Researchers measured psychosis (PANSS) and cognitive impairments (Cogstate), and the symptom profile of persisting psychosis due to chronic heavy ketamine abuse resembled that of schizophrenia
Enormous interest has recently been focused on a potential role for ketamine in treating depression. A non-opioid anesthetic with a long track record, ketamine may now present an entirely new mechanism of action to address the huge unmet medical need in patients with depressive symptoms. However, development of treatments must take into account the ability of ketamine to produce a range of side effects, including dissociative and hallucinogenic effects, psychosis and cognitive impairment. Efforts to develop dosing regimens and formulations to minimize, or even design-out off-target effects will be important to future development.
Because of its ability to produce dissociative and hallucinogenic effects, ketamine is also a drug of abuse. And about 3% of ketamine abusers develop psychotic symptoms that last far beyond the period of intoxication (beyond two hours following drug administration). In fact, this ketamine associated persisting psychosis (KPP) displays similar cognitive and behavioral effects as schizophrenia (SZ).
Suspecting the role of N-methyl-D-aspartate (NMDA) receptor dysfunction in both KPP and SZ, researchers recently compared the cognitive function of patients in a KPP group, a SZ group and a non-psychotic ketamine users (KNP) group, using the Positive and Negative Syndrome Scale (PANSS) to measure symptom severity of SZ and the Cogstate computerized test battery to measure cognitive function across several core domains.
After the PANSS evaluation, the 149 participants completed the nine Cogstate tests, including Detection (speed of processing), Identification (attention/vigilance), One Back (attention and visual working memory), Two Back (attention and working memory), the International Shopping List Test with Delayed Recall (verbal learning and memory), the Groton Maze Learning Test (spatial problem solving/error monitoring) with Delayed Recall (visual Learning and memory), and the Social Emotional Cognition Test (social cognition).
The results showed that:
- chronic heavy ketamine abusers with persistent psychotic symptoms beyond ketamine discontinuation (KPP) had more severe impairment of verbal memory and spatial problem-solving than those without persistent psychosis (KNP)
- schizophrenia (SZ) was associated with more severe cognitive impairments than KNP
- the cognitive impairments in the KPP group did not differ from the SZ in the severity of their cognitive impairments or symptoms as reflected by PANSS total or subscale (positive, negative, general psychopathology) scores.
The study has been published in Schizophrenia Research.
“Results of this study suggest that ketamine-dependent individuals with psychosis have similar psychotic symptoms profiles and cognitive deficits as individuals with chronic schizophrenia,” said Robert H. Pietrzak, PhD, MPH, associate professor of psychiatry at Yale and scientific consultant for Cogstate. “They further suggest that the cognitive domains that are most affected in both disorders are spatial problem solving (i.e., Groton Maze Learning Test performance) and verbal memory (i.e., International Shopping List Test performance).”
The researchers acknowledge a few limitations to the study including the lack of a healthy control group prior to any use of ketamine or a SZ diagnosis. Nevertheless, the results showed that there is still much to learn about heavy ketamine use, in either a social or medical setting.
“Clinically, this study’s findings underscore the importance of prevention of ketamine abuse, which can lead to psychosis and cognitive impairments comparable to those observed in chronic schizophrenia,” said Ke Xu, MD, PhD, assistant professor of psychiatry at the Yale School of Medicine. “Further research is needed to understand vulnerability factors, such as genes implicated in glutamate signaling, that may lead to the development of psychosis and cognitive dysfunction in ketamine abusers.”