Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia
Introduction
Ketamine, an uncompetitive N-methyl-d-aspartate glutamate receptor (NMDAR) antagonist, has been used in behavioral studies in animals and humans as a pharmacologic model for symptoms and cognitive impairments associated with schizophrenia (Abi-Saab et al., 1998, Krystal et al., 2003, Lahti et al., 2001, Zugno et al., 2013). Ketamine acute administration in healthy subjects produces symptoms that experienced raters employing validated rating scales for assessing schizophrenia score as positive symptoms (psychosis), negative symptoms (withdrawal, amotivation, blunted affect), thought disorder (Adler et al., 1998, Adler et al., 1999), and cognitive impairment (Curran and Monaghan, 2001, Krystal et al., 1999, Krystal et al., 1994, Lahti et al., 1995, Malhotra et al., 1997). Ketamine also produces alterations in cortical circuit function in healthy subjects that resemble schizophrenia, including reductions in working memory-related prefrontal cortical activation (Anticevic et al., 2013, Driesen et al., 2013) and functional connectivity (Dawson et al., 2014). Recent data suggest that genes associated with NMDA receptor signaling, potentially mimicking some aspects of NMDA receptor antagonism, contribute in important ways to the heritable risk for schizophrenia (Tarabeux et al., 2011, Timms et al., 2013). For these reasons, the effects of NMDA receptor antagonists emerge as one of the central models for schizophrenia drug development (Coyle et al., 2002, Javitt, 2008, Nikiforuk et al., 2013, Vollenweider and Kometer, 2010).
In both animals and humans, the effects of chronic ketamine administration also have been used as a model for schizophrenia (Moghaddam and Krystal, 2012, Schobel et al., 2013, Stone et al., 2013). In contrast to studies of acute ketamine effects, the “chronic model” studies change in behavior and brain structure that persist after repeated ketamine administration (Chatterjee et al., 2012, Edward Roberts et al., 2014, Wiescholleck and Manahan-Vaughan, 2013). Typically, long-term ketamine abuse is associated with mild levels of persisting symptoms and cognitive impairments, below the severity levels associated with psychotic disorders, accompanied by reductions in cortical volumes and cortical activation (Morgan et al., 2009, Morgan et al., 2010). However, a small minority of ketamine or phencyclidine abusers (another NMDA antagonist) develops a persisting psychiatric syndrome that has been suggested to resemble “endogenous” psychotic disorders, such as schizophrenia and bipolar disorder (Fauman and Fauman, 1980, Fine and Finestone, 1973, Javitt et al., 2012). These observations stimulate a generation of basic animal research on the chronic effects of NMDA receptor antagonists. Importantly, the chronic effects of NMDA receptor antagonists emerge as a distinct animal model from the acute effects of these drugs for medication development for schizophrenia (Cannon et al., 2013, Jentsch and Roth, 1999, Moghaddam and Jackson, 2003).
The purpose of the current study was to conduct a preliminary analysis of symptom dimensions in comparison of two forms of ketamine-associated psychosis (acute ketamine effects in healthy subjects, individuals hospitalized attributed to chronic ketamine abuse) and two phases of the illness (early course, chronic illness) in groups of schizophrenic inpatients. Because no theoretical model of symptom dimensions for ketamine psychosis is available, we conducted data driven, exploratory factor analyses for ketamine associated psychosis and schizophrenia psychosis. Two general strategies were employed to address this aim: 1) to characterize the degree of concordance of the factor structure of the principal symptom assessment tool for schizophrenia, PANSS (Kay et al., 1987); and 2) to compare the severity of the symptom clusters typically reported in studies of schizophrenia patients.
Section snippets
Methods
The study was approved by Yale Human Research Protection Program, and the Institutional Review Boards in Guangzhou Brain Hospital and Beijing Hui-Long-Guan Hospital. All participants in this study gave written informed consent prior to their participation.
Subjects with ketamine psychosis
There was no significant group difference in age between the acute ketamine and chronic ketamine groups (p = 0.22). There were significantly more men in the chronic ketamine group than in the acute ketamine group (p < 0.05). Subjects in the acute ketamine group were significantly more educated than subjects in the chronic ketamine group (p < 0.05). All subjects in the chronic ketamine group were Han Chinese, while there were mixed ethnicities in the acute ketamine group (Table 1).
The patients
Discussion
This study provided the evidence for homology in the symptom dimensions between ketamine-associated psychosis and schizophrenia psychosis. The factor structure was similar for the positive, negative, cognitive and depressed domains measured by the PANSS. In contrast, the excitement domain, which included items associated with the sedative and dissociative effects of ketamine, differentiated the acute effects of ketamine from the persisting symptoms in the other groups. These symptoms are
Funding source
This work is supported by grants from Chinese National Key Clinical Program in Psychiatry to Guangzhou Brain Hospital and from Health Bureau of Guangzhou (No: 20131A011091), China, the grant K12 DA000167 from National Institute on Drug Abuse, US, and APA/Merck Early Academic Career Award, US.
Contributors
Ni Fan and Ke Xu designed the study and wrote the protocol. Ke Xu wrote the first draft of the manuscript and Ni Fan revised the manuscript. John H Krystal and Robert H Pietrzak contributed to data interpretation, discussion and the manuscript preparation. Xiaoyin K, YiDing and Chao Zhou recruited the chronic ketamine abusers. Yuping Ning and Hongbo He helped on subject recruiting. Xifan Zhang, Daping Wang and Yuping Liu helped enrolling ketamine abusers. John H Krystal, Diana Limoncelli and
Conflict of interest
Dr. Krystal has served as a scientific consultant to Novartis Pharma AG and Naurex, Inc. He holds stock in Biohaven Medical Sciences and stock options in Mnemosyne Pharmaceuticals, Inc. Dr. Krystal is a co-sponsor for three patents. Dr. Petrakis provides consultation for Alkermes Company and Recovery Centers of America.
Acknowledgment
This work is supported by grants from Chinese National Key Clinical Program in Psychiatry to Guangzhou Brain Hospital and from Health Bureau of Guangzhou (No: 20131A011091), China, the grant K12 DA000167 from National Institute on Drug Abuse, US, and APA/Merck Early Academic Career Award, US. We thank the Alcohol Center at Veteran Affair of Connecticut Healthcare and the Center of Translational neuroscience of Alcoholism supported by National Institute on Alcohol Abuse and Alcoholism.
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