This case study (n=1) presents the first known case of successfully treating functional neurological disorder (FND), concurrent with depression, with esketamine. The study suggests that (es)ketamine may be a possible tool in treating FND.

Abstract

“Functional neurological disorder (FND) is a complex neuropsychiatric condition characterized by the presence of neurological symptoms and signs (either motor or sensory) that cannot be explained by any known medical or mental disease. It is frequently presented with psychiatric comorbidities, such as major depression. Its prognosis is poor, with low improvement or recovery rates at 1 year after their onset, and no particular treatment has demonstrated significant efficacy in this regard. Here, we describe the management of a patient affected by treatment-resistant depression (TRD) and FND characterized by mixed paralysis (sensory and motor) in the left arm, and who was successfully treated with esketamine nasal spray, achieving remission in both disorders. The US Food and Drug Administration and the European Medicines Agency recently approved esketamine, the S-enantiomer of ketamine, for treatment of TRD. It is a fast-acting drug that provides a rapid-onset improvement of depressive symptoms. We have presented the first case, to our knowledge, of functional neurological symptoms being successfully treated with esketamine in a patient with comorbid TRD. While the novelty of this data implies a clear need for further research, it is suggested that esketamine might be a useful tool for the treatment of FND, acting through different theorized mechanisms that are in tune with recent advances in knowledge of the etiopathology of FND.“

Authors: Júlia Vendrell-Serres, Óscar Soto-Angona, Amanda Rodríguez-Urrutia, Gara Arteaga-Henríquez & Josep A. Ramos-Quiroga

Summary

Functional neurological disorder (FND) is a complex neuropsychiatric condition characterized by the presence of one or more symptoms that cannot be explained by any known medical or mental health condition, and that cause significant distress in different areas.

Although there is still a scarcity of effective options for the treatment of FND, cognitive – behavioral therapy (CBT) might be more effective than placebo, although the effect size was small.

Esketamine nasal spray, an antidepressant with a novel mechanism of action, blocks N-methyl-D-aspartate receptors expressed on gamma-aminobutyric-acidergic inhibitory interneurons, leading to enhanced glutamatergic firing and increased brain-derived neurotrophic factor expression.

Esketamine nasal spray is used to treat TRD. It is administered twice weekly for 4 weeks, and then once a week or every other week.

Case report

A 49-year-old man with a history of chronic hypertension and psychiatric history of MDD was admitted to the psychiatric emergency room with a major depressive episode and limited mobility of the left limb. He was diagnosed with functional neurologic disorder (FND), with paralysis of the left extremity.

Upon first consultation, the patient was not receiving any pharmacological treatment. Paroxetine was prescribed, mirtazapine was added at night, and aripiprazole was boosted with CBT, but the patient’s functional neurological symptoms persisted.

The patient had paresis of the left extremity for 1 year, concurrent with numbness, and major functional limitations. Esketamine nasal spray medication was initiated on treatment day 1, and the dose was increased on day 2 to 84 mg administered using three nasal spray devices.

The patient recovered full mobility of the left superior extremity and has recovered 5/5 muscular strength.

The patient presented an almost complete recovery of mobility, with a persistent increase in autonomy for daily activities, through to the present day.

Discussion

Esketamine, a drug that has recently been approved for the treatment of TRD, was used to improve the symptoms of a patient with comorbid FND. Esketamine has remarkable psychoactive effects, which might be related to its antidepressant properties.

Esketamine has been shown to improve depressive symptoms and functional motor symptoms in patients with functional neurological disorders. This suggests that esketamine might be a useful tool for the treatment of functional neurological disorders.

Esketamine could improve brain plasticity via stimulation of BDNF production and activation of the mammalian target of rapamycin (mTOR) pathway. This could explain the rapid onset of esketamine’s effect and the sustained improvement in depressive symptoms and functional neurological symptoms.

Several theories have attempted to explain the neurobiological basis of FND, with conflicting findings. However, emotional circuits, especially limbic networks, and patient beliefs about their own symptoms seem to be important for prognosis of functional neurological symptoms.

Ketamine and esketamine have not been tested for functional neurological symptoms, but they have been shown to be efficacious for treating chronic pain, which overlaps in several aspects with FND.

Conclusion

This is the first report of an improvement in functional neurological symptom disorder after treatment with esketamine. The absence of valid treatment options should encourage further research.

J.Vendrell-Sérres has received fees from Lundbeck, Janssen and Angelini, and J.A.R.Q. has received travel awards for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Takeda, Shionogi, Bial, Medice, Rubió, Uriach and Raffo.