2026 ECNP Congress

PS01-1181

A retrospective pilot analysis of patients with persistent neuropsychiatric symptoms in post-acute infectious syndromes treated with (es)ketamine

Noam Hartman — D. Ivkic, I. Bozic, L. Reinfried, M.C. Dorczok, A.C. Moser, G. Fugger, D. Rujescu, L. Pezawas, S. Doering, D. Winkler, M. Spies, B. Ludwig, F. Buchmayer, A. Weidenauer, L. Bartova · Medical University of Vienna, Department of Psychiatry and Psychotherapy- Clinical Division of General Psychiatry, Vienna, Austria

2026 ECNP Congress

Background

Neuropsychiatric manifestations are common in post-acute infectious syndromes (PAIS), particularly in Long COVID (LC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). One common phenotype includes post-exertional malaise, fatigue, cognitive dysfunction, sleep disturbances, autonomic dysregulation, and pain [1]. These symptoms show substantial clinical and neurobiological overlap with depressive and anxiety disorders. Converging evidence implicates neuroinflammation with microglial activation [2], glutamatergic dysregulation [3], and hypothalamic-pituitary-adrenal stress-axis dysfunction [4] as pathophysiological mechanisms. Without established protocols, strategies from mood and anxiety disorders show therapeutic promise. In LC patients with severe and/or persistent neuropsychiatric symptoms, one case series published by our group [5] and three case reports highlight the potential benefit of (es)ketamine.

Aims

This analysis aimed to characterize clinical features of patients with neuropsychiatric symptoms in LC or ME/CFS who received intranasal or intravenous (es)ketamine after insufficient response to conventional psychopharmacological treatments in routine in- or outpatient care.

Methods

A total of 17 patients treated between September 2023 and February 2026 for LC- or ME/CFS-related neuropsychiatric symptoms with an (es)ketamine induction regimen adapted from treatment-resistant depression were included. The Montgomery-Åsberg Depression Rating Scale (MADRS) served as primary outcome, capturing affective, cognitive, psychomotor, and vegetative symptom dimensions relevant to LC and ME/CFS. Pre- to post-treatment changes were assessed using a paired-samples t-test. A univariate ANCOVA examined predictors of post-treatment MADRS scores, with pre-treatment MADRS and psychiatric comorbidity as covariates. Clinical characteristics were analysed descriptively to explore subgroup patterns.

Results

The cohort (n = 17) showed a statistically significant reduction in total MADRS scores from pre- to post-induction (32.24 [SD = 9.85] to 12.65 [SD = 7.39]; p < 0.001, 95% CI [16.19, 22.99]; d = 2.96). The ANCOVA model was significant (F(2,14) = 10.54, p = 0.002, R² = 0.601), with pre-treatment MADRS as the only significant predictor (F(1,14) = 15.25, p = 0.002, η²p = 0.52); psychiatric comorbidity was not (p = 0.200). Descriptive subgroup analysis for mean MADRS reduction: in-patient treatment: 20,38 points (n = 8, SD = 8.21), out-patient treatment: 18.89 points (n = 9, SD = 5.23). Intranasal administration 19.36 points (n = 14, SD = 7.10), intravenous administration 20.67 points (n = 3, SD = 4.51).

Discussion

(Es)ketamine treatment was associated with significant MADRS reduction, suggesting improvement of neuropsychiatric symptoms in patients with LC or ME/CFS. The large effect size should be interpreted cautiously given the retrospective design, small heterogeneous sample, and use of the MADRS, which has not been validated specifically for LC and ME/CFS. Nonetheless, the MADRS may capture clinically relevant symptom dimensions in this population, given the observed overlap between LC, ME/CFS and affective as well as anxiety disorders. The ANCOVA was underpowered and its findings, like the descriptive subgroup observations, should be considered exploratory and hypothesis-generating. Overall, results align with the mechanistic rationale for (es)ketamine in LC and ME/CFS and with previous evidence [5]. Based on these findings, randomised controlled trials using LC- and ME/CFS-specific outcome measures alongside established neuropsychiatric scales are urgently needed to further evaluate the potential effects of (es)ketamine in this population.

References

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  2. Braga, J., Lepra, M., Kish, S. J., Rusjan, P. M., Nasser, Z., Verhoeff, N., Vasdev, N., Bagby, M., Boileau, I., Husain, M. I., Kolla, N., Garcia, A., Chao, T., Mizrahi, R., Faiz, K., Vieira, E. L., & Meyer, J. H., 2023. Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms. JAMA Psychiatry, 80(8), 787-795.
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  4. Camici, M., Del Duca, G., Brita, A. C., & Antinori, A., 2024. Connecting dots of long COVID-19 pathogenesis: a vagus nerve- hypothalamic-pituitaryadrenal-mitochondrial axis dysfunction. Front Cell Infect Microbiol, 14, 1501949.
  5. Bozic, I., Ivkic, D., Reinfried, L., Donath, J., Schmidt, C., Graf, S., Handschuh, P., Dold, M., Winkler, D., Naderi-Haiden, A., Praschak-Rieder, N., Rujescu, D., Weidenauer, A., & Bartova, L., 2025. The role of esketamine in persistent long COVID with predominant psychiatric manifestations. EurNeuropsychopharmacol, 93, 66-67.