¹Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria, ²Medical University of Vienna, Department of Neurology, Vienna, Austria, ³Department of Psychiatry and Psychotherapy, University Hospital St. Poelten, St. Poelten, Austria, ⁴Leben Psyche Zentrum, Outpatient Psychiatric Clinic, Vienna, Austria

Background: Neuropsychiatric manifestations of Long COVID (LC) frequently include post-exertional malaise (Cheng et al., 2025), fatigue, cognitive dysfunction and impairment, sleep disturbances, post-traumatic stress, autonomic dysregulation, pain, inner tension, psychomotor retardation, aberrations in appetite and weight (Badenoch et al., 2022; O'Mahoney et al., 2025), showing substantial clinical and neurobiological overlap with depressive and anxiety diseases, as demonstrated, for example, in neuroimaging studies (Braga et al., 2023; Churchill et al., 2023; Douaud et al., 2022; Runia et al., 2022; Siqueira et al., 2025). Converging evidence implicates neuroinflammation (Lai et al., 2023; Matschke et al., 2020), glutamatergic dysregulation (Fujimoto et al., 2025; Horowitz et al., 2023), impaired neuroplasticity (Chagas & Serfaty, 2024; Kempuraj et al., 2024), and stress-axis dysfunction (Camici et al., 2024) as central mechanisms of neuropsychiatric LC. In the absence of established treatment protocols for LC, structured psychopharmacological approaches derived from depressive and anxiety diseases are increasingly applied in specialized clinical settings for the alleviation of neuropsychiatric LC symptoms (Bartova et al., 2023; Crosby et al., 2021; McIntyre et al., 2024; Reinfeld, 2023) with one case series (Bozic et al., 2025) and three other case reports (Baldwin et al., 2023; Brode et al., 2025; Remick et al., 2024) highlighting (Es)Ketamine´s positive effect on severe and persistent neuropsychiatric LC symptoms.

Aims & Objectives: To describe clinical outcomes of intranasal and intravenous esketamine when used as an off-label fourth-step escalation strategy within a proposed, structured psychopharmacological treatment algorithm for neuropsychiatric LC in routine clinical care (Table 1).

Method: Fifteen in and outpatients with neuropsychiatric LC were treated according to a stepwise, symptom-oriented psychopharmacological algorithm (Table 1). All pharmacological treatments, including intranasal or intravenous esketamine, were prescribed off-label for LC but followed established clinical standards from depressive and anxiety diseases. Esketamine was administered only after insufficient response to adequate prior treatment stages, analogously to approved protocols for treatment resistant depression (TRD) (Johnston et al., 2024). Clinical data derived from this routine care treatment were retrospectively analyzed. Outcome assessment focused on core neuropsychiatric symptom domains, tolerability, and safety.

Results: The present preliminary retrospective analysis of routine clinical data indicates clinically meaningful improvement across multiple symptom domains, including fatigue, cognitive dysfunction, depressive symptoms, anxiety, sleep disturbances, pain, and autonomic hyperreactivity. In analogy to its on-label use in TRD, esketamine has been generally well tolerated in LC patients, with no unexpected safety concerns observed in clinical routine. These findings are in line with emerging clinical reports on esketamine use in persistent neuropsychiatric LC (Baldwin et al., 2023; Bozic et al., 2025; Brode et al., 2025; Remick et al., 2024).

Discussion & Conclusions: These preliminary results suggest that esketamine, applied off-label as a clearly defined escalation step within a proposed, structured treatment algorithm (Table 1), may represent a feasible and beneficial option for selected patients with neuropsychiatric LC. They support the neurobiological rationale for glutamatergic modulation in LC and provide a foundation for future controlled clinical trials to systematically evaluate optimal treatment allocation, efficacy and long-term outcomes. ​
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Table 1. Overview of the proposed, stepwise psychopharmacological treatment algorithm for neuropsychiatric Long COVID
Treatment step	Therapeutic strategy	Representative Substances
Step I	Evidence-based phyto-psychopharmacotherapy	Silexan, Ginkgo biloba, Rhodiola rosea
Step II	Antidepressant treatment	SSRIs, SNRIs, vortioxetine, bupropion, mirtazapine
Step III	Add-on strategies	aripiprazole, pregabalin, daridorexant
Step IV	Glutamatergic modulation	esketamine
Table summarizing a proposed four-step psychopharmacological treatment algorithm for neuropsychiatric Long COVID, with esketamine positioned as the fourth escalation step (Ivkic et al., 2025).

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