Adult Emergence Agitation: A Veteran-Focused Narrative Review.

Emergence agitation (EA) is a self-limited state of psychomotor excitement during awakening from general anesthesia. EA is confined to the emergence period as consciousness is restored, which sharply distinguishes it from other postoperative delirium states. Sporadic episodes of EA may become violent with the potential for harm to both patients and caregivers, but the long-term consequences of such events are not fully understood. Current literature on EA in adults is limited to small-scale studies with inconsistent nomenclature, variable time periods that define emergence, a host of different surgical populations, and conflicting diagnostic criteria. Therefore, true incidence rates and risk factors are unknown. In adult noncardiac surgery, the incidence of EA is approximately 19%. Limited data suggest that young adults undergoing otolaryngology operations with volatile anesthetic maintenance may be at the highest risk for EA. Currently suggested EA mechanisms are theoretical but might reflect underblunted sympathetic activation in response to various internal (eg, flashbacks or anxiety) or external (eg, surgical pain) stimuli as consciousness returns. Supplemental dexmedetomidine and ketamine may be utilized for EA prevention. Compared to the civilian population, military veterans may be more vulnerable to EA due to high rates of posttraumatic stress disorder (PTSD) manifesting as violent flashbacks; however, confirmatory data are limited. Nonetheless, expert military medical providers suggest that use of patient-centered rapport tactics, PTSD trigger identification and avoidance, and grounding measures may alleviate hyperactive emergence phenomena. Future research is needed to better characterize EA in veterans and validate prophylactic measures to optimize care for these patients. This narrative review provides readers with an important framework to distinguish EA from delirium. Furthermore, we summarize current knowledge of EA risk factors, mechanisms, and adult management strategies and specifically revisit them in the context of veteran perioperative health. The anesthesiology care team is ideally positioned to further explore EA and develop effective prevention and treatment protocols.

Trazodone as an Alternative Treatment for Neuroleptic-Associated Akathisia: A Placebo-Controlled, Double-Blind, Clinical Trial.

BACKGROUND: Akathisia is a distressing extrapyramidal complication that follows the use of antipsychotic medications. Early treatment of neuroleptic-associated akathisia (NAA) is of great importance because it may lead to poor therapeutic response and ultimately treatment noncompliance. Considering the lack of adequate response of some patients to conventional treatments and the assumption that serotonin might be involved in the pathophysiology of the disease in addition to dopaminergic mechanisms, we aimed to evaluate the effectiveness of trazodone as an antidepressant agent with strong antagonistic effects on serotonin receptors in the treatment of akathisia. METHODS: In a double-blind clinical trial, 52 patients receiving antipsychotic medications who were diagnosed to have mild to severe NAA using Barnes Akathisia Rating Scale were treated with trazodone 50 mg daily for 5 days and compared with the placebo control group. RESULTS: Patients receiving trazodone did not show a significant difference compared with the control group in terms of the severity of akathisia symptoms until the third day of the study. In contrast, at the end of the fifth day, there was a significant improvement in objective (P = 0.01) and subjective (P = 0.001) symptoms of akathisia and the global clinical assessment of akathisia scale (P = 0.001). Moreover, there was no clear difference between trazodone and placebo group in terms of adverse effects. CONCLUSIONS: Considering the antagonistic effect of trazodone on postsynaptic 5-hydroxytryptamine2A receptors as a possible mechanism of efficacy of this agent in the treatment of NAA, this study suggests that trazodone might be an effective and relatively safe drug.

Neurological soft signs in schizophrenia spectrum disorders are not confounded by current antipsychotic dosage.

Neurological soft signs (NSS) have garnered increasing attention in psychiatric research on motor abnormalities in schizophrenia spectrum disorders (SSD). However, it remains unclear whether the assessment of NSS severity could have been confounded by current antipsychotic dosage. In this study, we recruited 105 patients with SSD that underwent a comprehensive motor assessment evaluating NSS and extrapyramidal motor symptoms (EPMS) by means of standardized instruments. Current antipsychotic dosage equivalence estimates were determined by the classical mean dose method (doses equivalent to 1 mg/d olanzapine). We used multiple regression analyses to describe the relationship between NSS, EPMS and antipsychotic medication. In line with our expectations, current antipsychotic dosage had no significant effects on NSS total score (p = 0.27), abnormal involuntary movements (p = 0.17), akathisia (p = 0.32) and parkinsonism (p = 0.26). Further, NSS total score had a significant effect on akathisia (p = 0.003) and parkinsonism (p = 0.0001, Bonferroni corr.), but only marginal effect on abnormal involuntary movements (p = 0.08). Our results support the notion that NSS are not significantly modulated by current antipsychotic dosage in SSD. The associations between NSS, akathisia and parkinsonism, as revealed by this study, support the genuine rather than medication-dependent origin of particular motor abnormalities in SSD.

Activation in Children and Adolescents Treated With Selective Serotonin Reuptake Inhibitors: A Weighty Reason?

BACKGROUND: Activation is a behavioral adverse event related to the use of psychotropic medication. Its high incidence in pediatrics and in childhood-onset neuropsychiatric disorders suggests it may be linked to neurodevelopment. However, previous studies have scarcely examined the role that factors relevant to developmental pharmacokinetics, such as body weight, may play in the onset of activation in children and adolescents. METHODS: We conducted a retrospective analysis of hospitalized patients to identify the risk factors for activation in children and adolescents treated with selective serotonin reuptake inhibitors. Our focus was on factors related to development, including body weight, to explore the relationship between activation and neurodevelopmental processes. RESULTS: Among the 139 participants (mean age, 14 ± 2.3 years), activation appeared in 29 (20.9%). Age 12 years or younger and comorbid diagnosis of autism spectrum disorder were associated with statistically significant increases in the risk of activation, but no association was found regarding body weight. CONCLUSIONS: Our findings support the hypothesis that activation is closely linked to brain development processes. Longitudinal studies are needed to explore this line of research further.

Motor function in an animal model with ouabain-induced bipolar disorder and comorbid anxiety behavior.

In a clinical setting, anxiety disorder is highly correlated with bipolar I disorder in humans. However, the comorbidity of anxiety behavior and bipolar disorder still remains unclear in an animal model. This study utilized an ouabain-induced animal mode to examine anxiety and mania in an open field test. In the present study, 5 µl of artificial cerebrospinal fluid (aCSF) or ouabain (10-5, 10-4, and 10-3 M) were administered into the left ventricle. The animals' motor functions and anxiety behaviors were measured for 15 min. The results showed that 10-3 M ouabain significantly increased the animal's total distance traveled, average speed, and maximum speed compared to the control group. The time spent inside (i.e., how much time rats spent in the center of the square) and the inside-outside times of the central square (i.e., how many times rats ran across the center square) of the higher-concentration groups (10-4 M and 10-3 M) were significantly decreased. Therefore, a high concentration of ouabain may induce hyperactivity. The 10-4 M and 10-3 M ouabain groups exhibited more anxiety behaviors. The study is the first model to examine comorbid anxiety behaviors and bipolar disorder in an animal model. The study provides some insights for comorbid anxiety and bipolar disorder in clinics.

Palmitoylethanolamide attenuates cocaine-induced behavioral sensitization and conditioned place preference in mice.

Cocaine addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and drug-taking behaviors. Previous studies have demonstrated that cocaine, as well as other drugs of abuse, alters the levels of lipid-based signaling molecules, such as N-acylethanolamines (NAEs). Moreover, brain levels of NAEs have shown sensitivity to cocaine self-administration and extinction training in rodents. Given this background, the aim of this study was to investigate the effects of repeated or acute administration of palmitoylethanolamide (PEA), an endogenous NAE, on psychomotor sensitization and cocaine-induced contextual conditioning. To this end, the potential ability of repeated PEA administration (1 or 10 mg/kg, i.p.) to modulate the acquisition of cocaine-induced behavioral sensitization (BS) and conditioned place preference (CPP) was assessed in male C57BL/6J mice. In addition, the expression of cocaine-induced BS and CPP following acute PEA administration were also studied. Results showed that repeated administration of both doses of PEA were able to block the acquisition of cocaine-induced BS. Furthermore, acute administration of both doses of PEA was able to abolish the expression of BS, while the highest dose also abolished the expression of cocaine-induced CPP. Taken together, these results indicate that exogenous administration of PEA attenuated psychomotor sensitization, while the effect of PEA in cocaine-induced CPP depended on whether PEA was administered repeatedly or acutely. These findings could be relevant to understand the role that NAEs play in processes underlying the development and maintenance of cocaine addiction.

Intoxication by gamma hydroxybutyrate and related analogues: Clinical characteristics and comparison between pure intoxication and that combined with other substances of abuse.

OBJECTIVE: To study the profile of European gamma-hydroxybutyrate (GHB) and gammabutyrolactone (GBL) intoxication and analyse the differences in the clinical manifestations produced by intoxication by GHB/GBL alone and in combination with other substances of abuse. METHOD: We prospectively collected data on all the patients attended in the Emergency Departments (ED) of the centres participating in the Euro-DEN network over 12 months (October 2013 to September 2014) with a primary presenting complaint of drug intoxication (excluding ethanol alone) and registered the epidemiological and clinical data and outcomes. RESULTS: We included 710 cases (83% males, mean age 31 years), representing 12.6% of the total cases attended for drug intoxication. Of these, 73.5% arrived at the ED by ambulance, predominantly during weekend, and 71.7% consumed GHB/GBL in combination with other substances of abuse, the most frequent additional agents being ethanol (50%), amphetamine derivatives (36%), cocaine (12%) and cannabis (8%). Among 15 clinical features pre-defined in the project database, the 3 most frequently identified were altered behaviour (39%), reduced consciousness (34%) and anxiety (14%). The severity ranged from mild cases requiring no treatment (308 cases, 43.4%) to severe cases requiring admission to intensive care (103 cases, 14.6%) and mechanical ventilation (49 cases, 6.9%). No deaths were reported. In comparison with only GHB/GBL consumption, patients consuming GHB/GBL with co-intoxicants presented more vomiting (15% vs. 3%, p<0.001) and cardiovascular symptoms (5.3% vs. 1.5%, p<0.05), a greater need for treatment (59.8% vs. 48.3%, p<0.01) and a longer ED stay (11.3% vs. 3.6% patients with ED stay >12h, p<0.01). CONCLUSIONS: The profile of the typical GHB/GBL-intoxicated European is a young male, requiring care for altered behaviour and reduced level of consciousness, mainly during the weekend. The clinical features are more severe when GHB is consumed in combination with other substances of abuse.

Clinical and treatment-related determinants of subjective quality of life in patients with first-episode psychosis.

Subjective quality of life (SQoL) has been increasingly studied in first-episode psychosis (FEP). Prior research primarily examined the impact of psychiatric symptoms on SQoL. Relationship between treatment-related factors and SQoL is under-studied. In this study, 159 Chinese patients who had completed 2-year treatment from early intervention service in Hong Kong were recruited. Assessments on premorbid adjustment, clinical profiles including social anxiety measure, functioning, antipsychotic-induced extrapyramidal side-effects and attitude toward medication treatment were conducted. SQoL was evaluated by Chinese version SF36 which generated mental and physical component summary (MCS and PCS) scores for analysis. Our results showed that more severe positive symptoms, higher level of depression, greater social anxiety, more negative attitude toward antipsychotic medications and greater degree of akathisia independently predicted lower MCS score. Higher social anxiety level and poorer functioning predicted lower PCS score. Our results indicate that affective and positive symptoms, functioning, and treatment-related variables are critical determinants of SQoL in FEP patients. These identified factors thus represent potentially malleable therapeutic targets for early detection and prompt intervention to promote enhancement of SQoL in the early stage of illness.

Clozapine induced akathisia: a case report and review of the evidence.

Clozapine is a second-generation antipsychotic medication, which is mostly used in patients with treatment resistant schizophrenia. It is considered to be associated with lower incidence of extrapyramidal side-effects. Akathisia is considered to be a rare side-effect of clozapine. In this report, we describe a patient who developed akathisia while receiving clozapine and review the literature. Existing literature suggests that except for few initial reports, data suggests that clozapine is in general associated with lower incidence of akathisia compared to first generation antipsychotics. Data comparing clozapine with other atypical antipsychotics is equivocal.

Drug attitude in adolescents: a key factor for a comprehensive assessment.

OBJECTIVE: Very few studies have evaluated the subjective experience (SE) in children and adolescents treated with antipsychotics. The present study aimed to evaluate the SE of antipsychotics in adolescents diagnosed with different psychiatric conditions and to identify explanatory variables of adolescents' SE and compliance with treatment. METHODS: The Drug Attitude Inventory (DAI) was used to evaluate SE in 67 adolescents in 2 different countries (Italy and United Kingdom). Compliance was measured using a Likert scale completed by both patients and parents. To evaluate other parameters correlated to the SE, the following scales were administered: Clinical Global Impression Scale, Children's Global Assessment Scale, Extrapyramidal Symptoms Rating Scale, Barnes Akathisia Rating Scale, and EuroQoL (for quality of life). Multiple and logistic regression analyses were applied. RESULTS: No significant difference in drug attitude was found between psychotic and nonpsychotic patients. Our results showed a highly significant association between DAI and compliance (Spearman index, 0.33; P = 0.005); for all other variables, DAI associated significantly only with quality of life (r = 0.25; P = 0.03). The multivariable analysis confirmed the presence of a strong association between compliance and DAI (P = <0.001). In our sample, drug attitude was the only variable found to be correlated with the compliance, whereas extrapyramidal adverse effects showed an only marginally significant association. CONCLUSIONS: Our observations provide confirmation, also in adolescents, that drug attitude is strongly correlated with treatment compliance and underline the need in clinical assessments to always consider the patient's viewpoint.

Antagonism of the adenosine A2A receptor attenuates akathisia-like behavior induced with MP-10 or aripiprazole in a novel non-human primate model.

Akathisia is a subset of the larger antipsychotic side effect profile known as extrapyramidal syndrome (EPS). It is associated with antipsychotic treatment and is characterized as a feeling of inner restlessness that results in a compulsion to move. There are currently no primate models available to assess drug-induced akathisia; the present research was designed to address this shortcoming. We developed a novel rating scale based on both the Barnes Akathisia Rating Scale (BARS) and the Hillside Akathisia Scale (HAS) to measure the objective, observable incidence of antipsychotic-induced akathisia-like behavior in Cebus apella non-human primates (NHPs). To induce akathisia, we administered the atypical antipsychotic aripiprazole (1 mg/kg) or the selective phosphodiesterase 10A (PDE10A) inhibitor MP-10 (1-3 mg/kg). Treatment with both compounds produced significantly greater akathisia scores on the rating scale than vehicle treatment. Characteristic behaviors observed included vocalizations, stereotypies, teeth grinding, restless limb movements, and hyperlocomotion. Adenosine A2A receptor antagonists have previously been shown to be effective in blocking antipsychotic-induced EPS in primates. The selective A2A receptor antagonist, SCH 412348 (10-30 mg/kg), effectively reduced or reversed akathisia-like behavior induced by both aripiprazole and MP-10. This work represents the first NHP measurement scale of akathisia and demonstrates that NHPs are responsive to akathisia-inducing agents. As such, it provides a useful tool for the preclinical assessment of putative antipsychotics. In addition, these results provide further evidence of the utility of A2A receptor antagonists for the treatment of antipsychotic-induced movement disorders.

Akathisia: a life-threatening side effect of a common medication.

The authors describe the case of a 38-year-old man with a history of schizoaffective disorder, who attempted suicide following the recent starting of a neuroleptic agent that resulted in the development of intolerable akathisia. He survived the attempt, and following changes in his medications the akathisia resolved with no further suicidal ideation.

An aripiprazole discontinuation syndrome.

Major depression is a common and debilitating illness. Over recent years, new pharmacologic treatments have been approved for this disorder, including the atypical antipsychotics. One of the benefits of these medications is their significant efficacy as augmenting agents for unipolar, nonpsychotic major depressive disorder (MDD).Aripiprazole (marketed as Abilify, Bristol-Myers Squibb/ Otsuka Pharmaceuticals) was the first medication of this class approved for adjunctive treatment of MDD, and is the 5th most commonly prescribed medication in the United States in 2010. However, despite the frequency of its use, little has been described regarding events surrounding aripiprazole discontinuation. Here I describe what is, to my knowledge, the first reported case of an aripiprazole discontinuation syndrome. While directly relevant to psychiatrists and behavioral specialists, the symptoms described here are pertinent for internists and neurologists who may encounter this medication in their clinical practice.

The relationship of Akathisia with treatment emergent suicidality among patients with first-episode schizophrenia treated with haloperidol or risperidone.

Akathisia as well as younger age, early illness onset and discharge are important risk factors for suicidality in patients with first-episode schizophrenia. The aim of the present study was to analyze on a single case basis the relationship between a sudden increase in suicidality, anxiety symptoms, medication dosing and clinician- and patient-rated akathisia. A small subsample of patients demonstrated a positive relationship between suicidality and akathisia scores within the titration period of the study medication.

Metoclopramide and homicidal ideation: a case report and literature review.

BACKGROUND: Metoclopramide is an anti-emetic and gastrointestinal pro-motility agent associated with well-known neuropsychiatric adverse effects, such as dyskinesia, akathisia, and depression. It has never been reported to be associated with homicidal ideation. OBJECTIVE: The authors review the literature on metoclopramide-induced adverse neuropsychiatric reactions and the mechanisms by which these may occur. METHODS: The authors present a case report of a patient who developed anxiety, agitation, suicidal and homicidal ideation following brief exposure to metoclopramide. RESULTS: The adverse effects of agitation and homicidal ideation were temporally related to the starting and stopping of metoclopramide. The patient subsequently developed agitation without homicidal ideation when given a serotonergic antidepressant a week later, suggesting that serotonin handling may have played a significant role in causing the patient's symptoms. CONCLUSIONS: Although metoclopramide is well-known for its side effects related to dopamine blockade, its action at 5-HT3 and 5-HT4 receptors may also be clinically significant in the genesis of neuropsychiatric side effects, especially related to mood and behavior.

Oxycodone induced delirium and agitation in an elderly patient following total right knee arthroplasty.

CASE: Opioids are commonly prescribed for pain, and are often connected to mental status adverse events. Delirium is a side effect associated with narcotic analgesics, with a higher incidence in the elderly. This report describes an elderly male that received a total knee arthroplasty and received morphine post-operatively. On post-operative day 2, morphine was discontinued due to mental status changes and switched to oxycodone/acetaminophen. Twenty-four hours after administering oxycodone, the patient's mental status declined. After the patient returned to baseline he was transferred to rehabilitation and re-challenged with oxycodone/acetaminophen. The re-challenge was inadvertent due to inadequate documentation of the adverse event and lack of understanding by the health care team of delirium associated with opioids. A similar rapid decline in mental status occurred. CONCLUSION: Clinicians should be cognizant of narcotic analgesics inducing mental status changes, even with an alternative. Detailed documentation of adverse events should occur to avoid accidental re-challenges.

Symptoms of agitated depression and/or akathisia.

Akathisia is a syndrome characterized by the unpleasant sensation of "inner" restlessness that manifests itself in the inability of sitting still or not moving. Many types of medicaments can cause akathisia as an adverse event of their use and they include: antipsychotics, antidepressants, antiemetics, antihistamines, and psychoactive substances. We will present the case of a 50 year old patient, treated on two occasions for psychotic depression. During the second hospitalization it is possible that antipsychotic treatment combined with an antidepressant caused akathisia or there were symptoms of agitated depression and akathisia present at the same time, which is very difficult to determine in everyday clinical practice. We can conclude that in this case, as in many others, akathisia as a possible adverse effect of psychopharmacs was very hard to identify. Therefore, it is necessary to have akathisia in mind when using certain medicaments, especially when combining several that use the same enzymatic system and consequently raise levels of at least one of them.