Current Understanding of the Neurobiology of Agitation

Abstract

Introduction: Managing agitation in the clinical setting is a challenge that many practitioners face regularly. Our evolving understanding of the etiological factors involved in aggressive acts has better informed our interventions through pharmacologic and behavioral strategies. This paper reviews the literature on the neurobiological underpinnings of aggressive behaviors, linking psychopathology with proposed mechanisms of action of psychiatric medications shown to be effective in mitigating agitation.

Methods: We performed a review of the extant literature using PubMed as a primary database. Investigation focused on neurobiology of agitation and its relation to the current evidence base for particular interventions.

Results: There are well-established pathways that can lead to increased autonomic response and the potential for violence. Psychopathology and substance-induced perceptual distortions may lead to magnification and overestimation of environmental threat, heightening the potential for aggression. Additional challenges have arisen with the advent of several novel drugs of abuse, many of which lead to atypical clinical presentations and which can elude standard drug screens. Our interventions still lean on the evidence base found in Project BETA (Best Practices in Evaluation and Treatment of Agitation). Although not a new drug and not included in the Project BETA guidelines, ketamine and its use are also discussed, given its unique pharmacology and potential benefits when other protocoled interventions have failed.

Conclusion: Aggression can occur due to manifold reasons in the clinical setting. Having an informed understanding of the possible determinants of agitation can help with more tailored responses to individual patients, limiting the unnecessary use of medications or of interventions that could be deemed forceful.

Figure 1

Schematic depiction of medial surface of cortex, subcortical areas, and brainstem, demonstrating key neural circuitry linked with the mechanisms of action of drugs used for the treatment of acute agitation. In states of heightened catecholaminergic tone, such as stimulant intoxication, acute psychosis, or mania, there may be excessive dopamine availability, binding amygdala D2 receptors and increasing conditioned fear responses. In addition, noradrenergic input from the locus coeruleus may also be elevated, contributing to autonomic arousal and feelings of paranoia. As levels increase, binding of norepinephrine will be shifted from the prefrontal cortex (PFC) to posterior cortical and subcortical regions (indicated by β and α1 receptors – schematically depicted for didactic simplicity), decreasing the individual’s ability to cognitively negotiate the situation at hand, particularly as PFC-amygdala coupling is diminished. Medications used for agitation can mitigate the effects of this neurotransmitter and circuitry make-up through the following mechanisms: 1) benzodiazepines, through GABA-A agonism, increase the PFC inhibitory control over the amygdala; 2) beta-blockers (e.g., propranolol, an agent with considerable lipophilicity), in addition to their peripheral effect on autonomic arousal, can decrease norepinephrine binding to posterior adrenoreceptors, thus allowing for greater PFC binding; (3) conventional, or typical antipsychotics, particularly the high-potency agents (e.g., haloperidol), work primarily through D2 receptor blockade – this occurs within the striatum, but also in the amygdala, decreasing threat perception; 4) atypical antipsychotics have a complex mechanism of action – a) D2 blockade occurs, though therapeutic occupancy is less than required with typical agents, b) several act as α1 receptor antagonists, decreasing subcortical adrenoreceptor binding, c) through subcortical serotonergic modulation, anxiolysis is promoted – several atypicals (e.g., clozapine, ziprasidone, lurasidone, quetiapine, and aripiprazole) agonize the Gi-linked (inhibitory) 5-HT1A receptor and all atypicals antagonize the Gq-linked (excitatory) 5-HT2A receptor, thus diminishing amygdala activation. Am, amygdala; CAP, conventional (first-generation) antipsychotic; D2R, dopamine 2 receptor; LC, locus coeruleus, NAc, nucleus accumbens; vmPFC, ventromedial prefrontal cortex; VTA, ventral tegmental area.

Figure 2

Depiction of dose-dependent inverted “U-shaped” curve associated with ketamine. Doses of ketamine used in antidepressant trials (0.5mg/kg) are associated with heightened down-stream glutamatergic neurotransmission, enhancing AMPA receptor activity. As doses increase toward those used in anesthesia and agitation (2–4mg/kg), there is a depression of glutamatergic tone, as well as an accretion of additional pharmacodynamic effects, including binding of opioid receptors. Thus, higher doses are typically required for behavioral control.