Objective
Studies of the effects of the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, ketamine, have suggested similarities to the symptoms of schizophrenia. Our primary goal was to evaluate the dimensions of the Positive and Negative Syndrome Scale (PANSS) in ketamine users (acute and chronic) compared to schizophrenia patients (early and chronic stages).
Method
We conducted exploratory factor analysis for the PANSS from four groups: 135 healthy subject administrated ketamine or saline, 187 inpatients of ketamine abuse; 154 inpatients of early course schizophrenia and 522 inpatients of chronic schizophrenia. Principal component factor analyses were conducted to identify the factor structure of the PANSS.
Results
Factor analysis yielded five factors for each group: positive, negative, cognitive, depressed, excitement or dissociation symptoms. The symptom dimensions in two schizophrenia groups were consistent with the established five-factor model (Wallwork et al., 2012). The factor structures across four groups were similar, with 19 of 30 symptoms loading on the same factor in at least 3 of 4 groups. The factors in the chronic ketamine group were more similar to the factors in the two schizophrenia groups rather than to the factors in the acute ketamine group. Symptom severities were significantly different across the groups (Kruskal–Wallis χ2(4) = 540.6, p < 0.0001). Symptoms in the two ketamine groups were milder than in the two schizophrenia groups (Cohen's d = 0.7).
Conclusion
Our results provide the evidence of similarity in symptom dimensions between ketamine psychosis and schizophrenia psychosis. The interpretations should be cautious because of potential confounding factors.
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 and 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 and Adler et al., 1999), and cognitive impairment ( Curran and Monaghan, 2001, Krystal et al., 1999, Krystal et al., 1994, Lahti et al., 1995 and 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 and 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 and 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 and 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 and 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 and 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 and 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 and 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 and 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.
