggest that patients with dementia required much higher doses of opiate, lorazepam and haloperidol for symptom management during their end-of-life care. This is contradictory to the commonly prevalent clinical understanding that these medications should be used in lower doses in patients with diagnosis of dementia. Further research is needed to study the relation of terminal diagnosis and medication requirements in end-of-life care. Further research is also needed to study physiological and biochemical changes during the terminal state that might influence amount of medications required to treat symptoms. Sponsored by the VA Caucus This research was funded by None

The Side Effect of Haloperidol in Schizophrenic Patients: Analysis of Red Blood Cell Distribution Width (RDW) and Mean Platelet Volume (MPV) Values

INTRODUCTION: Like the increase of pro-inflammatory cytokines and oxidative stress as schizophrenia pathophysiology, haloperidol also increases RDW and MPV values. Both of these values ​​have been clinicians concern because they are a risk factor for the various type of vascular disease.&#x0D; &#x0D; OBJECTIVE: This study aims to determine the side effect of haloperidol on RDW and MPV values in schizophrenic patients. &#x0D; &#x0D; METHODS: This research method uses observational analytic design with a prospective cohort approach with pre and posts analysis conducted at the Regional Special Hospital of South Sulawesi Province during May - July 2018 in 30 schizophrenic subjects. The subjects were diagnosed as first episode schizophrenia based on ICD 10, blood samples were taken, for RDW and MPV values ​​before and after haloperidol was given at the 4th and 8th weeks.&#x0D; &#x0D; RESULTS: The results showed that the mean RDW value at the 4th week was higher in 15 mg/day haloperidol group (15.8) compared to 7.5 mg/day haloperidol group (15.3) with p&amp;lt;0.05. Mean RDW value taken at 8th week was higher in 15 mg/day haloperidol group (16.4) compared to 7.5 mg/day haloperidol group (15.6) with p&amp;lt;0.001. Mean MPV value taken at 8th week was higher in 15 mg/day haloperidol group (13.3) compared to 7.5 mg/day haloperidol group (11.6) with p&amp;lt;0.001. &#x0D; &#x0D; CONCLUSION: This study showed an increase in the RDW value in schizophrenia subjects prior to the haloperidol administration. RDW ​​and MPV values were higher after haloperidol treatment compares to before haloperidol treatment. The increase of RDW and MPV values tend to be influenced by haloperidol dosage and administration duration.

An Interesting Case of Carbamazepine-Induced Stevens-Johnson Syndrome.

A 29-year-old Black female patient was admitted to a psychiatric ward with symptoms of major depressive disorder with psychosis. The patient was started on amitriptyline 50 mg/day and haloperidol 10 mg/day. On day 4 post-admission, the preferred first-line antidepressant, fluoxetine, became available and the patient was switched from amitriptyline to fluoxetine 20 mg/day. On the same day, the dose of haloperidol was reduced to 5 mg/day. Thirteen days post-initiation of these medications the patient became talkative, associated with emotional lability, an expansive mood, irritability and restlessness. The working diagnosis was changed to bipolar affective disorder in the manic phase. Fluoxetine was discontinued and carbamazepine 600 mg/day was added to the patient’s treatment regimen. Her manic symptoms started to resolve; however, 14 days post-initiation of carbamazepine, the patient had a fever; itchy, discharging eyes; respiratory distress; generalised symmetrical erythematosus rash; buccal ulceration; and conjunctival injection with difficulty opening her eyes. Carbamazepine was immediately discontinued and the patient received intravenous fluid resuscitation. The patient recovered considerably after 12 days of symptomatic and supportive management, and was transferred back to the psychiatric ward for the continuation of bipolar disorder management. Lithium therapy was instituted and the patient was subsequently discharged. Using the Algorithm of Drug causality for Epidermal Necrolysis (ALDEN) Stevens–Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) drug causality scoring system, carbamazepine and fluoxetine were evaluated as ‘very probable’ and ‘possible’ causes of SJS, respectively, in this patient. Fluoxetine-induced SJS was considered on account of previous case reports, however no evidence of causality was found in this patient. Consecutive administration with a potential increase in carbamazepine due to inhibition of cytochrome P450 (CYP) 3A4 metabolism by fluoxetine was also not ruled out. A diagnosis of carbamazepine-induced SJS was made and was considered an idiosyncratic adverse drug reaction.

Schizophrenia dimension-specific antipsychotic drug action and failure in amphetamine-sensitized psychotic-like rats

Schizophrenic patients suffer from various disruptions in their psyche, mood and cognition, most of which cannot be effectively treated with the available antipsychotic drugs. Some dimensions of the schizophrenia syndrome in man can be mimicked in animals by the amphetamine (AMPH)-sensitization-induced psychosis model. Using such a sensitization procedure, we induced a psychosis-like syndrome in rats, measured as a deficit in sensory information processing and memory deficits. We then investigated the possible restorative effects of continuous treatment with haloperidol (HAL), a typical antipsychotic drug, on distinct dimensions of the syndrome. We found that, continuous infusion of a clinically relevant dose of HAL (0.5 mg/kg/day) effectively ameliorated AMPH-sensitization-induced sensorimotor gating disruptions after seven days of treatment. However, the sensory information processing deficit reappeared after prolonged HAL treatment, suggesting a treatment failure in this dimension of the syndrome. HAL had at this dose little beneficial effects on the cognitive deficits. In contrast, a continuously administered low dose of HAL (0.05 mg/kg/day) successfully attenuated cognitive deficits, but aggravated the sensorimotor gating deficit under both short- or long-term treatment conditions. Post mortem neurochemical analysis revealed that the psychotic-like behavior induced by our manipulations might be explained by altered monoamine levels in distinct brain regions. These findings provide evidence for dissociating and dose-dependent HAL treatment action and failure at different dimensions of schizophrenia.

The effects of haloperidol on microglial morphology and translocator protein levels: An in vivo study in rats using an automated cell evaluation pipeline.

Altered microglial markers and morphology have been demonstrated in patients with schizophrenia in post-mortem and in vivo studies. However, it is unclear if changes are due to antipsychotic treatment. Here we aimed to determine whether antipsychotic medication affects microglia in vivo. To investigate this we administered two clinically relevant doses (0.05 mg n=12 and 2.5 mg n=7 slow-release pellets, placebo n=20) of haloperidol, over 2 weeks, to male Sprague Dawley rats to determine the effect on microglial cell density and morphology (area occupied by processes and microglial cell area). We developed an analysis pipeline for the automated assessment of microglial cells and used lipopolysaccharide (LPS) treatment ( n=13) as a positive control for analysis. We also investigated the effects of haloperidol ( n=9) or placebo ( n=10) on the expression of the translocator protein 18 kDa (TSPO) using autoradiography with [3H]PBR28, a TSPO ligand used in human positron emission tomography (PET) studies. Here we demonstrated that haloperidol at either dose does not alter microglial measures compared with placebo control animals ( p > 0.05). Similarly there was no difference in [3H]PBR28 binding between placebo and haloperidol tissue ( p > 0.05). In contrast, LPS was associated with greater cell density ( p = 0.04) and larger cell size ( p = 0.01). These findings suggest that haloperidol does not affect microglial cell density, morphology or TSPO expression, indicating that clinical study alterations are likely not the consequence of antipsychotic treatment. The automated cell evaluation pipeline was able to detect changes in microglial morphology induced by LPS and is made freely available for future use.

Parenteral Antipsychotic Choice and Its Association With Emergency Department Length of Stay for Acute Agitation Secondary to Alcohol Intoxication.

Acute agitation secondary to alcohol intoxication frequently requires parenteral sedatives for patient and caregiver safety. Antipsychotics play a prominent role; however, no consensus exists regarding the ideal agent. One important consideration when evaluating the choice of antipsychotic is its association with emergency department (ED) length of stay (LOS). We sought to determine the median ED LOS for patients receiving a single parenteral dose of an antipsychotic for acute agitation secondary to alcohol intoxication in an urban Level I trauma center. This was a retrospective review of patients receiving a single parenteral dose of droperidol, haloperidol, or olanzapine who were acutely intoxicated on alcohol from 2011 to 2016. Patients needing psychiatric assessment in our ED are discharged to a geographically separate department; thus, ED LOS is minimally impacted by waits for psychiatric assessment. Data were abstracted from the electronic medical record and are presented descriptively. A total of 40,601 patients were identified and screened; 24,319 patients were intoxicated but received no sedation. Of those remaining 4,495 received multiple drugs and/or benzodiazepines leaving 11,787 for analysis. Median age was 42 years, 76% were male, and 5% of patients were admitted. Mean breath ethanol concentration was 227 mg/dL. Antipsychotics administered were as follows: droperidol (n=3,790), haloperidol (n=1,449), and olanzapine (n=6,548). Median ED LOS was shortest for droperidol (499 minutes, 95% confidence interval [CI]= 493-506 minutes), which was significantly shorter than both haloperidol (524 minutes, 95% CI= 515-537 minutes) and olanzapine (533 minutes, 95% CI= 528-539 minutes). No cases of sudden cardiac death occurred. Droperidol, when given as monotherapy for sedation of acute agitation secondary to alcohol intoxication, was associated with significantly shorter ED LOS than either parenteral haloperidol or parenteral olanzapine. No difference in ED LOS was observed between haloperidol and olanzapine.

Effects of chronic antipsychotic drug exposure on the expression of Translocator Protein and inflammatory markers in rat adipose tissue

The precise effect of antipsychotic drugs on either central or peripheral inflammation remains unclear. An important issue in this debate is to what extent the known peripheral metabolic effects of antipsychotics, including increased adiposity, may contribute to increased inflammation. Adipose tissue is known to contribute to the development of systemic inflammation, which can eventually lead to insulin resistance and metabolic dysregulation. As a first step to address this question, we evaluated whether chronic exposure to clinically comparable doses of haloperidol or olanzapine resulted in the immune activation of rat adipose tissue. Samples of visceral adipose tissue were sampled from male Sprague–Dawley rats exposed to, haloperidol, olanzapine or vehicle (all n = 8), for 8 weeks. From these we measured a cytokine profile, protein expression of F4/80 (a phenotypic macrophage marker) and translocator protein (TSPO), a target for radiotracers putatively indicating microgliosis in clinical neuroimaging studies. Chronic olanzapine exposure resulted in significantly higher adipose IL-6 levels compared with vehicle-controls (ANOVA p = 0.008, Bonferroni post-hoc test p = 0.006); in parallel, animals exposed to olanzapine had significantly higher F4/80 expression when compared with vehicle-controls (Mann Whitney Test, p = 0.014), whereas there was no difference between haloperidol and vehicle groups (Mann Whitney test, p = 0.1). There were no significant effects of either drug on adipose TSPO protein levels. Nevertheless, we found a positive correlation between F4/80 and TSPO adipose protein levels in the olanzapine-exposed rats (Spearman’s rho = 0.76, p = 0.037). Our data suggest that chronic exposure to olanzapine, but not haloperidol, increases production of the pro-inflammatory cytokine IL-6 in adipose tissue and increased macrophages expression (F4/80), in the absence of measurable changes in TSPO with respect to vehicle. This may have potentially important consequences in terms of metabolic dysregulation associated with long-term antipsychotic treatment.

P147: Clinical characteristics and system factors of elderly treated for agitation in the emergency department: a data driven approach

Introduction: Aligning health systems appropriately to the needs of the elderly is an urgent global priority, according to the WHO. In Canada, ED length of stay has risen 16% for elderly patients in the last year. Agitation requiring chemical restraint is a common, high-risk problem for elderly in the ED. Improving outcomes in this heterogeneous population remain difficult due to inability to effectively identify and evaluate delirium, frailty, multi-morbidity, and incompatibility with the ED system. A data-driven approach to complex health problems is a recognized emerging tool for healthcare innovation. New opportunities for targeted quality improvement in the ED will be uncovered by identifying the clinical characteristics of elderly patients with agitation, and the system process factors that influence their outcomes. Methods: We studied 400 patients in a case-control study at two tertiary-care EDs over five years. Patients were randomly selected if age was greater than 75 years. 200 cases of patients who received an intravenous dose of haloperidol, midazolam and/or lorazepam were selected as a surrogate data marker for having agitation. Controls were randomly matched by age and ED diagnosis. Standardized clinical, systems and process variables were collected. We conducted a univariate analysis. Results: Elderly given intravenous medications for agitation had increased mortality (OR 3.8 CI: 1.6-10.7, p&lt;0.001) and ED length of stay (27 vs. 15 hours, p&lt;0.001). No statistical significance was found in clinical characteristics, CTAS scores, PRISMA7 frailty scores nor sentinel or return visits. There was no statistical difference in median hospital length of stay (8 vs. 6 days, p&lt;0.70). No differences were found in median time from ED physician seeing a patient to first consultant request (73 vs. 83 mins, p=0.75). The largest time intervals contributing to ED length of stay were from first consultant request to hospital request (15 vs. 12 hours, p=0.056) and hospitalization delay (13 vs. 7 hours, p=0.45). Conclusion: Identification of high-risk elderly patients for targeted intervention through a data-driven approach is feasible and informative. Traditional clinical characteristics remain unhelpful in identifying and evaluating outcomes in elderly with agitation. We have identified a process factor that is clinically relevant and pragmatic to evaluate in our ED system. Future research focused on optimizing systems process factors to improve quality of elderly care should be prioritized.

Antidopaminergic medication in healthy subjects provokes subjective and objective mental impairments tightly correlated with perturbation of biogenic monoamine metabolism and prolactin secretion.

ObjectivesOff-label prescription of antipsychotics to patients without psychotic symptoms has become a routine matter for many psychiatrists and also some general practitioners. Nonetheless, little is known about the possibly detrimental effects of antidopaminergic medications on general psychopathology, subjective mental state, or a possible association with physiological parameters in nonpsychotic individuals.MethodsIn this randomized, single-blinded study, groups of healthy volunteers (n=18) received low doses of reserpine, aripiprazole, haloperidol, or placebo on 7 successive days. Relevant physiological parameters (plasma prolactin, concentrations of catecholamine metabolites in plasma, and 24-hour urine) and each subject’s mental state (Positive and Negative Syndrome Scale, Hamilton Rating Scale for Depression, visual analogue scale, Beck Depression Inventory II) were assessed at the start and end of the trial.ResultsOf the three active treatments, only reserpine caused a significant increase in some plasma- and urine-catecholamine metabolites, but all three medications evoked objective and subjective changes in general psychopathology scores, which correlated with individual increases in plasma homovanillic acid concentrations. Both objective and subjective impairments were significantly more pronounced in the subgroup with greatest increase of plasma prolactin. Subjects experiencing the most pronounced side effects under haloperidol, which compelled them to drop out, showed significantly higher prolactin concentration increases than those who tolerated haloperidol well.ConclusionWe found consistent associations between altered markers of dopamine transmission and several objective and subjective mental impairments in healthy volunteers after 1 week’s treatment with antidopaminergic medications. These findings should draw attention to a more intensive risk–benefit evaluation in cases of off-label prescription of antipsychotic medications.

O7.3. DOSE-RESPONSE META-ANALYSIS TO IDENTIFY THE OPTIMUM AND EQUIVALENT DOSES OF ANTIPSYCHOTIC DRUGS FOR SCHIZOPHRENIA

BackgroundIt is important to better understand the optimum doses and equivalent doses of antipsychotic drugs. Several methods to understand these relationships have been published, but all these methods have weaknesses. In this paper we present a dose-response meta-analysis which theoretically is the most appropriate method for this purpose.MethodsWe identified all double-blind, placebo-controlled, studies that compared at least two fixed doses of second-generation antipsychotic drugs or haloperidol in people with acute schizophrenia or with predominant negative symptoms. For this purpose, we searched multiple electronic databases, the website of the FDA, and the clinical trial database clinicaltrials.gov. The method applied was dose response meta-analyses with a spline model. The outcome was the reduction of the PANSS or BPRS total score from baseline or – for negative symptoms - a negative symptom scale. With this method we identified 95% effective doses (these have also been called “near-to-maximum” doses). We applied linear splines to examine whether the dose-response curves had already reached a plateau. Moreover, the identified dose-response relationships of each drug were used to derive risperidone equivalent doses.ResultsWe identified 67 randomized-controlled trials that were eligible. The following 1mg risperidone equivalent doses were identified: amisulpride 86.6mg/day, aripiprazole 1.9mg/day, asenapine 2.4mg, brexpiprazole 0.56mg clozapine 91mg, haloperidol 1.01mg, iloperidone 3.2mg, lurasidone 23.5mg, olanzapine 2.4mg, paliperidone 13.4/2.1, quetiapine 77mg, risperidone 1mg, sertindole 3.6mg, ziprasidone 30mg.DiscussionFrom a conceptual point of view, dose-response meta-analysis is the most appropriate method to identify maximally effective doses and equivalent doses. The results of this meta-analysis will be compared with other published methods to define dose-response, in particular the minimum-effective dose method, the classical mean dose method, the daily-defined-doses (DDD) method and expert consensus methods. The results of this analysis are likely to provide information with impact for treatment decisions.

T193. CHRONIC HALOPERIDOL TREATMENT INDUCES SIGNIFICANT CHANGES IN MICROGLIA AND IN THE EXPRESSION OF THE 18 KDA TRANSLOCATOR PROTEIN TSPO IN NAIVE ADULT RAT BRAINS

BackgroundPositron emission tomography (PET) using radiolabeled ligands selective for the 18 kDa translocator protein (TSPO) is the most widely used technique to assess putative neuroimmune abnormalities in vivo. However, the results of TSPO PET in schizophrenia patients are ambiguous. In particular, the influence of antipsychotic medication exposure has not been definitively tested. We have previously established that chronic exposure to two different antipsychotics resulted in increased density and amoeboid morphology of brain microglia, particularly in the cortex (ACC) and corpus striatum (STR) (Cotel et al., 2015). Here we explore the consequences of such treatment on TSPO, in relation to changes in microglia. We hypothesize that chronic haloperidol treatment would increase the expression of TSPO in microglia and correlate with increased levels of circulating proinflammatory cytokines.MethodsAdult male Sprague-Dawley rats (12 week-old) were implanted with subcutaneous osmotic mini-pumps (ALZET® 2ML4) delivering a continuous dose of either common vehicle (20% β-cyclodextrin + 5% ascorbic acid) or haloperidol (2mg/kg/d) for 28 days (Kapur et al., 2003). Plasma was collected before perfusing the animals with 4% buffered PFA. Brains were carefully removed and processed for immunostaining against Iba1 and TSPO. Levels of plasma cytokines were measured using the pro-inflammatory 9-plex panel from Meso Scale Discovery (MSD®). TSPO expression was measured by its area fraction using FIJI software (10 snaps per animal per brain region, 20x magnification) in the ACC, STR, hippocampus (HPC), secondary somatosensory cortex (S2), primary motor cortex (M1). Numbers of resting and amoeboid microglia were determined by unbiased stereology (Gundersen, 1987) in the ACC, STR, and HPC. The Cavalieri estimator (StereoInvestigator 12.0,MBF Bioscience) was used to determine the volume of these regions. Data were analyzed by t-tests corrected for multiple comparisons, using GraphPad Prism 6.0.ResultsOnly 5 cytokines from the panel were above the limit of detection. Of these, IL-6 is significantly increased in haloperidol-treated animals (+186%, p<.01). IL-10, IL-4, KC/GRO, and TNFα plasma levels were not significantly affected. In parallel, TSPO expression was significantly increased in the ACC (+56%, p<.01), the STR (+77%, p<.01) and the S2 (+158%, p<.001). In the STR, the density of both resting and amoeboid microglia were significantly elevated in the treatment group (+22%, p<.05 and +45%, p<.001, respectively). A 2-way ANOVA revealed a significant interaction between treatment and brain region for amoeboid but not resting microglia. Peripheral IL-6 levels correlated negatively with TSPO levels in the STR in saline and haloperidol-treated groups (r=-0.82 and r=-0.62, respectively, p<.05). In addition, KC/GRO, although not different between groups, correlated positively with TSPO levels in STR in controls (r=0.77, p<.05), but negatively in HPC, M1, and S2 after haloperidol treatment (r=-0.66, r=-0.62, r=-0.6, respectively, p<.05).DiscussionAs hypothesized, TSPO expression is significantly affected by chronic haloperidol, with augmented levels in the ACC, STR and S2. These data are in line with an increased TSPO PET signal in medicated schizophrenia patients as compared to matched antipsychotic-naïve patients (Holmes et al., 2016). Furthermore, these data confirm and extend our prior findings demonstrating that microglial activation is present already after 28 days of exposure to haloperidol and this effect is most prominent in the STR. Further investigations are needed to determine which cell types drive changes in TSPO (glia, endothelium, astrocytes) and how this relates to their functions at a molecular level.

Factors Associated With Short and Long Term Cognitive Changes in Patients With Sepsis

This study aimed to assess cognition in patients with severe sepsis or septic shock and whether cognitive impairment was associated with clinical and laboratory parameters. We conducted a cohort study of patients with severe sepsis and septic shock evaluated within 24 h and one year after ICU discharge. Demographic, clinical and laboratory data were analyzed, and the following neuropsychological tests were applied: Consortium to Establish Registry for Alzheimer’s Disease, Mini-Mental State Examination, and Trail Making Test forms A and B. We included 33 patients, mean age of 49, 19% were female. Patients underperformed on most measures 24 h after ICU discharge, with improvement on follow-up. IQCODE, APACHE II scores, NSE and IFN-γ levels at ICU discharge were associated with poor cognitive performance, while higher educational level was associated with good cognitive performance. The time to first antibiotic dose, accumulated dose of haloperidol during UCI stay and mean glycemia were also associated with poor cognitive outcome. In general, patients with severe sepsis or septic shock have cognitive impairment that can improve over time. This improvement was associated with factors identified during their ICU stay, such as cognitive reserve, educational level, mean glycemia during ICU stay and NSE level.