Similar psychotic and cognitive profile between ketamine dependence with persistent psychosis and schizophrenia
Introduction
Ketamine hydrochloride, an uncompetitive N-methyl-d-aspartate glutamate (NMDA) receptor antagonist, is a short-acting general anesthetic for human and veterinary use (White et al., 1982). Recreational ketamine abuse rates increased significantly in many areas of the world over the past two decades (Dillon et al., 2003; Kalsi et al., 2011), particularly in East and South-East Asia (Howland et al., 2011; Joe Laidler, 2005).
Similarity between the cognitive and behavioral effects of ketamine in animals and humans and the signs and symptoms of schizophrenia (SZ) in humans, suggested that abnormalities in NMDA receptor function might contribute to the biology of schizophrenia (Abi-Saab et al., 1998; Javitt et al., 2012; Krystal et al., 2003; Lahti et al., 2001). Among people who chronically abuse ketamine, persisting mild delusional ideation (Morgan et al., 2009, Morgan et al., 2010), sensory disturbances, and other subthreshold psychotic symptoms (Fine and Finestone, 1973; Stone et al., 2014; Tang et al., 2015) are common. Approximately 3% of ketamine abusers develop psychotic symptoms that persist far beyond the period of intoxication, i.e., beyond two hours following drug administration (Abi-Saab et al., 1998; Adler et al., 1998; Kleinloog et al., 2015; Krystal et al., 1994; Liang et al., 2015; Zhang et al., 2014). In individuals with persisting ketamine-induced psychosis to an even greater extent than healthy individuals receiving a single dose of ketamine, their symptom factor structure was similar to that of SZ (Xu et al., 2015).
Cognitive impairments may be an important part of ketamine associated persisting psychosis (KPP). In SZ, independent of its association with psychosis, cognitive dysfunction is an important contributor of functional impairment. Both acute subanesthetic ketamine and individuals recently abstinent from chronic ketamine abuse are associated with cognitive impairments associated with schizophrenia (Morgan and Curran, 2006). Chronic ketamine abusers exhibit semantic and episodic memory impairment (Fletcher and Honey, 2006; Morgan et al., 2004). Ketamine abstainers also had worse performance for verbal fluency than non-ketamine users, but better than current users in source memory task and pattern recognition memory (Morgan et al., 2010). However, cognitive function in KPP has not been well-characterized.
The purpose of the current study was to characterize cognitive function in relation to psychosis symptoms in KPP as compared to non-psychotic ketamine users (KNP) and to SZ. In so doing, this study attempted to determine whether the propensity for psychosis among ketamine abusers was associated with greater cognitive impairments. It also attempted to further explore the similarities between KPP and SZ in relation to hypotheses related to the role of NMDA receptor dysfunction in symptoms and cognitive impairments in these two conditions.
Section snippets
Participants
We recruited treatment-seeking ketamine-dependent inpatients who were admitted to the Department of Addiction Sciences, Taipei City Psychiatric Center (TCPC), Taipei City Hospital and Chang-Gung Memorial Hospital in Taiwan for a detoxification and abstinence treatment program. Patients with SZ were recruited from the inpatient unit of TCPC. The project was approved by the Institutional Review Boards from above hospitals (IRB No TCHIRB-1020529) and the Human Research Protection Program at Yale
Participant description
As shown in Table 1, compared to SZ patients, both KNP and KPP groups were younger and had a lower proportion of female participants. Age of onset of ketamine use did not differ between KNP and KPP groups. The years of education were comparable across the three groups.
The ketamine-dependent patients in this study had abused ketamine chronically (7.1 ± 4.2 years of use) and heavily (3.8 ± 2.7 g and 8.0 ± 6.8 g respectively for average and maximum daily dose). The frequency of ketamine use was 26.1 ± 8.8
Discussion
The purpose of this study was to determine whether the persisting psychotic symptoms associated with ketamine abuse are associated with cognitive impairments. The principal findings of the current study are: 1) 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); 2) schizophrenia (SZ) was associated with more severe cognitive
Conflicts of interest
None.
Contributors
Ming-Chyi Huang and Ke Xu designed the study and wrote the protocol. Wan-Ju Cheng and Ming-Chyi Huang were responsible for the bulk of literature review and wrote the first draft of the manuscript. Wan-Ju Chen was responsible for the statistical analysis. Chun-Hsin Chen provided statistical consultancy. Ke Xu, Robert Pietrzak, and John Krystal contributed to data interpretation, discussion, and revision of the manuscript. Chun-Hsin Chen, Chih-Ken Chen, and Ming-Chyi Huang recruited the
Role of the funding source
The funding sources had no involvement in the study design, collection, analysis and interpretation of data, writing of the report or the decision to submit the article for publication.
Acknowledgement
This project is funded by the National Science Council (NSC102-2314-B-182-007), Ministry of Science and Technology (MOST103-2628-B-532-001-MY3, 106-2314-B-532-005-MY3), Taipei City Government (TCH105-01-62-040, 106-01-62-018, and 107-01-62-029), Chang-Gung Memorial Hospital, Keelung (CMRPG2D0261), Taiwan. The work is partially supported by the grant K12 DA000167 from National Institute on Drug Abuse, US, and APA/Merck Early Academic Career Award, US. The authors thank CogState (//www.cogstate.com
References (38)
- et al.
Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers
Biol. Psychiatry
(1998) - et al.
Patterns of use and harms associated with non-medical ketamine use
Drug Alcohol Depend.
(2003) - et al.
Profiling the psychotic, depressive and anxiety symptoms in chronic ketamine users
Psychiatry Res.
(2016) - et al.
Schizophrenia, ketamine and cannabis: evidence of overlapping memory deficits
Trends Cogn. Sci.
(2006) - et al.
Effects of ketamine in normal and schizophrenic volunteers
Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol.
(2001) - et al.
Metacognition within narratives of schizophrenia: associations with multiple domains of neurocognition
Schizophr. Res.
(2007) - et al.
Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis
Neuropsychopharmacology
(1999) - et al.
Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia
J. Psychiatr. Res.
(2015) - et al.
Profiles of psychiatric symptoms among amphetamine type stimulant and ketamine using inpatients in Wuhan, China
J. Psychiatr. Res.
(2014) - et al.
The cognitive impairments and psychological wellbeing of methamphetamine dependent patients compared with health controls
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(2016)
The NMDA antagonist model for schizophrenia: promise and pitfalls
Pharmacopsychiatry
Neurocognitive impairments in individuals at ultra-high risk for psychosis: who will really convert?
Aust N Z J Psychiatry
Cognitive impairment in aboriginal people with heavy episodic patterns of alcohol use
Addiction
Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients
Am. J. Psychiatr.
Pre-morbid characteristics and co-morbidity of methamphetamine users with and without psychosis
Psychol. Med.
Validation of the Chinese version of the CogState computerised cognitive assessment battery in Taiwanese patients with heart failure
J. Clin. Nurs.
Sensory disturbances following ketamine anesthesia: recurrent hallucinations
Anesth. Analg.
The acute effects of caffeinated versus non-caffeinated alcoholic beverage on driving performance and attention/reaction time
Addiction
Psychotropic dose equivalence in Japan
Psychiatry Clin. Neurosci.
Cited by (36)
Acute ketamine induces neuronal hyperexcitability and deficits in prepulse inhibition by upregulating IL-6
2024, Progress in Neuro-Psychopharmacology and Biological PsychiatryInfluence of the dose of ketamine used on schizophrenia-like symptoms in mice: A correlation study with TH, GAD<inf>67</inf>, and PPAR-γ
2023, Pharmacology Biochemistry and BehaviorIntravenous Ketamine for Late-Life Treatment-Resistant Depression: A Pilot Study of Tolerability, Safety, Clinical Benefits, and Effect on Cognition
2023, American Journal of Geriatric PsychiatryCitation Excerpt :Acute exposure to low doses of NMDA antagonists produces a NMDA receptor hypofunction state that is associated with transient neuronal injury,20 which is age-dependent (i.e., it appears to be more severe in older animals), and cognitive impairment. While these cognitive effects are transient and not detectable once the NMDA antagonist would no longer be expected to be present1820 observational studies in ketamine abusers suggest the potential for cognitive impairment with long-term use.19 The lack of evidence in this study of ketamine inducing cognitive impairment over 8 weeks of serial infusions is reassuring that repetitive exposure as used in this prospective study does not carry a risk of cognitive impairment initially identified in observational studies.
Comorbidity of ketamine dependence with major depressive disorder increases the vulnerability to neuroaxonal pathology
2023, Journal of Psychiatric ResearchAbnormal fractional Amplitude of Low-Frequency Fluctuation in chronic ketamine users
2022, Psychiatry Research - Neuroimaging