Promises and Pitfalls of NMDA Receptor Antagonists in Treating Violent Aggression

Abstract

Treatment options for chronically aggressive individuals remain limited despite recent medical advances. Traditional pharmacological agents used to treat aggression, such as atypical antipsychotics, have limited efficacy and are often replete with dangerous side effects. The non-competitive NMDAR antagonists ketamine and memantine are promising alternatives, but their effects appear to be highly dependent on dosage, context, and personal experience. Importantly, these drugs can increase aggression when combined with substances of abuse or during periods of heightened stress. This is likely due to mechanistic differences operating at specific synapses under different contexts. Previous findings from our lab and others have shown that early life stress, substance abuse, and attack experience promote aggression through NMDAR-dependent synaptic plasticity within aggression-related brain circuits. Ketamine and memantine affect these types of aggression in opposite ways. This has led us to propose that ketamine and memantine oppositely affect aggression brought on by early life stress, substance abuse, or attack experience through opposite effects on NMDAR-dependent synaptic plasticity. This would account for the persistent effects of these drugs on aggression and suggest they could be leveraged as a more long-lasting treatment option. However, a more thorough examination of the effects of ketamine and memantine on cellular and synaptic function will be necessary for responsible administration. Additionally, because the effects of ketamine and memantine are highly dependent on prior drug use, traumatic stress, or a history of aggressive behavior, we propose a more thorough medical evaluation and psychiatric assessment will be necessary to avoid possible adverse interactions with these drugs.

Visualizing traumatic stress-induced structural plasticity in a medial amygdala pathway using mGRASP

“…Such a reduction underscores the potential role of extrasynaptic receptors in regulating the synaptic and structural shifts prompted by traumatic events. Corroborating this notion, our prior research highlighted that memantine, a specific extrasynaptic NMDAR antagonist ( Emnett et al, 2013 ), diminishes aggression induced by traumatic stress ( Nordman, 2021 ; Bartsch and Nordman, 2022 ; Nordman et al, 2022 ), likely by targeting the MeApv-VmHvl pathway.…”

“…As of 2021, nearly one in five adults in the United States were diagnosed with a mental illness, and depressive disorders are a leading cause of disability (National Institutes of Health and the Substance Abuse and Mental Health Services Administration). Current treatment modalities, including pharmacotherapy and psychotherapy, have remained largely unchanged for decades, and often come with limitations such as adverse side effects and low remission rates ( Sachsse et al, 2006 ; American Psychiatric Association [APA], 2013 ; Watson et al, 2016 ; Bartsch and Nordman, 2022 ). These issues underscore the urgent need for innovative research methods to enhance our understanding and treatment of psychiatric conditions.…”

A single dose of ketamine enhances early life stress-induced aggression with no effect on fear memory, anxiety-like behavior, or depression-like behavior in mice.

“…Ketamine, memantine, and MK-801 are noncompetitive NMDAR antagonists with similar drug profiles. Despite these similarities, ketamine has shown opposing effects on aggression from memantine and MK-801, indicating there are differences in these drugs that are not fully understood (Bartsch & Nordman, 2022; Nordman, 2022).…”

“…Stress also appears to be a strong factor in the effects of ketamine in mice. For example, ketamine increases aggression in sleep-deprived rats and socially isolated mice (Bartsch & Nordman, 2022; Takahashi et al, 1984), but decreases aggression induced by neonatal maternal separation (Shin et al, 2019). Within the context of traumatic stress, we show that ketamine increases aggression induced by chronic social isolation followed by acute traumatic-like stress in the form of noncontingent foot shock during adolescence (Nordman et al, 2022).…”