Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia

This meta-analysis (n=998) investigated the subjective effects of ketamine (68,31mg on average) compared to the symptoms of psychosis among heavy ketamine abusers, and patients with early and late-stage schizophrenia. Common symptoms included blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of spontaneity and flow of conversation, and motor retardation, and chronic ketamine abusers and chronic schizophrenics also exhibited difficulty of abstract thinking.

Abstract

“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.”

Authors: Ke Xu, John H. Krystal, Yuping Ning, Hongbo He, Daping Wang, Xiaoyin Ke, Xifan Zhang & Ni Fan

Summary

The Positive and Negative Syndrome Scale was used to evaluate the effects of ketamine on healthy subjects, ketamine abusers, early course schizophrenia patients, and chronic schizophrenia patients.

Results: Factor analysis revealed five factors for each group, and 19 of 30 symptoms loaded on the same factor in at least 3 of 4 groups. Ketamine psychosis symptoms were milder than schizophrenia psychosis symptoms.

Confounding factors.

1. Introduction

Ketamine, an uncompetitive N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist, is used in behavioral studies in animals and humans to model symptoms and cognitive impairments associated with schizophrenia. Ketamine also produces alterations in cortical circuit function in healthy subjects that resemble schizophrenia.

In both animals and humans, chronic ketamine administration causes change in behavior and brain structure that persists after repeated ketamine administration. This “chronic model” is distinct from studies of acute ketamine effects, which are used for medication development for schizophrenia.

In the current study, we conducted data driven, exploratory factor analyses to compare the severity of symptom clusters in two forms of ketamine associated psychosis and two phases of the illness in groups of schizophrenic inpatients.

2.1. Participants

Data were extracted from previous studies and presented in the Supplemental Material.

135 healthy subjects were infused with ketamine or saline in randomized, single-blinded fashion. Data were extracted from the day in which subjects received ketamine or saline.

187 chronic ketamine abusers were recruited from substance abuse inpatient units in Guangzhou, China. They were heavy ketamine users who were voluntarily admitted to inpatient units for ketamine detoxification.

154 patients with early course schizophrenia were recruited from the inpatient unit of Beijing Hui-Long-Guan Psychiatric Hospital, Beijing, China.

Psychiatric symptomatology was assessed using the PANSS. A principal axis factor analysis was conducted with varimax rotation, and the factor structure was determined by Kaiser’s criteria and inspection of screen plots.

We conducted KruskaleWallis test to compare the symptom severity in five groups including saline infusion in healthy subjects, acute ketamine infusion, chronic ketamine use, early-course of schizophrenia and chronic schizophrenia.

3.1.1. Subjects with ketamine psychosis

There was no significant group difference in age between the acute ketamine and chronic ketamine groups, but subjects in the chronic ketamine group were more educated.

The chronic ketamine group consisted of particularly severe ketamine abusers, aged 19.97 years old, with an average daily dose of 3.37 g and maximal dose of 6.9 g. Eighty-six percent of ketamine abusers were polydrug users.

3.1.2. Subjects with schizophrenia psychosis

The average age of patients in the chronic schizophrenia group was significantly older than the average age of patients in the early schizophrenia group. All patients were treated with antipsychotics.

3.2. Factor structure of PANSS in the acute ketamine, chronic ketamine, early schizophrenia and chronic schizophrenia groups

Principal component factor analysis identified five factors for chronic ketamine psychosis, two schizophrenia groups, and acute ketamine psychosis. Among the five factors, 19 items were common to all four groups, suggesting highly consistent symptoms between ketamine-psychosis and schizophrenia-psychosis.

The six common symptoms of Negative factor were seen across all four groups: blunted affect, emotional withdrawal, poor rapport, passive/ apathetic social withdrawal, lack of spontaneity &flow of conversation, and motor retardation.

In the chronic ketamine, early schizophrenia and chronic schizophrenia groups, excitement, hostility, poor impulse control were present, but none of these symptoms were loaded on the disassociation factor.

The PANSS scores obtained from the saline infusion among healthy controls were used as reference. The total PANSS score and each subscale score were compared among five groups, and the chronic ketamine group had significantly greater scores than the acute ketamine group.

The ratings of negative and general pathology subscales were greater in the chronic ketamine abuse group than in the acute ketamine administration group, and the ratings in positive and general pathology domains were greater in the early schizophrenia group.

3.3.2. Comparisons of each item rating in four groups

We compared the ratings of each item among the four psychosis groups and found that the ratings on emotional items and somatic concerns were greatest in the chronic ketamine group.

4. Discussion

This study provided evidence that ketamine-associated psychosis and schizophrenia psychosis share similar symptom dimensions. The chronic ketamine group showed a more severe psychiatric response than the acute ketamine group, which might suggest that chronic ketamine effects provide a better overall model of schizophrenia than acute ketamine effects.

In this study, the acute ketamine group manifested milder symptoms than the other groups. However, higher subanesthetic ketamine doses may produce symptoms more similar in intensity to the other groups.

The factor structures of PANSS in the schizophrenia groups are consistent with the previously well-established five factor model for schizophrenia. The differences between early course and chronic studies are consistent with a lifelong neurodevelopmental model for schizophrenia.

The depressed domain was consistent across four groups, but the depressive symptoms were significantly different among four groups. The depressive symptom in the chronic ketamine group was as severe as in the early stage of schizophrenia group.

This study has a number of limitations, including the fact that it was unable to control for racial, ethnic, cultural, and contextual differences across the groups. However, the symptom clusters measured by the PANSS are similar across different ethnicities.

In a study of schizophrenia patients from Caucasian, Chinese and Brazilian backgrounds, four out of five symptom dimensions were shared, suggesting that common underlying neurobiological mechanisms may share across different ethnic backgrounds.

Patients with chronic schizophrenia had long time treatment with a variety of antipsychotic medications, while three other groups had not. There was no significant correlation between the PANSS score and the dose of the latest antipsychotic medication, or between the course of illness and the total PANSS score.

We could not rule out the influences of other substances because of the high-rate of polydrug use among ketamine users, but the predominant individuals using ketamine as the drug of choice within the past six months prior to enrollment to the study were heavy ketamine users who required inpatient treatment for ketamine detoxification.

This study explores the similarities in symptoms between ketamine psychosis and schizophrenia psychosis and supports the hypothesis that drugs that reverse the acute and chronic effects of ketamine might treat schizophrenia.

Contributors

Ke Xu, Ni Fan, John H Krystal, Diana Limoncelli and Ismene Petrakis designed the study, Ke Xu wrote the first draft of the manuscript, Ni Fan revised the manuscript, and all authors contributed to and approved the final manuscript.