INTRODUCTION
Agitation, as defined by the American Association for Emergency Psychiatry BETA project, is “an extreme form of arousal that is associated with increased verbal and motor activity.”[1] The pathophysiology of agitation remains a complex topic, as it presents in an episodic pattern and varies among individuals with an underlying primary psychiatric illness or substance use. Excessive bottom-up activation occurs in response to environmental stimuli or threat overestimation, with inappropriate behavioral control from higher cortical centers. Threat overestimation results in activation of the hypothalamic-pituitary adrenal axis and subsequent release of excitatory neurotransmitters (glutamate, acetylcholine, norepinephrine, and dopamine).[2] High doses of norepinephrine in the prefrontal cortex impair working memory and executive functioning.[3] Dopamine increases amygdala excitation and exacerbates fear responses, paranoia and delusions. Agitated states also result in decreased levels of serotonin and gamma-aminobutyric acid (GABA), the two major inhibitory neurotransmitters of the central nervous system. The higher cortical centers controlled by serotonin and GABA are thus unable to modulate dysphoric reactions.[2]
Agitation is an increasingly common presentation within emergency departments (EDs), psychiatry units, and long-term care facilities. The prevalence of agitation within EDs compromises around 2.6% of total patient encounters.[4] Traditionally, all agitated patients were immediately restrained, secluded, or given high-dose psychotropic medications. Currently, verbal de-escalation is typically trialed upon initial presentation. Noise and other distracting factors should be limited, while the patient is provided comfort and empathy. When agitation is severe and persists despite these interventions, medications must be administered for safety concerns. It is reported that 3-20 per 1,000 ED visits for agitation are medically managed, with over 50% given involuntarily.[5] The medications administered voluntarily or involuntarily should differ based on the etiology of the agitation and the clinical setting. Physiologic stress as a response to extrinsic factors such as the death of a family member, loss of an occupation, financial insecurity, or other life stressors, has been shown to be a leading cause of acute agitation.[2] Other causes include alcohol use or withdrawal, drug intoxication or withdrawal, underlying primary psychiatric or mental health disorders, and underlying medical causes. Common primary mental health disorders that fall into this category include bipolar disorder, schizophrenia, autism spectrum disorder, intellectual disability, anxiety, and depression. Underlying medical etiologies include head trauma, sepsis, dementia, delirium, electrolyte abnormalities, endocrine disorders, postictal states, and toxic exposures.[2] Understanding the etiology of agitation is critical in proper patient care as adverse reactions to sedation have been reported in up to 15.9% of patients medically managed in the ED.[6] Adverse reactions include hypoxia, hypotension, bradycardia, QTc prolongation, and airway obstruction. These effects are commonly observed in the elderly population (65 years or older), patients with alcohol intoxication, and individuals prescribed multiple sedative medications.[6]
An additional population requiring careful monitoring for adverse reactions to sedation includes the pregnant female. Acute agitation during pregnancy should be treated as an obstetric emergency, as the distress may jeopardize both the patient and the fetus, resulting in preterm labor, placental abnormalities, postnatal death and spontaneous abortion. In this narrative review article, a summary of general agitation recommendations, with an emphasis on agitation during pregnancy, will be explored. Understanding the safety of psychotropic medications in the reproductive age or pregnant female is critical in optimizing patient care and devising standardized treatment protocols for ED management of acute agitation.
METHODS
A narrative review was conducted. Medical literature published in any language since 1960 until 2022 was identified utilizing MEDLINE/PubMed and the Cochrane Library. Additional references were collected through use of the reference lists of published articles identified by the selected databases. Initial search terms included typical and atypical psychotropic medication, diphenhydramine, ketamine, haloperidol, and benzodiazepines. Articles were then subcategorized into general drug information, mechanism of action, contraindications, and selective utilization in the management of acute agitation. A separate search was conducted to identify the reported teratogenicity and adverse effect profiles of the selected drug classes. There were no methodological limitations in relation to the initial acquisition and analysis of data. As literature pertaining to human and in-vitro subjects was limited, articles referencing animal models and epidemiologic studies were included. Articles were screened by abstract and then selected on the basis of full-text publications. Sample size and generalizability were taken into account in article selection. The author possessed a distinction in research and was the only reviewer who performed selection and data extraction. A total of 39 research articles were included in the final manuscript.
RESULTS
Agitation: drug overview
There are four major drug classes utilized in the management of acute agitation: typical psychotropics (first-generation), atypical psychotropics (second-generation), benzodiazepines, and ketamine. Typical psychotropics mainly include haloperidol and droperidol. Haloperidol, a high potency typical psychotropic, exerts its effects through antagonism of dopamine D2 receptors. Haloperidol can be administered orally (PO), intravenously (IV), or intramuscularly (IM), with an average time to sedation of around 25-28 min. Haloperidol has demonstrated the greatest utility in agitation secondary to delirium.[2] The primary adverse effects are extrapyramidal symptoms (EPS), including akathisia and dystonia. These effects can be mitigated by the addition of an anticholinergic agent, such as diphenhydramine or benztropine. Haloperidol may also result in QTc prolongation. Alternatively, droperidol, an analog of haloperidol, can be administered IV or IM with an average time to sedation around 15-30 min. Droperidol can also result in QTc prolongation and EPS. However, when compared to haloperidol, droperidol has been shown to require less frequent dosing with similar effects on mental status. [7]
Atypical psychotropics, such as clozapine, olanzapine, quetiapine, lurasidone, and ziprasidone have a higher affinity for serotonin 5-HT2 receptors and a lower affinity for D2 receptors. Consequently, they are capable of exerting therapeutic effects with a lower risk of EPS. Risperidone has equal affinity for 5-HT2A and D2 receptors, while aripiprazole is an antagonist of 5-HT2A and partial agonist of D2 receptors. Risperidone and aripiprazole have demonstrated improvement in repetitive behaviors in patients with agitation secondary to frustration or communication difficulties, as seen in autism spectrum disorder.[2] The effects on aggression, irritability and restlessness stem from antagonism of the dopamine receptors. The effects on communication skills, emotional and social interaction, and restricted activity patterns stem from antagonism of the serotonin receptors.[2]
Only ziprasidone, olanzapine, risperidone, and aripiprazole are available as parenteral agents.[8] Ziprasidone is available PO or IM with time to onset 15-20 min. Ziprasidone is associated with high risk of QTc prolongation. Systemic reviews involving ziprasidone have yet to be published.[9] Olanzapine can be given IM or IV for severe agitation, with a peak concentration at 15-45 min. Intramuscular administration of both ziprasidone and olanzapine requires reconstitution and therefore has limited efficacy in acute agitation. Olanzapine should not be combined with benzodiazepines or in patients suspected of having anticholinergic overdose due to the risk of hypotension and cardiopulmonary depression. For agitation secondary to a primary psychiatric condition, the World Federation of Societies of Biological Psychiatry (WFSBP) recommends the use of typical or atypical psychotropics to rapidly calm, without overtly sedating, the individual and address the underlying dopaminergic psychosis.[10] Typical and atypical psychotropics are further recommended by the WFSBP for agitation secondary to alcohol intoxication.[10] Haloperidol is particularly well-studied in treating agitation associated with alcohol intoxication. [2]
Compared to typical and atypical psychotropics, benzodiazepines exert a significantly enhanced sedating effect. Benzodiazepines increase the affinity of GABA to GABA-A receptors. GABA is the most abundant central nervous system (CNS) inhibitory neurotransmitter. Benzodiazepines thus cause significantly pronounced and dose-dependent CNS depression, respiratory depression, anxiolysis, sensory and motor impairments, and anterograde amnesia. The two main benzodiazepines utilized for acute agitation include midazolam and lorazepam. Midazolam can be given intranasally, IV, IM, rectally (PR), or PO, with onset varying from 1-5 min IV to 13-18 min IM. Lorazepam is longer acting with an average time to sedation around 32 min. Midazolam is typically preferred over lorazepam for acute agitation due to its quicker time of onset and shorter half-life. Nobay et al[11] demonstrates shorter time to onset of sedation and time to arousal with midazolam use; however, the efficacy among lorazepam, haloperidol, and midazolam was similar.
When agitation is secondary to alcohol withdrawal, benzodiazepine withdrawal, or stimulant toxicity, benzodiazepines are considered first-line therapy rather than psychotropics due to their CNS depressant effects.[2] Furthermore, the American College of Emergency Physicians (ACEP) recommends the use of benzodiazepines or conventional psychotropics for acute agitation requiring rapid de-escalation.[12] The combination of benzodiazepines and psychotropics is a common practice that has not consistently shown improvement in the control of agitation.[6,13] While the combination of the two agents increases the risk of sedation, it may also allow the mitigation of each drug’s individual adverse effects. Through significant CNS depression, benzodiazepines can help mitigate the EPS of typical psychotropics. Similarly, haloperidol may mitigate the paradoxical agitation associated with benzodiazepine use.[14] In contrast, atypical psychotropics, particularly olanzapine, should not be used in combination with benzodiazepines due to significant drug interactions potentially resulting in hypotension, bradycardia, and respiratory depression.
Ketamine is an emerging drug utilized in acute agitation. Ketamine is a nonbarbiturate dissociated anesthetic that functions as a noncompetitive N-methyl-D-aspartate (NMDA) and glutamate receptor antagonist. By antagonizing NMDA receptors, ketamine rapidly controls symptoms of depression and acute suicidal ideation. Ketamine also functions as a partial agonist on opiate receptors. Ketamine thus causes a unique dissociative effect, maintaining the patient in a state of sedation, comfortable awareness, and analgesia.[15] Ketamine can be given IV or IM with an average time to sedation of 5 min. Ketamine is thus a preferred agent for the rapid control of severe and combative agitation. While the time to onset is rapid, ketamine’s effects rapidly decline at a clearance rate of 12-17 mL/(kg·h), and redosing is frequently needed within 10 to 15 min. Due to its weak sympathomimetic activity, ketamine has been noted to worsen tachycardia and hypertension in non-agitated patients. A dysphoric emergence phenomenon has also been reported in 10%-20% of adult patients sedated with ketamine.[15] The dysphoric phenomena can be treated with low doses of benzodiazepines. Other adverse effects include hypersalivation (11%), vomiting (2%-8%), laryngospasm (1%), increased rate of intubation (2%) and transient hypoxia (0%-4%).[15] The etiology of agitation should be considered prior to ketamine use. Ketamine should be avoided in patients with unclear primary psychiatric diagnoses as administration may paradoxically worsen agitation.[16] The ACEP Clinical Policy lists psychiatric illness as an absolute contraindication for ketamine sedation. Various clinical trials involving ketamine administration in patients with schizophrenia have demonstrated an increase in schizophrenic symptoms in the short term with a return to baseline within 90 min in 100% of clinical subjects.[16]
Agitation: agent of choice in pregnancy
Psychiatric emergencies are common within the perinatal and postnatal periods.[17] Major depressive disorder occurs in one in six pregnant women, and one in four women with bipolar disorder experience mood exacerbation during this time. Furthermore, increased agitation during pregnancy is correlated with increased obstetric complications, including preterm delivery, placental abnormalities, spontaneous abortion, fetal demise, and suicidality.[17] Consequently, an agitated pregnant patient should be considered an obstetric emergency.
As with all agitated patients, the initial evaluation should consist of careful consideration regarding the etiology of agitation. A broader differential approach includes consideration of hypoxia, hypercapnia, amniotic and venous thromboembolism, coagulopathy, intracranial hemorrhage, trauma, delirium, primary psychiatric disorder, alcohol intoxication or withdrawal, and drug intoxication or withdrawal. Eclampsia must also be considered in women beyond 20 weeks of gestation.
All psychotropic medications readily cross the placenta, are present in amniotic fluid, and can enter breast milk to varying degrees. While randomized control studies cannot be ethically conducted on pregnant patients requiring acute sedation, animal models and epidemiologic studies have demonstrated the effects of psychotropic medications on transmission to the fetus. See Table 1. There are three primary areas of effects that occur due to psychotropic medication taken during pregnancy: 1) teratogenicity, 2) perinatal syndromes (neonatal toxicity) and 3) postnatal behavioral sequelae. Drug exposure during the first trimester has the most significant effect on outcome, as blastogenesis and organogenesis occur during this time. Epidemiologic studies suggest that most psychotropic drugs, including typical psychotropics, atypical psychotropics, benzodiazepines, and diphenhydramine, are relatively safe during pregnancy. The absolute risk of congenital malformations from long-term use of such drugs is 2%-3% within the first trimester.[18] As such, current recommendations favor the use of a single agent at a higher dose, with higher protein binding and fewer medication interactions.
Table 1. Five major drug classes utilized in the treatment of acute agitation, with a focus on the mechanism of action, adverse effect profiles, general recommendations for use, and use during pregnancy
| Drug class | Mechanism of action | Adverse effects | General recommendations for use in agitation | Use in pregnancy |
|---|---|---|---|---|
| Typical psychotropics (haloperidol, droperidol) | Dopamine D2 receptor antagonism | ● QTc prolongation ● Extrapyramidal symptoms (EPS) | ● Agitation secondary to a primary psychiatric condition (WFSBP) ● Agitation secondary to alcohol intoxication (WFSBP) ● Agitation secondary to delirium (haloperidol) | ● High potency agents (haloperidol): first-line in pregnancy. No reported effects in 2nd to 3rd trimester use. Limited case reports regarding 1st trimester use ● Low potency agents (chlorpromazine, perphenazine): sedative and hypotensive effects; higher risk of congenital malformations after 1st trimester use (cleft palate, micromelia, CNS and skeletal malformations, embryonic death, decreased fetal growth, alterations in offspring behavior)[19] |
| Atypical psychotropics (clozapine, olanzapine, quetiapine, lurasidone, ziprasidone) | Antagonism of serotonin 5-HT2 receptors, lower affinity for D2 receptors | ● Lower EPS risk ● Higher metabolic adverse effects ● Ziprasidone: high risk of QT prolongation | ● Agitation secondary to a primary psychiatric condition (WFSBP) ● Agitation secondary to alcohol intoxication (WFSBP) ● Agitation secondary to frustration or communication difficulties including autism spectrum disorder (risperidone and aripiprazole) | ● Clozapine/risperidone: NO evidence of impaired fertility or congenital malformations in human and animal models.[26⇓-28] Potential oral agent for agitation in pregnancy ● Other agents: increased risk of gestational metabolic complications and neonates large for gestational age[23] ● Quetiapine: soft tissue anomalies and delays in skeletal ossification[22] ● Olanzapine: higher rates of placental passage, early resorptions and fetal nonviability[22,25] |
| Benzodiazepines (midazolam, lorazepam) | Increase affinity of GABA to GABA-A receptors Dose dependent CNS depression | ● CNS depression ● Respiratory depression ● Sensory and motor impairments ● Anterograde amnesia | ● Agitation secondary to alcohol withdrawal ● Agitation secondary to benzodiazepine withdrawal ● Agitation from stimulant toxicity | ● Avoid if possible in pregnancy ● Animal models with mal-rotated limbs, malformed skulls, microphthalmia, gastroschisis, reduction of tibial, tarsal, metatarsal bones[31] ● Absolute risk difference: 13.9 per 1,000 pregnancies for overall malformations and 11.5 per 1,000 pregnancies for heart defects in infants of mothers exposed to benzodiazepines in the 1st trimester [31] ● Benzodiazepine withdrawal during post-natal period [32,33] |
| Ketamine | Noncompetitive NMDA and glutamate receptor antagonist Partial agonist on opiate receptors | ● Can worsen tachycardia and hypertension ● Dysphoric emergence phenomena[14] ● Hypersalivation, vomiting, laryngospasm, increased rate of intubation, transient hypoxia[14] ● Potential increase in schizophrenic symptoms[16] | ● Rapid control of severe and combative agitation | ● Impaired learning abilities, spatial and conditioned memory in rat offspring [36] ● Neuronal loss, pyramidal neuronal abnormalities, and reduced hippocampal cell proliferation in rat offspring [35,37] ● Impairment of neuronal development in prefrontal cortex. Indirectly associated with abnormal offspring behaviors (depression, anxiety, memory impairment)[38] ● Neurodegeneration in developing rhesus macaque brains[39] |
| Diphenhydramine | Competes with histamine for H1-receptor sites on effector cells in GI tract, blood vessels, and respiratory tract; anticholinergic and sedative effects | ● Anticholinergic symptoms (blurred vision; urinary retention; tachycardia; nausea, constipation) ● CNS depression or paradoxical agitation /insomnia | ● Mild to moderate agitation | ● FDA approved in pregnancy ● No major malformations reported with 1st trimester exposure ● Individual case reports of cleft palates and neonatal withdrawal [29,30] |
WFSBP: World Federation of Societies of Biological Psychiatry; CNS: central nervous system; GABA: gamma-aminobutyric acid; NMDA: N-methyl-D-aspartate; GI: gastrointestinal
In the setting of acute agitation during pregnancy, high-potency typical psychotropics, such as haloperidol, are recommended over low-potency typical psychotropics such as chlorpromazine or perphenazine due to decreased sedative and hypotensive effects.[19] A recent meta-analysis demonstrated a higher risk of congenital malformations after first trimester exposure to low potency psychotropics which has not been demonstrated with higher potency agents, such as haloperidol.[19] Teratogenic effects include cleft palate, micromelia, and CNS and skeletal malformations. Other adverse effects include embryonic death, fetal death, decreased fetal growth, and long-lasting alterations in offspring behavior. While no congenital defects have been reported with the use of haloperidol in the second and third trimesters, conflicting data exist regarding the effects of first trimester haloperidol use. Two case reports have shown an increased risk of limb reduction defects with haloperidol use in the first trimester.[20] In contrast, Van Waes et al[21] found no association between fetal anomalies and haloperidol use in hyperemesis gravidarum during the first trimester. While no congenital abnormalities have been reported in second or third trimester Haloperidol use, an increased risk of neonatal withdrawal, EPS, and sedation have been reported in neonates of mothers exposed to Haloperidol in the second and third trimesters. EPS in neonates includes hypertonicity, tremor, restlessness, dystonia, and parkinsonism.[22] Such adverse effects were observed only in neonates of mothers exposed to repeated haloperidol use, rather than a single use. Consequently, the Clinical Consensus Guidelines published in 2001 recommend the use of haloperidol for acute agitation in pregnancy with a 76% consensus rate.[23] Furthermore, Ladavac et al[24] studied the pharmacological management of agitated pregnant women within the psychiatric emergency service and found that haloperidol alone was the most frequently utilized medication. Risperidone was the second most commonly utilized medication.
As with low-potency typical psychotropics, atypical psychotropics have been associated with an increased risk of neonatal complications. Atypical psychotropics show an increased risk of gestational metabolic complications and neonates large for gestational age.[23] In animal models, quetiapine demonstrates embryotoxic and fetotoxic effects including soft tissue anomalies and delays in skeletal ossification.[22] Similarly, olanzapine demonstrates fetotoxic effects in animal models such as early resorptions and fetal nonviability.[22] Newport et al [25] described higher rates of placental passage (72.1% ±42%), lower birth weight, and increased perinatal complications associated with olanzapine as compared to other psychotropic medications. In contrast, clozapine and risperidone demonstrate no evidence of impaired fertility or congenital malformations in human and animal models.[26⇓-28] The placental passage of risperidone has been estimated at 49.2% ± 33.9% in human.[25] Risperidone is therefore a potential oral agent for the management of agitation in pregnancy. There is a paucity of evidence regarding long-term cognitive and behavioral outcomes in infants exposed to atypical psychotropics. However, atypical psychotropics are not generally utilized in the acute setting of severe agitation as patients frequently require IV or IM rapidly acting medications.
First-generation antihistamines, specifically diphenhydramine, are considered pregnancy safe according to the FDA. No major malformations have been reported with first-trimester exposure to antihistamines. However there are individual case reports of cleft palates and neonatal withdrawal that have been documented.[29,30] With the paucity of adverse effects reported, diphenhydramine is an excellent agent of choice in mild to moderate agitation.
As discussed above, benzodiazepines are often administered for rapid de-escalation of acute agitation. Lorazepam and midazolam are two of the most utilized benzodiazepines, yet both should be avoided in pregnant patients. Benzodiazepines readily cross the placenta, as evidenced by high levels of the drugs in umbilical cord blood. Animal models treated with benzodiazepines demonstrate occasional anomalies including malrotated limbs, malformed skulls, microphthalmia, gastroschisis, and reduction of tibial, tarsal, and metatarsal bones.[31] In a population-based cohort study by Noh et al., the absolute risk difference for overall malformations was 13.9 per 1,000 pregnancies and 11.5 per 1,000 pregnancies for heart defects in infants of mothers exposed to benzodiazepines in the first trimester. [31] The incidence of malformations and heart defects was higher among women over 35 years old, those with multi-fetal pregnancy, and those with a history of epilepsy. The risk of overall malformations was comparable between short- and long-acting benzodiazepines.[31]
In addition, infants of mothers with several weeks of benzodiazepine ingestion have shown withdrawal symptoms during the postnatal period. Symptoms include hypoactivity, hypotonia, hypothermia, respiratory depression, apnea, and feeding difficulties (“floppy-baby syndrome”). Such symptoms are more pronounced in neonates of mothers exposed to benzodiazepines in the third trimester or at delivery. [32,33] Current literature has not investigated the risk associated with a one-time acute exposure in the EDs.
While ketamine is an emerging agent for the control of severe agitation, evidence has shown that ketamine easily traverses the blood-placental barrier from mother to fetus.[34] Dong et al[35] demonstrated that ketamine exposure in utero results in reduced neuronal development in offspring. Li et al[36] demonstrated impaired learning abilities, spatial and conditioned memory in offspring of female rats anesthetized with 3 h of IV ketamine injection. Similarly, Zhao et al[37] demonstrated neuronal loss, pyramidal neuronal abnormalities, and reduced hippocampal cell proliferation in the offspring of pregnant rats exposed to ketamine in the second trimester. In a later study by Zhao et al,[38] maternal ketamine exposure resulted in cell apoptosis and neuronal loss specifically in the prefrontal cortex of the fetal brain. By impairing neuronal development of the prefrontal cortex, ketamine is indirectly associated with abnormal behaviors in offspring, including depression, anxiety, and memory impairment. In addition to rat models, the neurotoxic effects of maternal ketamine exposure have been demonstrated in non-human primates. Brambrink et al[39] demonstrated that ketamine induced neurodegeneration in developing fetal and neonatal rhesus macaque brains. A ketamine exposure duration of 5 h was sufficient to induce significant neuronal apoptosis. Neuronal loss was 2.2 times greater in fetal brains than in neonates. Given the neurotoxic and neurobehavioral effects demonstrated in animal models and the lack of adequate human data, the use of ketamine is not recommended for use during pregnancy.
In the case that medical management is not sufficient to manage acute agitation, physical restraint is utilized for safety precautions. However, physical restraint can be very dangerous in pregnancy, especially in the third trimester, due to potential inferior vena caval (IVC) compression. If restraint is needed, the patient should be placed in the left lateral decubitus position or have their right side supported.[1]
Bias and limitation assessment
A comprehensive narrative review was performed on the literature regarding agitation and adverse fetal outcomes associated with ED management of acute agitation. Significant effort was made to limit selection bias with specified search criteria and inclusion of all relevant data supporting or differing from the stated theory. Despite such efforts, the study is limited in that it is not a systematic review and, thus, did not follow specified academic guidelines. Subjective methodology and author selection of data from published references may serve to limit the intrinsic scientific validity. An additional limitation includes the small sample size secondary to the lack of published data on human and in-vitro subjects. Further studies are warranted to assess long-term fetal outcomes of psychotropic medication use.
CONCLUSIONS
The safety of psychotropic medications in pregnancy has not been well established on human and thus, the risks and benefits of their use should be carefully considered. Alternative nonpharmacological strategies are preferred for mild to moderate agitation. In moderate agitation nonresponsive to verbal de-escalation, diphenhydramine is an effective sedating agent with minimal short- and long-term adverse effects. Diphenhydramine will also help mitigate extrapyramidal symptoms if psychotropics are needed. In moderate to severe agitation, high-potency typical psychotropics are preferred due to their neutral effects on hemodynamics. Haloperidol is the most frequently utilized medication, with risperidone as the second most common agent. As the fetal risk associated with multiple doses of psychotropic medications remains unknown, weighing the risks and benefits of each agent, while utilizing the lowest effective dose of a single agent remains critical. Further research is necessary to analyze the teratogenicity and long-term adverse effects associated with psychotropic medications. Identification of such risks will aid in improving patient care and devising standardized treatment protocols for ED management of acute agitation in the reproductive age and pregnant female.
Funding: The authors did not receive support from any organization for the submitted work.
Ethical approval: Not needed.
Conflicts of interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
Author contribution: We certify that all listed authors meet the journal’s specific requirements regarding the duties and responsibilities of authorship.
Reference
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The prefrontal cortex (PFC) supports cognitive and behavioral processes that guide goal directed behavior. Moreover, dysregulated prefrontal cognitive dysfunction is associated with multiple psychiatric disorders. Norepinephrine (NE) signaling in the PFC is a critical modulator of prefrontal cognition and is targeted by a variety of drugs used to treat PFC-dependent cognitive dysfunction. Noradrenergic modulation of PFC-dependent cognition is complex, with concentration and receptor-specific actions that are likely dependent on neuronal activity state. Recent studies indicate that within the PFC, noradrenergic α1 and α2 receptors exert unique modulatory actions across distinct cognitive processes that allow for context-dependent modulation of cognition. Specifically, high affinity post-synaptic α2 receptors, engaged at moderate rates of NE release associated with moderate arousal levels, promote working memory. In contrast, lower affinity α1 receptors, engaged at higher rates of release associated with high arousal conditions (e.g. stress), impair working memory performance while promoting flexible attention. While these and other observations were initially interpreted to indicate high rates of NE release promotes the transition from focused to flexible/scanning attention, recent findings indicate that α1 receptors promote both focused and flexible attention. Collectively, these observations indicate that while α2 and α1 receptors in the PFC differentially modulate distinct cognitive processes, this cannot be simply ascribed to differential roles of these receptors in 'focused' vs. 'flexible' cognitive processes. Translationally, this information indicates that: (1) not all tests of prefrontal cognitive function may be appropriate for preclinical programs aimed at specific PFC-dependent disorders and (2) the treatment of specific PFC cognitive deficits may require the differential targeting of noradrenergic receptor subtypes. This article is part of a Special Issue entitled SI: Noradrenergic System.Copyright © 2015 Elsevier B.V. All rights reserved.
The characteristics and prevalence of agitation in an urban county emergency department
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We seek to determine the characteristics and prevalence of agitation among patients in an urban county emergency department (ED).This was a prospective observational study of ED patients at an urban Level I trauma center. All ED patients were screened during daily randomized 8-hour enrollment periods. Adult agitated patients, defined as having an altered mental status score greater than 1, were included. Trained research volunteers collected demographics and baseline data, including the presenting altered mental status score, use and type of restraints, and whether any initial sedative was given. The altered mental status score, vital signs, and any medications or treatments given were recorded every 5 minutes thereafter until the patient had an altered mental status score less than 1. Providers were asked to describe clinical events resulting in an intervention occurring during the patient course, including hypotension, vomiting, increased monitoring, use of supplemental oxygen or airway adjunct, or intubation. The provider also completed a checklist to determine the presence of delirium symptoms.A total of 43,838 patients were screened (45.1% women; median age 33 years; range 0 to 102 years). The prevalence of agitation was 2.6% (1,146/43,838; median altered mental status score 2). Of these patients, 84% (969/1,146) required physical restraint and 72% (829/1,146) required sedation with an intramuscular injection. Sedative agents were olanzapine in 39% of patients (442/1,146), droperidol in 20% (224/1,146), haloperidol in 20% (226/1,146), a benzodiazepine in 6% (68/1,146), and ketamine in 5% (52/1,146). Delirium characteristics were observed in 0.6% of patients (260/43,838), representing 23% of agitated patients in the ED. Clinical events were observed in 13% of agitated patients (114/866) without delirium symptoms and 26% (68/260) with delirium symptoms. Characteristics associated with a clinical event included delirium symptoms (odds ratio [OR] 1.6; 95% confidence interval [CI] 1.2 to 2.4), a cause related to a drug other than alcohol (OR 1.7; 95% CI 1.1 to 2.9), or a nondrug-induced cause of agitation (OR 3.5; 95% CI 2.3 to 5.6).The prevalence of agitation in the ED was 2.6%. Agitated patients frequently required restraint and sedation, with significant rates of clinical events requiring intervention.Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.
Medical evaluation and triage of the agitated patient: consensus statement of the American Association for Emergency Psychiatry Project Beta Medical Evaluation Workgroup
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Numerous medical and psychiatric conditions can cause agitation; some of these causes are life threatening. It is important to be able to differentiate between medical and nonmedical causes of agitation so that patients can receive appropriate and timely treatment. This article aims to educate all clinicians in nonmedical settings, such as mental health clinics, and medical settings on the differing levels of severity in agitation, basic triage, use of de-escalation, and factors, symptoms, and signs in determining whether a medical etiology is likely. Lastly, this article focuses on the medical workup of agitation when a medical etiology is suspected or when etiology is unclear.
Risk factors for sedation-related events during acute agitation management in the emergency department
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The objective was to describe the incidence, nature, and risk factors for adverse events (AEs) among patients who received parenteral sedation for acute agitation in an emergency department (ED) setting.We undertook a prospective observational study and a clinical trial of parenteral sedation for the management of acute agitation. We included agitated adult patients who required parenteral sedation from 2014 to 2017 in 12 Australian EDs, excluding those with incomplete information or aged under 18 years. The primary outcome was the number of patients who experienced at least one AE. Multivariable logistic regression was used to determine factors associated with AEs.A total of 904 patients were included in the analyses (62.3% male; median age = 34 years, range = 18 to 95 years). Of these, 144 (15.9%) patients experienced at least one AE. The most common AEs were oxygen desaturation (7.4%), airway obstruction (3.6%), bradycardia (1.9%), hypotension (1.7%), and prolonged QTc interval (1.3%). No deaths or serious AEs were reported. The following factors had an increased adjusted odds ratio (OR) for experiencing an AE: age 65 years and older (OR = 2.8, 95% confidence interval [CI] = 1.2 to 7.2), more than one type of parenteral sedation administered within 60 minutes (OR = 2.1, 95% CI = 1.4 to 3.1), and alcohol intoxication (OR = 1.8, 95% CI = 1.2 to 2.6).Sedation-related AEs are common, especially respiratory events. Elderly patients, sedation with multiple sedatives within 60 minutes, and alcohol intoxication increased the risk.© 2019 by the Society for Academic Emergency Medicine.
Droperidol for psychosis-induced aggression or agitation
An update of safety of clinically used atypical antipsychotics
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The atypical antipsychotic (APs) drugs have become the most widely used agents to treat a variety of psychoses because of their superiority with regard to safety and tolerability profile compared to conventional/'typical' APs.We aimed at providing a synthesis of most current evidence about the safety and tolerability profile of the most clinically used atypical APs so far marketed. Qualitative synthesis followed an electronic search made inquiring of the following databases: MEDLINE, Embase, PsycINFO and the Cochrane Library from inception until January 2016, combining free terms and MESH headings for the topics of psychiatric disorders and all atypical APs as following: ((safety OR adverse events OR side effects) AND (aripiprazole OR asenapine OR quetiapine OR olanzapine OR risperidone OR paliperidone OR ziprasidone OR lurasidone OR clozapine OR amisulpride OR iloperidone)).A critical issue in the treatment with atypical APs is represented by their metabolic side effect profile (e.g. weight gain, lipid and glycaemic imbalance, risk of diabetes mellitus and diabetic ketoacidosis) which may limit their use in particular clinical samples. Electrolyte imbalance, ECG abnormalities and cardiovascular adverse effects may recommend a careful baseline and periodic assessments.
Pharmacologic management of the agitated child
DOI:10.1097/PEC.0000000000000112
PMID:24694885
[Cited within: 1]
Agitation is a chief complaint that causes many children and adolescents to present to emergency medical attention. There are many reasons for acute agitation, including toxicologic, neurologic, infectious, metabolic, and functional disorders. At times it may be necessary to pharmacologically treat the agitation to prevent harm to the patient, caregivers, or hospital staff. However, one should always be mindful that the differential diagnosis is broad, and a complete although timely assessment with targeted testing must be done before concluding that the agitation is rooted solely in nonorganic causes. There are various pharmacologic choices for the treatment of agitation, and they will be reviewed here. While treatment of agitation may be necessary to keep the patient as well as staff safe, as well as to facilitate medical evaluation in some cases, care must be taken to treat the patient with compassion, never using pharmacologic treatment for reasons of punishment or staff convenience. The focus is on the pharmacologic management of acute agitation of patients in the pediatric age group, in the context of a full evaluation for possible nonfunctional causes of agitation. Goals, risks, and benefits of medication use will be reviewed.
World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia - a short version for primary care
DOI:10.1080/13651501.2017.1291839 URL [Cited within: 2]
A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients
DOI:10.1197/j.aem.2003.06.015
PMID:15231461
[Cited within: 1]
To determine if midazolam is superior to lorazepam or haloperidol in the management of violent and severely agitated patients in the emergency department. Superiority would be determined if midazolam resulted in a significantly shorter time to sedation and shorter time to arousal.This was a randomized, prospective, double-blind study of a convenience sample of patients from an urban, county teaching emergency department. Participants included 111 violent and severely agitated patients. Patients were randomized to receive intramuscular midazolam (5 mg), lorazepam (2 mg), or haloperidol (5 mg).The mean (+/-SD) age was 40.7 (+/-13) years. The mean (+/-SD) time to sedation was 18.3 (+/-14) minutes for patients receiving midazolam, 28.3 (+/-25) minutes for haloperidol, and 32.2 (+/-20) minutes for lorazepam. Midazolam had a significantly shorter time to sedation than lorazepam and haloperidol (p < 0.05). The mean difference between midazolam and lorazepam was 13.0 minutes (95% confidence interval [95% CI] = 5.1 to 22.8 minutes) and that between midazolam and haloperidol was 9.9 minutes (95% CI = 0.5 to 19.3 minutes). Time to arousal was 81.9 minutes for patients receiving midazolam, 126.5 minutes for haloperidol, and 217.2 minutes for lorazepam. Time to arousal for midazolam was significantly shorter than for both haloperidol and lorazepam (p < 0.05). The mean difference in time to awakening between midazolam and lorazepam was 135.3 minutes (95% CI = 89 to 182 minutes) and that between midazolam and haloperidol was 44.6 minutes (95% CI = 9 to 80 minutes). There was no significant difference over time by repeated-measures analysis of variance between groups in regard to changes in systolic and diastolic blood pressure (p = 0.8965, p = 0.9581), heart rate (p = 0.5517), respiratory rate (p = 0.8191), and oxygen saturation (p = 0.8991).Midazolam has a significantly shorter time to onset of sedation and a more rapid time to arousal than lorazepam or haloperidol. The efficacies of all three drugs appear to be similar.
Benzodiazepines for psychosis-induced aggression or agitation
Treatment options for acute agitation in psychiatric patients: theoretical and empirical evidence
Subanesthetic doses of ketamine stimulate psychosis in schizophrenia
DOI:10.1016/0893-133X(94)00131-I
PMID:8526975
[Cited within: 3]
We administered ketamine to schizophrenic individuals in a double-blind, placebo-controlled design using a range of subanesthetic doses (0.1, 0.3, and 0.5 mg/kg) to evaluate the nature, dose characteristics, time course, and neuroleptic modulation of N-methyl-D-aspartate (NMDA) antagonist action on mental status in schizophrenia. Ketamine induced a dose-related, short (< 30 minutes) worsening in mental status in the haloperidol-treated condition, reflected by a significant increase in BPRS total score for the 0.3 mg/kg (p =.005) and 0.5 mg/kg (p =.01) challenges. Positive symptoms (hallucinations, delusions, thought disorder), not negative symptoms accounted for these changes. These ketamine-induced psychotic symptoms were strikingly reminiscent of the subject's symptoms during active episodes of their illness. Results from six patients who were retested in the same design after being neuroleptic-free for 4 weeks failed to indicate that haloperidol blocks ketamine-induced psychosis. Several subjects evidenced delayed or prolonged (8-24 hours) psychotomimetic effects such as worsening of psychosis with visual hallucinations. These data suggest that antagonism of NMDA-sensitive glutamatergic transmission in brain exacerbates symptoms of schizophrenia.
Behavioral emergencies: special considerations in the pregnant patient
DOI:10.1016/j.psc.2017.05.017 URL [Cited within: 2]
Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines
DOI:10.1176/ajp.153.5.592 URL [Cited within: 1]
Antipsychotic use in pregnancy: patient mental health challenges, teratogenicity, pregnancy complications, and postnatal risks
DOI:10.3390/neurolint14010005
PMID:35076595
[Cited within: 3]
Pregnant women constitute a vulnerable population, with 25.3% of pregnant women classified as suffering from a psychiatric disorder. Since childbearing age typically aligns with the onset of mental health disorders, it is of utmost importance to consider the effects that antipsychotic drugs have on pregnant women and their developing fetus. However, the induction of pharmacological treatment during pregnancy may pose significant risks to the developing fetus. Antipsychotics are typically introduced when the nonpharmacologic approaches fail to produce desired effects or when the risks outweigh the benefits from continuing without treatment or the risks from exposing the fetus to medication. Early studies of pregnant women with schizophrenia showed an increase in perinatal malformations and deaths among their newborns. Similar to schizophrenia, women with bipolar disorder have an increased risk of relapse in antepartum and postpartum periods. It is known that antipsychotic medications can readily cross the placenta, and exposure to antipsychotic medication during pregnancy is associated with potential teratogenicity. Potential risks associated with antipsychotic use in pregnant women include congenital abnormalities, preterm birth, and metabolic disturbance, which could potentially lead to abnormal fetal growth. The complex decision-making process for treating psychosis in pregnant women must evaluate the risks and benefits of antipsychotic drugs.
The potential risks of commonly prescribed antipsychotics: during pregnancy and lactation
Safety evaluation of Haloperidol in the treatment of hyperemesis gravidarum
The potential risks of commonly prescribed antipsychotics: during pregnancy and lactation
PMID:21152171
[Cited within: 5]
Chlorpromazine, haloperidol, fluphenazine, clozapine, risperidone, quetiapine, olanzapine, ziprasidone, and aripiprazole are antipsychotics commonly used in psychiatric medicine. Approximately one third of pregnant women with psychotic symptoms use antipsychotics at least once. This review will discuss the effects of antipsychotic use during pregnancy and lactation on the fetus and infant.Although adequate and well-controlled studies have not been done in any one of these antipsychotic drugs, animal studies have revealed evidence of teratogenic or embryo/fetotoxic effects in all of them. Toxicities include skeletal malformations, central nervous system (CNS) defects, cleft palate, cardiac abnormalities, decreased fetal growth, and fetal death. For example, in pregnant women, congenital malformations and perinatal death have been reported with chlorpromazine use. Both chlorpromazine and fluphenazine in monotherapy have been shown to cause extrapyramidal symptoms and respiratory distress in infants born to mothers treated with these medications. Haloperidol use during pregnancy has been linked to severe limb reduction defects.Effects of antipsychotic use in lactating mothers are mostly unknown. However, the use of chlorpromazine has been reported to result in drowsiness and lethargy in breastfed infants. Additionally, clozapine has been reported to cause sedation, decreased suckling, restlessness, irritability, seizures, and cardiovascular instability of infants were also reported with clozapine use in lactating mother. Use of antipsychotic drugs by pregnant and lactating mother may only be justified if the potential benefit outweighs the potential risk to the fetus.
The expert consensus guideline series. Treatment of behavioral emergencies
Emergency management of agitation in pregnancy
DOI:10.1016/j.genhosppsych.2006.09.003 URL [Cited within: 1]
Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes
DOI:10.1176/appi.ajp.2007.06111886 URL [Cited within: 3]
Trifluoperazine and pregnancy
PMID:20327411 [Cited within: 2]
No complications with risperidone treatment before and throughout pregnancy and during the nursing period
DOI:10.4088/jcp.v63n0114c PMID:11838633 [Cited within: 2]
Use of antihistamine medications during early pregnancy and isolated major malformations
Safety of antihistamines during pregnancy and lactation
PMID:20463270
[Cited within: 2]
Many of my pregnant and breastfeeding patients suffer from allergies and frequently ask me about the safety of antihistamines during pregnancy and breastfeeding. Should I advise them to use the older sedating medications? I have heard that they might be safer than the newer nonsedating class of drugs. Or have the newer ones been studied as well?First-generation antihistamines are considered safe to use during pregnancy. There are relatively fewer data on the nonsedating second-generation antihistamines; however, published studies are reassuring. All antihistamines are considered safe to use during breastfeeding, as minimal amounts are excreted in the breast milk and would not cause any adverse effects on a breastfeeding infant.
First-trimester exposure to benzodiazepines and risk of congenital malformations in offspring: a population-based cohort study in South Korea
DOI:10.1371/journal.pmed.1003945
URL
[Cited within: 5]
Benzodiazepines are frequently prescribed during pregnancy; however, evidence about possible teratogenicity is equivocal. We aimed to evaluate the association between first-trimester benzodiazepine use and the risk of major congenital malformations.
The fetal safety of benzodiazepines: an updated meta-analysis
DOI:S1701-2163(16)34772-7
PMID:21272436
[Cited within: 2]
Benzodiazepines are commonly used by women of reproductive age, and hence many pregnant women are exposed to them. An updated meta-analysis of their fetal safety synthesized nine studies with over one million pregnancies, yielding an odds ratio of 1.07 (95% CI 0.91 to 1.25). While benzodiazepines do not appear to increase teratogenic risk in general, case-controls suggest a twofold increased risk of oral cleft.
Transplacental passage of ketamine after intravenous administration
DOI:10.1111/aas.1977.21.issue-1 URL [Cited within: 1]
Ketamine exposure during embryogenesis inhibits cellular proliferation in rat fetal cortical neurogenic regions
DOI:10.1111/aas.12689
PMID:26822861
[Cited within: 2]
Developmental neurotoxicity of ketamine, an N-methyl-D-aspartate receptor antagonist, must be considered due to its widespread uses for sedation/analgesia/anesthesia in pediatric and obstetric settings. Dose-dependent effects of ketamine on cellular proliferation in the neurogenic regions of rat fetal cortex [ventricular zone (VZ) and subventricular zone (SVZ)] were investigated in this in vivo study.Timed-pregnant Sprague-Dawley rats at embryonic day 17 (E17) were given with different doses of ketamine intraperitoneally (0, 1, 2, 10, 20, 40, and 100 mg/kg). Proliferating cells in the rat fetal brains were labeled by injecting 100 mg/kg of 5-bromo-2'-deoxyuridine (BrdU) intraperitoneally. BrdU-labeled cells were detected by immunostaining methods. The numbers of BrdU-positive cells in VZ and SVZ of rat fetal cortex were employed to quantify proliferation in the developing rat cortex.Ketamine dose-dependently reduced the number of BrdU-positive cells in VZ (P < 0.001) and SVZ (P < 0.001) of the rat fetal cortex. SVZ showed greater susceptibility to ketamine-induced reduction of proliferation in rat fetal cortex, occurring even at clinically relevant doses (2 mg/kg).These data suggest that exposure to ketamine during embryogenesis can dose-dependently inhibit the cellular proliferation in neurogenic regions of the rat fetal cortex.© 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.
Ketamine administered pregnant rats impair learning and memory in offspring via the CREB pathway
DOI:10.18632/oncotarget.15405
PMID:28430606
[Cited within: 2]
Ketamine has been reported to impair the capacity for learning and memory. This study examined whether these capacities were also altered in the offspring and investigated the role of the CREB signaling pathway in pregnant rats, subjected to ketamine-induced anesthesia. On the 14th day of gestation (P14), female rats were anesthetized for 3 h via intravenous ketamine injection (200 mg/Kg). Morris water maze task, contextual and cued fear conditioning, and olfactory tasks were executed between the 25th to 30th day after birth (B25-30) on rat pups, and rats were sacrificed on B30. Nerve density and dendritic spine density were examined via Nissl's and Golgi staining. Simultaneously, the contents of Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII), p-CaMKII, CaMKIV, p-CaMKIV, Extracellular Regulated Protein Kinases (ERK), p-ERK, Protein Kinase A (PKA), p-PKA, cAMP-Response Element Binding Protein (CREB), p-CREB, and Brain Derived Neurotrophic Factor (BDNF) were detected in the hippocampus. We pretreated PC12 cells with both PKA inhibitor (H89) and ERK inhibitor (SCH772984), thus detecting levels of ERK, p-ERK, PKA, p-PKA, p-CREB, and BDNF. The results revealed that ketamine impaired the learning ability and spatial as well as conditioned memory in the offspring, and significantly decreased the protein levels of ERK, p-ERK, PKA, p-PKA, p-CREB, and BDNF. We found that ERK and PKA (but not CaMKII or CaMKIV) have the ability to regulate the CREB-BDNF pathway during ketamine-induced anesthesia in pregnant rats. Furthermore, ERK and PKA are mutually compensatory for the regulation of the CREB-BDNF pathway.
Ketamine administered to pregnant rats in the second trimester causes long-lasting behavioral disorders in offspring
DOI:10.1016/j.nbd.2014.02.009
PMID:24780497
[Cited within: 2]
Commonly used anesthetic agents, e.g. ketamine, may be neurotoxic to the developing brain but there has been little attention to the neurobehavioral consequences for offspring when used for maternal anesthesia. We hypothesize that treatment of pregnant rats with ketamine during the second trimester would affect brain development of the offspring. Pregnant rats on gestational day 14, about equal to midtrimester pregnancy in humans, received a sedative dose of ketamine intravenously for 2h. Brain hippocampal morphology of their pups at postnatal days 0 (P0) and P30 was examined by Nissl-staining and the characteristics of dendrites were determined using the Golgi-Cox staining, while cell proliferation in subventricular zone (SVZ) and dentate gyrus (DG) was labeled with bromodeoxyuridine (BrdU). Their neurobehavioral functions were tested at P25-30 after which the NR1 and NR2 subunits of N-methyl-d-aspartate (NMDA) receptor, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95) in the hippocampus were analyzed by western blot. When pregnant rats were exposed to ketamine, there was neuronal loss, pyramidal neuronal abnormality and reduced cell proliferation in the hippocampus of offspring. These morphological abnormalities were associated with depression- and anxiety-like behaviors, and impaired memory up to young adult age. The treatment further caused NR2A receptor subunit up-regulation and NR2B receptor subunit, BDNF and PSD-95 down-regulation. These data suggest that maternal anesthesia with ketamine during the fetal brain development period can cause fetal brain damage and subsequent neurobehavioral abnormality, which is likely associated with the imbalanced expression of NMDA receptor subunits. Copyright © 2014. Published by Elsevier Inc.
Prenatal ketamine exposure causes abnormal development of prefrontal cortex in rat
DOI:10.1038/srep26865
PMID:27226073
[Cited within: 2]
Ketamine is commonly used for anesthesia and as a recreational drug. In pregnant users, a potential neurotoxicity in offspring has been noted. Our previous work demonstrated that ketamine exposure of pregnant rats induces affective disorders and cognitive impairments in offspring. As the prefrontal cortex (PFC) is critically involved in emotional and cognitive processes, here we studied whether maternal ketamine exposure influences the development of the PFC in offspring. Pregnant rats on gestational day 14 were treated with ketamine at a sedative dose for 2 hrs, and pups were studied at postnatal day 0 (P0) or P30. We found that maternal ketamine exposure resulted in cell apoptosis and neuronal loss in fetal brain. Upon ketamine exposure in utero, PFC neurons at P30 showed more dendritic branching, while cultured neurons from P0 PFC extended shorter neurites than controls. In addition, maternal ketamine exposure postponed the switch of NR2B/2A expression, and perturbed pre- and postsynaptic protein expression in the PFC. These data suggest that prenatal ketamine exposure impairs neuronal development of the PFC, which may be associated with abnormal behavior in offsprings.
Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain
DOI:10.1097/ALN.0b013e318242b2cd
PMID:22222480
[Cited within: 2]
Exposure of rhesus macaque fetuses for 24 h or neonates for 9 h to ketamine anesthesia causes neuroapoptosis in the developing brain. The current study clarifies the minimum exposure required for and the extent and spatial distribution of ketamine-induced neuroapoptosis in rhesus fetuses and neonates.Ketamine was administered by IV infusion for 5 h to postnatal day 6 rhesus neonates or to pregnant rhesus females at 120 days' gestation (full term = 165 days). Three hours later, fetuses were delivered by cesarean section, and the fetal and neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by activated caspase-3 staining.Both the fetal (n = 3) and neonatal (n = 4) ketamine-exposed brains had a significant increase in apoptotic profiles compared with drug-naive controls (fetal n = 4; neonatal n = 5). Loss of neurons attributable to ketamine exposure was 2.2 times greater in fetuses than in neonates. The pattern of neurodegeneration in fetuses was different from that in neonates, and all subjects exposed at either age had a pattern characteristic for that age.The developing rhesus macaque brain is sensitive to the apoptogenic action of ketamine at both a fetal and neonatal age, and exposure duration of 5 h is sufficient to induce a significant neuroapoptosis response at either age. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains.
