NMDA Antagonist-Induced Neurotoxicity and Psychosis

NMDA antagonists such as ketamine, PCP, and MK-801 were initially investigated as anesthetics with quick onset and short duration that preserved brainstem reflexes. However, they paradoxically induced arousal and seizures while selectively depressing neocortical areas and stimulating limbic areas on EEG, leading to their classification as dissociative anesthetics. These drugs also produce a model psychosis resembling schizophrenia, including both positive and negative symptoms, making them a more complete animal model for the disease than dopamine agonists, which only induce positive symptoms.

Study at a glance

Abstract

There has been much research on N-methyl-D-aspartate (NMDA) antagonists since they were first discovered in mid-part of the 20th century. Initially, it was hoped that that some noncompetitive NMDA antagonists (the most common being ketamine, phencyclidine [PCP], and, more recently, MK-801) could be utilized as a new class of anesthetics with quick onset, short duration, and surprisingly good preservation of brainstem reflexes (1). Unfortunately, while these drugs induced an anesthetic state, they concomitantly induced certain aspects of arousal and even seizures (2–4).This finding correlated quite well with these drug’s ability to selectively depress neocortical areas while stimulating limbic areas as measured by the electroencephalogram (EEG) (3,4).To reflect this paradoxical ability to both inhibit and excite, these types of drugs were placed in their own drug class named dissociative anesthetics (4,5). Another unfortunate property of NMDA antagonists included the ability to induce a model psychosis almost indistinguishable from schizophrenia (for an excellent review, see Jentsch and Roth [6]).As ketamine and PCP developed as drugs of abuse, this psychosis became familiar in emergency rooms across the country (7). After further research, it became apparent that this class of drugs possessed the ability to produce both positive and negative symptoms of schizophrenia, which has made it one of the most widely accepted animal models for this disease (6). This made NMDA antagonists a more complete animal model than dopamine agonists, the only other class of psychotomimetic drugs that induce only the positive symptoms of schizophrenia.