This meta-analysis (n=998) investigated the subjective effects of ketamine (68,31mg) 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.
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.
Papers cited by this study that are also in Blossom
Vollenweider, F. X., Kometer, M. · Nature Reviews Neuroscience (2010)
Ketamine is an uncompetitive N-methyl-D-aspartate (NMDAR) glutamate receptor antagonist that, when given acutely to healthy humans, produces positive, negative, thought-disorder and cognitive symptoms that overlap with those seen in schizophrenia. Chronic ketamine exposure and long-term abuse have also been used as a model for schizophrenia because of persistent behavioural and brain-structure changes after repeated administration; however, most community ketamine users show only mild, subclinical sequelae and only a minority develop a persisting psychiatric syndrome resembling endogenous psychoses. Previous work therefore leaves uncertainty about whether symptom dimensions produced by acute ketamine, chronic ketamine abuse, and schizophrenia are concordant. Xu and colleagues set out to compare symptom dimensions across four groups—healthy subjects receiving ketamine or saline (acute ketamine), inpatients with chronic ketamine abuse, inpatients with early-course schizophrenia, and inpatients with chronic schizophrenia—using data-driven exploratory factor analysis of the Positive and Negative Syndrome Scale (PANSS). The primary aims were to characterise the degree of concordance of PANSS factor structures across these groups and to compare severity of symptom clusters typically reported in schizophrenia studies.
The investigators assembled PANSS data from four sources. Acute ketamine data came from 135 healthy subjects who received ketamine or saline in randomized, single-blind infusion studies; the saline-day data served as a reference for group comparisons. Chronic ketamine data comprised 187 heavy ketamine abusers voluntarily admitted to inpatient detoxification units in Guangzhou, China, with documented ketamine in urine and at least six months of ketamine as the drug of choice; patients with prior psychiatric or neurological disease were excluded, but polydrug users and those with current depressive symptoms were included. Early-course schizophrenia comprised 154 inpatients from Beijing with symptom duration under five years and first psychiatric admission, and who were antipsychotic‑naïve at assessment. Chronic schizophrenia included 522 inpatients from the same Beijing hospital; all were receiving antipsychotic treatment and chlorpromazine‑equivalent doses were recorded. Ethical approvals were obtained from Yale and the Chinese hospital boards and all participants gave written informed consent. Psychotic symptoms were assessed with the PANSS, which has 7 positive items (P), 7 negative items (N) and 16 general psychopathology items (G). To identify underlying dimensions, the team performed principal axis factor analysis with varimax rotation for each group separately, using Kaiser’s criterion (eigenvalues > 1.0) and inspection of scree plots; a cutoff of 1.5 was mentioned for determining factor number. Items with loadings > 0.4 were retained; items were allowed to load on different factors across groups. Symptom severity comparisons used non-parametric tests: Kruskal–Wallis for omnibus comparisons across five groups (saline, acute ketamine, chronic ketamine, early schizophrenia, chronic schizophrenia) and Wilcoxon tests for pairwise post-hoc comparisons, with Bonferroni correction for multiple testing. Item-wise comparisons among the four psychosis groups excluded the healthy saline control due to low variability.
Principal axis factor analyses yielded five-factor solutions in each group, interpreted as negative, positive, cognitive, depressed, and either excitement or dissociation domains. The chronic ketamine and both schizophrenia groups showed a factor labelled excitement, whereas the acute ketamine group’s fifth factor was better characterised as dissociation—consistent with acute ketamine’s sedative and dissociative effects. Across the four groups, 19 of 30 PANSS items were ‘‘common’’ (present on the same factor in at least three groups), indicating substantial overlap between ketamine-associated and schizophrenia symptom dimensions. Fifteen of those common items matched items in a previously established five-factor model for schizophrenia. The negative factor was the most consistent across groups: six items loaded commonly (N1 blunted affect, N2 emotional withdrawal, N3 poor rapport, N4 passive/apathetic social withdrawal, N6 lack of spontaneity and flow of conversation, and G7 motor retardation), aligning with Wallwork’s negative-factor configuration. The positive factor commonly included delusion (P1), hallucination (P3), excitement (G9) and lack of insight (G12), with suspiciousness (P6) and grandiosity (P5) appearing as less consistent/load‑specific items. The depressed domain commonly comprised anxiety (G2), guilty feelings (G3) and depression (G6). The cognitive factor commonly contained stereotyped thinking (N7), poor attention (G11) and disturbance of volition (G13). The excitement/disassociation factor differed between groups: excitement, hostility (P7) and poor impulse control (G14) were present in chronic ketamine and schizophrenia groups, whereas the acute ketamine group’s analogous factor included conceptual disorganisation (P2), somatic concern (G1), difficulty in abstract thinking (N5), uncooperativeness (G8) and lack of judgment/insight (G12), interpreted as dissociation. On severity, total PANSS and the classic three PANSS subscales (positive, negative, general) differed significantly across the five groups (Kruskal–Wallis χ2(4) = 540.6, p < 0.0001). Pairwise tests (Bonferroni corrected) showed both schizophrenia groups had higher total PANSS scores than the two ketamine groups (χ2(1) = 379.2, p < 0.0001; Cohen’s d = 1.7). The chronic ketamine group had greater total symptoms than the acute ketamine group (χ2(1) = 84.7, p < 0.0001; Cohen’s d = 1.4). Within schizophrenia, early-course patients had more severe overall, positive and general pathology symptoms than chronic schizophrenia patients (χ2(1) = 379.2, p < 0.0001; Cohen’s d = 1.3). Chronic ketamine subjects scored higher than acute ketamine subjects on negative and general pathology subscales (p < 0.0001). Item-level comparisons among the four psychosis groups indicated that emotional items (G2 anxiety, G3 guilty feelings, G6 depression) and somatic concerns were most pronounced in the chronic ketamine group. Relevant group characteristics reported in the results included demographic and exposure differences: chronic ketamine users were predominantly male, all Han Chinese, with heavy and prolonged use (mean daily dose 3.37 ± 2.72 g, mean duration 6.3 ± 3.1 years, 75.4% daily users) and high rates of polydrug use (86%; co‑use rates: MDMA 44%, amphetamine 11%, codeine 11%). Early-course schizophrenia patients were antipsychotic‑naïve at assessment; chronic schizophrenia patients were medicated with a mean chlorpromazine equivalent of 493.08 ± 533.62 mg.
Xu and colleagues interpret their findings as evidence of homology in key symptom dimensions between ketamine-associated psychosis and schizophrenia, specifically across positive, negative, cognitive and depressed domains measured by the PANSS. They note that the excitement domain differentiated acute ketamine—where dissociative and sedative effects predominate—from the persisting symptom structure seen in chronic ketamine and schizophrenia groups, which is consistent with known acute ketamine effects. The greater similarity of chronic ketamine to schizophrenia than acute ketamine is highlighted as a possible indication that repeated ketamine exposure produces a model more aligned with schizophrenia; alternatively, the authors argue the chronic ketamine sample may represent an extreme neuroadaptive response to repeated exposure or an underlying vulnerability unmasked by ketamine. Acute ketamine generally produced milder symptoms in this dataset, and the authors emphasise ketamine’s steep dose–response in healthy humans as a factor that could influence symptom intensity across infusion studies. The PANSS factor structure found in the schizophrenia samples largely replicated prior five-factor models: 18 of 20 items in Wallwork’s model loaded concordantly in early-course schizophrenia and 17 in chronic schizophrenia. Early-course patients showed more severe overall, positive and general symptoms than chronic patients, a pattern the authors situate within a neurodevelopmental course of illness. The depressed domain (G2, G3, G6) was configured similarly across groups but differed in severity; notably, chronic ketamine subjects had depressive symptom levels comparable to early schizophrenia, whereas acute ketamine produced little change in depression compared with saline. Several important limitations are acknowledged. First, cross-cultural, ethnic and contextual differences—acute ketamine participants were a mixed‑ethnicity US ‘‘super‑healthy’’ sample, whereas the other groups were Han Chinese in China—could affect PANSS measurement and introduce confounds. Second, clinical and sample differences across groups (illness stage, gender distribution, polydrug use, chronicity and markedly uneven sample sizes) may have influenced findings. Third, chronic schizophrenia patients were medicated, often with clozapine, although the authors report no significant correlations between antipsychotic dose (chlorpromazine equivalents) and PANSS total or subscale scores after correction for multiple testing. Fourth, high rates of polydrug use in chronic ketamine users make it difficult to exclude contributions from substances such as MDMA, amphetamines or codeine. Finally, inter-rater reliability could not be established across groups, although within‑group agreement was reported as high (kappa > 0.8). Taken together, the authors remain cautious but suggest their data support further biological investigation into glutamate synaptic dysfunction as a shared mechanism and the idea that agents reversing acute and chronic ketamine effects in humans could have relevance for schizophrenia treatment.
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. 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, and cognitive impairment. Ketamine also produces alterations in cortical circuit function in healthy subjects that resemble schizophrenia, including reductions in working memory-related prefrontal cortical activationand functional connectivity. 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. For these reasons, the effects of NMDA receptor antagonists emerge as one of the central models for schizophrenia drug development. In both animals and humans, the effects of chronic ketamine administration also have been used as a model for schizophrenia. In contrast to studies of acute ketamine effects, the "chronic model" studies change in behavior and brain structure that persist after repeated ketamine administration. 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. 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. 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. 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; and 2) to compare the severity of the symptom clusters typically reported in studies of schizophrenia patients.
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.
Data for acute ketamine, early and chronic schizophrenia groups were extracted from our previously reported studies. For more information on these studies, please see references. Inclusion and exclusion criteria for each group are presented in the Supplemental Material. Acute ketamine administration: data were extracted from 135 healthy subjects using PANSS assessment. All participants in the studies were infused with ketamine or saline in randomized, single-blinded fashion. This study only reported on data from day in which subjects received ketamine or saline. Data from the day of saline was used as a reference for the purpose of group comparisons. The subject characteristics including demographics, methods including dose of ketamine administration are described in Tableand Supplemental Table. Chronic ketamine use: 187 chronic ketamine abusers were recruited from substance abuse inpatient units in Guangzhou Brain Hospital and Guangzhou Baiyun Mental Health Institute, Guangdong, China. These individuals were heavy ketamine abusers and were voluntarily admitted to inpatient units for ketamine detoxification. Inclusion criteria were: 1) subjects voluntarily seeking inpatient treatment; 2) subjects with ketamine as a drug of choice for longer than 6 months prior to interview; and 3) documentation of the presence of ketamine in a urine sample. Patients with a prior history of psychiatric and neurological diseases were excluded. Patients who used other substances or who presented with current symptoms of depression were included because of high co-morbidity rates. The patterns of the ketamine use are reported in Table. Early course of schizophrenia: A total of 154 patients with early course schizophrenia (operationalized as 1) symptom duration of less than five years, and 2) first psychiatric admission) who were not previously exposed to psychiatric medications were recruited from the inpatient unit of Beijing Hui-Long-Guan Psychiatric Hospital, Beijing, China. Demographics and clinical features are presented in Table. A detailed description of these participants was reported elsewhere. Chronic schizophrenia: A total of 522 inpatients with schizophrenia were recruited from Beijing Hui-Long-Guan psychiatric hospital, Beijing, China. The average dose of each antipsychotic with chlorpromazine equivalent is listed in Supplemental Table.
Psychiatric symptomatology was assessed using the PANSS. The PANSS includes: positive symptom domain (P, 7 items), negative domain (N, 7 items) and general pathology domain (G, 16 items).
All data analyses were conducted using JMP Statistic Discovery from SAS, version 9.0 (). To identify the factor structure of the PANSS, we conducted principal axis factor analysis with varimax rotation. The factor solutions for each group were determined by the Kaiser's criteria (eigenvalue greater than 1.0 or more) and inspections of screen plots. We used the cutoff 1.5 to determine the number of factors. Only items whose factor loading was greater than 0.4 were retained for establishing factor structure. Items were allowed to be cross-loaded on different factors in different groups. To compare the symptom severity in five groups including saline infusion in healthy subjects as a benchmark for comparison, acute ketamine infusion, chronic ketamine use, early-course of schizophrenia and chronic schizophrenia, we conducted KruskaleWallis test (the non-parametric equivalent to one-way ANOVA) on the total PANSS scores and the subscale scores for each of three classic clusters (Positive, Negative, and General pathology subscales). Posthoc pairwise comparisons between the groups were performed using Wilcoxon test. Individual symptom severity in ketamine psychosis and schizophrenia psychosis was compared using Krus-kaleWallis test for each item rating among four groups. The healthy control group was excluded for these comparisons due to low variability. Bonferroni corrections were applied to adjust for multiple comparisons.
There was no significant group difference in age between the acute ketamine and chronic ketamine groups (p ¼ 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). The patients in the chronic ketamine group were particularly severe ketamine abusers. Age of onset was 19.97 years old. Ketamine use was heavy with average daily dose of 3.37 ± 2.72 g (range of 0.1e15 g) and maximal dose was 6.9 ± 6.0 g (range of 0.7e28 g). Average duration of use was 6.3 ± 3.1years and 75.4% of them were daily users. The average number of hospitalizations for the treatment was 3.19 ± 2.57. Eighty-six percent of ketamine abusers were polydrug users. The most common drugs co-used with ketamine were 3,4-methylenedioxy-N-methylamphetamine MDMA (44%), amphetamine (11%), codeine (11%).
There was no significant difference in gender and years of education between two schizophrenia groups. The average age of the chronic schizophrenia group was significant older than the average age of inpatients in early schizophrenia group (p < 0.001). The age of first hospitalization did not significantly differ between two schizophrenia groups (p > 0.05). All patients in the chronic schizophrenia group were treated with antipsychotics. The average dose of chlorpromazine equivalents (mg) was 493.08 ± 533.62. The detailed medication and dose of chlorpromazine equivalents is presented in Supplemental Table. No subject in either chronic schizophrenia or early schizophrenia group abused substances except cigarette smoking. 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 each group: negative, positive, cognitive, depressed, and excitement (for chronic ketamine and two schizophrenia groups) or dissociation (for acute ketamine). The fifth factor was interpreted to represent excitement and had similar structure in the chronic ketamine and two schizophrenia groups, but appeared to represent disassociation domain in the acute ketamine group. Factor structures and loadings for each group are presented in Table. To evaluate the degree of the similarity of factor structure among the four groups, we described items in each factor as common symptoms and uncommon symptoms. The common symptom presented across at least 3 out of 4 groups. The uncommon symptoms were loaded in one or two groups only. Among the 30 PANSS items, 19 items were common, suggesting highly consistent symptoms between ketamine-psychosis and schizophrenia-psychosis (Table). Among 19 common items, 15 items were the same as the previously established five factor model for schizophrenia(Table: items are highlighted as red). The detailed factor structures were described below. Negative factor: The items in this factor were most consistent across the four groups. Six common symptoms were: blunted affect (N1), emotional withdrawal (N2), poor rapport (N3), passive/ apathetic social withdrawal (N4), lack of spontaneity &flow of conversation (N6), and motor retardation (G7). These six symptoms were completely identical of Negative factor in Wallwork's five factor model. The uncommon symptom of difficulty of abstract thinking (N5) was in the chronic ketamine and chronic schizophrenia groups. Conceptual disorganization (P2) and poor attention (G11) were seen in the chronic schizophrenia group only. Positive factor: Four common symptoms were delusion (P1), hallucination (P3), Excitement (G9) and lack of insight (G12). Uncommon symptoms of suspiciousness/persecution (P6) showed in the early schizophrenia and chronic schizophrenia, while grandiosity (P5) showed only in the chronic schizophrenia group. Depressed factor: Three out of five symptoms were common across four groups: anxiety (G2), guilty feelings (G3), and depression (G6). Uncommon symptoms, somatic concern (G1) and tension (G4), were loaded on this factor in the chronic schizophrenia only. Cognition factor: The common symptoms in this factor were stereotyped thinking (N7), poor attention (G11) and disturbance of volition (G13). Uncommon symptom, tension, (G4) was seen in the acute ketamine group only and conceptual disorganization (P2)/ difficulty in abstract thinking (N5) were identified in the early schizophrenia group only. Excitement or Disassociation factor: Three common symptoms were excitement (P4), hostility (P7), poor impulse control (G14) and were present in the chronic ketamine, early schizophrenia and chronic schizophrenia groups. However, none of these items were loaded on this factor in the acute ketamine group. In the acute ketamine group, this factor was constructed by conceptual disorganization (P2), somatic concern (G1), difficulty in abstract thinking (N5), uncooperativeness (G8) and lack of judgment and insight (G12) and was interpreted as disassociation factor. 3.3. Symptom severity comparisons 3.3.1. Comparison of total PANSS score and three subscale scores in five groups PANSS scores obtained from the saline infusion among healthy controls were used as reference. Because symptom dimensions in the four psychosis groups were not completely identical, we were unable to directly compare the severity of symptom cluster across groups based on the five-factor model. Instead, we compared the severity of symptom cluster in the classic three-factor model of PANSS with positive, negative, and general pathology subscales. Total PANSS score and each subscale score were compared among the five groups (Fig., left). Furthermore, we performed pairwise post hoc comparison of each symptom cluster (Fig., right). Total PANSS scores among five groups were significantly different (KruskaleWallis test c 2 (4) ¼ 540.6, df ¼ 4, p < 0.0001) (Fig., left). Each pairwise comparison was also significant after Bonferroni correction (p values < 0.0005) (Fig., right). Total scores of the PANSS in the two schizophrenia groups were significantly greater than in the scores of the two ketamine groups (c 2 (1) ¼ 379.2, p value <0.0001, Cohen's d ¼ 1.7). The total PANSS in the chronic ketamine group was significantly greater than the score in the acute ketamine group (c 2 (1) ¼ 84.7, p < 0.0001, Cohen's d ¼ 1.4). In the two schizophrenia groups, early-course of schizophrenia was associated with more severe symptoms than chronic schizophrenia (c 2 (1) ¼ 379.2, p < 0.0001, Cohen's d ¼ 1.3). The scores of symptom clusters in positive, negative and general pathology subscales were significantly different in the five groups (Fig.) (p values < 0.0001). Post hoc comparisons showed that the ratings of negative and general pathology subscales in the chronic ketamine group were greater than the ratings in the acute ketamine group (p values < 0.0001), suggesting that chronic ketamine abuse produces more severe symptoms than acute ketamine administration. For the two schizophrenia groups, the ratings in positive and general pathology domains were greater in the early schizophrenia group than in the chronic schizophrenia group (p values < 0.0001).
We further compared the rating of each item among the four psychosis groups and performed post-hoc pairwise comparisons. As showed in Fig., although the symptom dimensions were similar between ketamine psychosis and schizophrenia, symptom severity across groups differed significantly. The p values of post hoc pairwise comparisons are listed in Supplemental Table. Of note, the ratings on emotional items (anxiety G2, feeling of guilty G3, and depression G6) and somatic concerns were greatest in the chronic ketamine group.
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 expected consequences of acute ketamine infusion in humans. Similarly, the factor structure of symptoms in the chronic ketamine group showed greater similarity than the acute ketamine group to the symptom factor structure of the two schizophrenia groups. This difference might be interpreted to suggest that chronic ketamine effects provide a better overall model of schizophrenia than acute ketamine effects. However, the severe psychiatric responses to repeated ketamine administration observed in the chronic ketamine are highly atypical among community-based chronic ketamine users. Thus, it would seem that the chronic ketamine group in this study either represents an extreme neuroadaptation to repeated ketamine exposure or the expression of an underlying propensity for developing a psychotic disorder revealed in the response to chronic ketamine administration. In this study, the acute ketamine group generally manifested milder symptoms than the other groups. Ketamine has a very steep dose response curve in healthy humans such that differences of a few tenths of a mg/kg may determine whether or not psychotic symptoms are observed. Although there was not a correlation between ketamine dose and the level of psychosis observed across studies, the between study dose differences constitute a very narrow range of ketamine dosing. Thus it is possible that higher subanesthetic ketamine doses would produce symptom levels more similar in intensity to the other groups. The factor structures of PANSS identified in the schizophrenia groups are consistent with the previously well-established five factor model for schizophrenia. Among 20 items in Wallwork's five factor model, 18 items are loaded on the same factors in the early course of schizophrenia group and 17 symptoms are loaded on the same factors in the chronic schizophrenia group, which validates the factor structure findings in this study. Between the two groups of schizophrenia, individuals in the early course of schizophrenia had more severe overall symptoms, positive and general pathology symptoms than those in chronic schizophrenia. The differences between early course and chronic studies are consistent with a lifelong neurodevelopmental model for this disorder. Of note, the configuration of the depressed domain was consistent across four groups (G2, G3, G6). However, the scores of three symptoms in the depressed domain were significantly different among four groups with the lowest score in the acute ketamine group. The score of G6 in the acute ketamine group was no difference with the saline control (p > 0.05). In the chronic ketamine group, the depressive symptom (G6) was as severe as in the early stage of schizophrenia group. These findings were consistent with other previous studies with ketamine infusion in healthy subjects and frequent ketamine abusers, suggesting acutely ketamine administration in healthy subjects has little effect on depressive symptoms. However, repeated, long-term ketamine use for the treatment of depression may increase risk of depression. This study has a number of limitations. First, this study was unable to control for the racial, ethnic, cultural, and contextual differences across the groups. For example, the acute ketamine group is a U.S. young adult sample of mixed ethnicity selected as a "super healthy" group devoid of risk factors for psychosis. In contrast, the chronic ketamine, early schizophrenia and chronic schizophrenia groups were Han Chinese individuals that were recruited from Chinese provinces that speak different Chinese dialects (chronic ketamine versus early schizophrenia and chronic schizophrenia. We previously reported that measurement of the PANSS in the U.S. and Chinese groups can be influenced by ethnicity and culture. Symptom severity measured by the PANSS in our acute ketamine U.S. group from the U.S. and three other groups from China might be influenced by such culture differences. However, the symptom clusters of measured by the PANSS are similar across different ethnicities. For example, a recent study reported the same five factors of the PANSS were shared in schizophrenia patients among Caucasian, Chinese and Brazilian groups. In this study, four out of five symptom dimensions were shared among four groups from two ethnic groups, suggesting that common underlying neurobiological mechanisms of psychosis may share across different ethnic backgrounds. Additionally group differences also included different stage (chronic ketamine/early schizophrenia versus chronic schizophrenia) and gender (chronic ketamine versus early and chronic schizophrenia), presence of polydrug abuse (chronic ketamine versus early and chronic schizophrenia), chronicity of illness (early schizophrenia versus chronic ketamine and chronic schizophrenia, and uneven sample size between groups. These group differences may have introduced unappreciated confounds into the data. Second, patients in the chronic schizophrenia group had long time treatment with a variety of antipsychotic medications, while three other groups had not. All patients in this group met the criteria of refractory schizophrenia and half of the patients were treated with clozapine. To address the effects of antipsychotics on the PANSS score, we tested the correlation between the PANSS score and dose for the latest antipsychotic medication (Chlorpromazine equivalents). We found that there was no significant correlation (r 2 ¼ 0.009, p ¼ 0.06). We further tested the correlation of antipsychotic dose and each subscale of the PANSS and found no significant correlations (ps > 0.05). Consistent with previous findings, correlation between course of illness and general pathology subscale was significant (p ¼ 0.02), however, there was no significant correlation after correcting for multiple testing. No significant correlation for the course of schizophrenia and total PANSS score was observed (p > 0.5). In the early stage of schizophrenia group, all patients had no prior history of antipsychotic exposure. They were recruited during the first admission to a psychiatric hospital and PANSS was assessed prior to administration of antipsychotics. These results suggest that it is reasonable to compare psychotic symptom clusters in two schizophrenia groups with psychosis in two ketamine groups. Third, because of high-rate of polydrug use among ketamine users, we were unable to rule out the influences of other substances. We attempted to address this concern by recruiting the predominant individuals using ketamine as the drug of choice within the past six months prior to enrollment to the study. They were heavy ketamine users who required inpatient treatment for ketamine detoxification. Nevertheless, co-use of other drugs could be potential confounding factors for in the assessment of ketamine-associated psychosis. Three drugs, MDMA, amphetamine and codeine, commonly co-use drugs in this chronic ketamine group. Previously, several cases of persistent psychosis induced by MDMA use was reported, but no reports used the PANSS to assess psychotic symptoms. Our previous study found that amphetamine administration was associated with positive psychotic symptoms, while ketamine administration was associated with broader spectrum of psychotic symptoms including positive, negative symptoms and cognitive impairments. It is likely that ketamine associated psychosis in our chronic ketamine group is not fully influenced by amphetamine use. Finally, because of the nature of the study, we are unable to conduct inter-rater reliabilities across groups although the agreement within each group was high (kappa > 0.8). With these limitations in mind, we are cautious the interpretations of the findings. In summary, this study explores the similarities in the dimensions of symptoms in ketamine psychosis and schizophrenia psychosis. These similarities support the ongoing exploration for the biological bases of the similarities observed across these groups in the effort to better understand the nature of glutamate synaptic dysfunction in schizophrenia. These data also support continued exploration of the hypothesis that drugs reverse the acute and chronic effects of ketamine in humans might play a role in the treatment of schizophrenia.
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