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

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.