Improvement of functional neurological disorder after administration of esketamine nasal spray: a case report

Functional neurological disorder (FND), also referred to as conversion disorder, is a neuropsychiatric condition in which patients display motor or sensory symptoms that are not explained by identifiable neurological disease and that cause marked functional impairment. Vendrell-Serres and colleagues note that FND is common in both neurology and psychiatric settings, often co-occurs with mood and anxiety disorders (especially major depressive disorder), and has a generally poor prognosis with low rates of improvement at 1 year. The introduction emphasises that there is no established, consistently effective pharmacological treatment for FND and that evidence for psychological and physical therapies is limited or has modest effect sizes. This case report describes an individual with long-standing major depressive disorder who developed treatment-resistant depression (TRD) together with a one-year history of mixed sensory–motor paralysis of the left arm diagnosed as FND. The study sets out to describe the clinical course after administration of esketamine nasal spray, recently approved for TRD, and to explore possible mechanisms by which esketamine might ameliorate functional neurological symptoms. The authors present the case as, to their knowledge, the first published instance of FND improving after esketamine treatment, and position the report as a stimulus for further research into this potential indication.

This paper is a single-patient case report from Vall d'Hebron University Hospital. The extracted text describes a 49-year-old man with chronic hypertension and a 20-year history of major depressive disorder who presented in October 2019 with a major depressive episode and abrupt onset mixed paralysis (sensory and motor) of the left upper limb. Neurological assessment included computed tomography, magnetic resonance imaging and electromyography, all reported as without pathological findings. The diagnosis of FND was based on clinical characteristics—rapid onset, attenuation with distraction, increase with attention, and incongruence with investigation results—and represented his first episode of functional paralysis. Before esketamine, the patient received multiple antidepressant strategies and adjuncts without adequate response: paroxetine (up to 60 mg/day) with clonazepam, later mirtazapine 15 mg with aripiprazole 15 mg, cognitive–behavioural therapy (CBT) started in February 2020 (biweekly sessions), and subsequently venlafaxine titrated to 300 mg/day. Despite partial improvement in mood with some combinations, the functional motor symptoms persisted for about 1 year and caused substantial loss of autonomy. Esketamine nasal spray was initiated in October 2020 after informed consent for treatment and publication. The induction regimen began at 56 mg (two 28 mg devices) on day 1, increased to 84 mg (three devices) on day 2, then continued as 84 mg twice weekly for 4 weeks. Maintenance treatment was then given flexibly every 2 weeks. Clinical assessments reported in the extracted text include the Montgomery–Åsberg Depression Rating Scale (MADRS) for depressive symptoms and the Medical Research Council (MRC) power grade for muscular strength. Adverse-effect monitoring documented transient dissociative symptoms within 2 hours of dosing. As a case report, no statistical analyses or control comparisons were performed; the methods consist of clinical observation and longitudinal symptom measurement.

After the first esketamine session the patient showed rapid improvement in depressive symptoms, with sustained remission at 5 months while receiving maintenance dosing every 2 weeks (remission as indicated by MADRS scores reported in the paper's figure). Concomitantly, motor and sensory functional symptoms improved from the first treatment: within about 2 hours after administration the patient experienced almost complete recovery of mobility in the left upper limb, although a small diminution of effect occurred a few days after each session. Over follow-up the improvement persisted such that the patient ultimately regained full mobility, reported normal use of the limb in daily activities, demonstrated 5/5 muscle strength on the MRC scale and had complete resolution of numbness. Adverse effects were limited to mild dissociative symptoms after administration, which resolved completely within 2 hours; no other adverse events were reported in the extracted text. The authors note that before esketamine the patient required assistance with everyday activities, whereas after treatment he achieved increased autonomy. The extracted text refers to a figure summarising treatments and symptom progression but does not provide specific MADRS or numerical strength values beyond the MRC grade.

Vendrell-Serres and colleagues interpret this case as the first reported instance of FND improving after esketamine treatment in a patient with comorbid TRD, and they urge cautious consideration of its implications. They propose several non-mutually exclusive mechanisms that might account for the parallel improvement in depression and functional motor symptoms. One possibility is that alleviation of depressive symptoms contributed to remission of functional neurological signs, noting that psychiatric comorbidity is common in FND though causal links are not established. A second mechanism advanced by the authors is enhanced neuroplasticity: esketamine may stimulate brain-derived neurotrophic factor (BDNF) expression and activate the mammalian target of rapamycin (mTOR) pathway, promoting synaptogenesis and restoration of synaptic function more directly or rapidly than conventional oral antidepressants. The rapid onset of both mood and motor improvements in this case is cited as consistent with such plasticity effects, though the authors observe some waning of motor benefit between doses and speculate that more frequent dosing might be required for FND. Third, the discussion highlights network-level and cognitive models: emotional (limbic) circuits and their influence on cortico–striato–thalamo–cortical circuits are implicated in FND, and esketamine's downstream glutamatergic effects overlap with mechanisms attributed to classic psychedelics that alter large-scale networks such as the default mode network. Changes in self-awareness, self-imagery and patients’ prior beliefs about symptoms—phenomena that can be influenced by suggestion or altered states of consciousness—are also proposed as relevant, with esketamine-induced dissociation potentially facilitating revision of maladaptive priors. Finally, the authors note that ketamine and related dissociative anaesthetics have analgesic effects and have been used in chronic pain, a condition with some clinical overlap with FND; other dissociative agents have shown preliminary promise in FND, which the authors cite as further support for investigating esketamine. Throughout, they acknowledge the novelty of a single-case observation and call for further research, while also observing that current therapeutic options for FND are limited and that additional study is warranted.

The authors conclude that this is, to their knowledge, the first report of improvement in functional neurological disorder following esketamine nasal spray treatment in a patient with comorbid treatment-resistant depression. They state that the finding is novel but preliminary, and that the lack of validated treatments and the generally poor prognosis of FND justify further investigation of esketamine for this indication. The conclusion reiterates that recent advances in understanding FND's aetiology provide theoretical support for exploring esketamine's potential benefits.