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https://doi.org/10.1177/20451253211022187
https://doi.org/10.1177/20451253211022187
Ther Adv Psychopharmacol
2021, Vol. 11: 1–6
DOI: 10.1177/
20451253211022187
© The Author(s), 2021.
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From Drug Misuse to Useful Drugs
Introduction
Functional neurological disorder (FND; also
known as conversion disorder) is a complex neu-
ropsychiatric condition characterized by the pres-
ence of one or more symptoms (either motor or
sensory) that cannot be explained by any known
medical or mental health condition, and that
causes significant distress in different areas (e.g.
social, occupational). Importantly, and as out-
lined in the fifth edition of the Diagnostic and
Statistical Manual of Mental Disorders,1 these
symptoms are not deliberately generated or
feigned by the patient; and although FND has
been traditionally viewed as an exclusion diagno-
sis, new models based on the most recent evi-
dence have proposed a positive diagnosis based
on specific neurological signs, such as Hoover’s
sign.2,3
Evidence suggests a prevalence of up to 4–11 per
100,000 in the general population, increasing to
11–22 per 100,000 in primarily psychiatric set-
tings, and reaching an estimation of 20% of all
patients being treated at a neurologic outpatient
clinic.4,5
Moreover, comorbidity with other psychiatric
disorders is common; depressive and anxiety dis-
orders being the most frequently found diagno-
ses. Personality disorders are also prevalent in
these patients, as well as somatic symptoms disor-
ders, and other medical and neurological disor-
ders such as epilepsy.1
FND presents a poor outcome and prognosis,
with low improvement and recovery rates 1 year
after onset. In most studies, functional motor
Improvement of functional neurological
disorder after administration of esketamine
nasal spray: a case report
Júlia Vendrell-Serres, Óscar Soto-Angona , Amanda Rodríguez-Urrutia,
Gara Arteaga-Henríquez and Josep A. Ramos-Quiroga
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.
Keywords: esketamine, functional neurological disorder, treatment resistant depression,
mixed paralysis
Received: 31 December 2020; revised manuscript accepted: 14 May 2021.
Correspondence to:
Óscar Soto-Angona
Department of Psychiatry,
Vall d’Hebron University
Hospital, Passeig de la
Vall d’Hebron, 119–129
Barcelona 08035, Spain
osoto@vhebron.net
Júlia Vendrell-Serres
Department of Psychiatry,
Vall d’Hebron University
Hospital, Barcelona,
Catalonia, Spain
Group of Psychiatry,
Mental Health and
Addiction, Vall d’Hebron
Research Institute (VHIR),
Barcelona, Spain
Department of Psychiatry
and Forensic Medicine,
Universitat Autònoma de
Barcelona, Barcelona,
Spain
Gara Arteaga-Henríquez
Department of Psychiatry,
Vall d’Hebron University
Hospital, Barcelona,
Catalonia, Spain
Group of Psychiatry,
Mental Health and
Addiction, Vall d’Hebron
Research Institute (VHIR),
Barcelona, Spain
Biomedical Network
Research Centre
on Mental Health
(CIBERSAM), Barcelona,
Catalonia, Spain
Amanda Rodríguez-
Urrutia
Josep A. Ramos-Quiroga
Department of Psychiatry,
Vall d’Hebron University
Hospital, Barcelona,
Catalonia, Spain
Group of Psychiatry,
Mental Health and
Addiction, Vall d’Hebron
Research Institute (VHIR),
Barcelona, Spain
Department of Psychiatry
and Forensic Medicine,
Universitat Autònoma de
Barcelona, Barcelona,
Spain
Biomedical Network
Research Center
on Mental Health
(CIBERSAM), Barcelona,
Catalonia, Spain
1022187TP
P0010.1177/20451253211022187Therapeutic Advances in PsychopharmacologyJ
Vendrell-Serres, Ó Soto-Angona
research-article20212021
Case Report
Therapeutic Advances in Psychopharmacology 11
2 journals.sagepub.com/home/tpp
symptoms and functional seizures are the same or
worse in the majority of patients at follow up, and
the long duration of symptoms seems to be the
most relevant predictor of a negative outcome.6
Despite the high prevalence and poor prognosis of
this disorder, there is still a scarcity of effective
options and no standard protocol for the treat-
ment of FND. Two recent Cochrane reviews on
the efficacy of pharmacological and non-pharma-
cological treatments for somatic symptom disor-
der, which include FND, concluded that only
cognitive–behavioral therapy (CBT) might be
more effective than placebo, although the effect
size was small. No clear differences were found
between any drug and placebo.7,8 Although rand-
omized clinical trial evidence is limited, promising
data are emerging, and a greater role for physical
therapy has recently been recognized when motor
symptoms predominate. Treatment of the afore-
mentioned comorbidities frequently present in
FND is also fundamental to a better outcome.2
According to the World Health Organization,
major depressive disorder (MDD), the most com-
mon comorbidity of FND, is the leading cause of
disability worldwide. Even with the many treat-
ment options available for MDD, up to one third
of patients do not adequately respond. Esketamine
nasal spray (the S-enantiomer of racemic keta-
mine) has been developed as an antidepressant
with a novel mechanism of action and has recently
been approved for treatment-resistant depression
(TRD). This glutamate-receptor antagonist
selectively blocks N-methyl-D-aspartate recep-
tors expressed on gamma-aminobutyric-acider-
gic inhibitory interneurons, leading to enhanced
glutamatergic firing. This increases α-amino-3-
hydroxy-5-methyl-4-isoxazole propionic acid
receptor stimulation, leading to an array of molec-
ular and cellular events, including increases in
brain-derived neurotrophic factor (BDNF) expres-
sion. These changes are thought to induce produc-
tion of synaptic proteins and synaptogenesis, and
eventually restoration of synaptic function.9
The dosing schedule for esketamine nasal spray is
different from previous treatments for TRD. It is
divided into an induction phase and a mainte-
nance phase. In the 4-week induction phase, dos-
ing is flexible, with different doses recommended
twice weekly depending on age and ethnicity. The
maintenance phase begins after the initial 4 weeks,
in which esketamine nasal spray can be adminis-
tered flexibly: once a week, or every other week.10
We describe here the management of a patient
affected by TRD and functional neurological dis-
order characterized by mixed paralysis (sensory
and motor) in the left arm, who improved upon
receiving treatment with esketamine nasal spray.
To our knowledge, this indication has not been
reported before in the literature.
Case report
We present a 49-year-old man with a history of
chronic hypertension and a psychiatric history of
MDD that was first diagnosed 20 years ago,
whereupon he received treatment with paroxetine
with good response, with later treatment with-
drawal without relapse.
He was admitted to the psychiatric emergency
room at Vall d’Hebron University Hospital on
October 2019 with a major depressive episode and
limited mobility of the left limb, without identifying
any potential triggering event. Neurological symp-
toms (of sudden onset) were characterized by a
mixed paralysis (sensory and motor) affecting the
left extremity, and were assessed by a psychiatrist
and a neurologist. Complementary explorations
were performed, including computed tomography,
nuclear magnetic resonance and electromyogra-
phy, without pathological findings. Given the clini-
cal features characterized by rapid onset, attenuation
with distraction and increase with attention, as well
as incongruence with the results of complementary
tests, a FND was diagnosed, with paralysis of the
left extremity. This was the first episode of func-
tional paralysis and sensory loss for this patient.
Upon first consultation, the patient was not receiv-
ing any pharmacological treatment. Paroxetine
was prescribed, initially 20 mg/day and increased
to 60 mg/day over the following month, adding up
to 0.5 mg/8 h clonazepam, with little response.
In January 2020, mirtazapine 15 mg was added at
night, and boosted with aripiprazole 15 mg/day,
together with the start of CBT in February 2020.
CBT sessions were performed every 2 weeks and
are ongoing; the main objective was to treat
depression symptoms, but functional neurologi-
cal symptoms were also addressed. During the
ensuing months, the patient presented partial
improvement of the depressive symptoms, but
the functional neurological symptomatology per-
sisted. In June 2020, we decided to switch the
antidepressant to venlafaxine, up to 300 mg/day;
again, with little response.
J Vendrell-Serres, Ó Soto-Angona et al.
journals.sagepub.com/home/tpp 3
In October 2020, we proposed treatment with
esketamine nasal spray to the patient, who agreed
and provided written informed consent for the treat-
ment as well as publication of their medical data.
Before starting treatment, paresis of the left
extremity had persisted for 1 year, concurrent
with numbness. There was a significant loss of
strength and mobility, and major functional lim-
itations and loss of autonomy, as a result of
which, the patient needed help with everyday
activities.
Esketamine nasal spray medication was initiated
on treatment day 1, beginning at a dose of 56 mg
administered using two nasal spray devices
(28 mg per device) with good tolerance, so on
day 2, the dose was increased to 84 mg (three
nasal spray devices). Thereafter, the patient
received treatment at a dose of 84 mg twice a
week for 4 weeks.
After administration of esketamine, the patient
presented mild dissociative symptoms. At 2 h after
administration, the patient reported complete
remission of dissociative symptomatology without
presenting other adverse effects.
The patient responded to the treatment from the
first session with improvement of depressive
symptoms. He is still in maintenance treatment,
taking esketamine every 2 weeks, and, after
5 months’ follow up, his depressive symptoms
continue in remission (as shown in the
Montgomery–Åsberg Depression Rating Scale in
Figure 1).
Also, from the first treatment session, the patient
presented an improvement in mobility of the left
superior extremity, which persists. He has recov-
ered full mobility, uses his limb in daily activity,
and presents a 5/5 muscular strength, assessed
using the Medical Research Council power grade.
His numbness has also fully disappeared.
Administered treatments and symptom progres-
sion over time are summarized in Figure 2.
It should be noted that, during the first 2 h after
administration, the patient presented an almost
complete recovery of mobility, which slightly wors-
ened a few days after the treatment session, although
he was still able to perform tasks he was unable to
before, and with a persistent increase in autonomy
for daily activities, through to the present day.
Discussion
To our knowledge, this is the first reported case of
FND improvement after treatment with esketa-
mine in a patient with comorbid TRD.
Esketamine has recently been approved for the
treatment of TRD. In addition to its antidepres-
sant properties, esketamine is unique, as it allows
rapid-onset improvement of depressive symp-
toms.11 It is the S-enantiomer of racemic keta-
mine, a well-known drug that has recently been
shown to have robust antidepressant effects.9
However, primary use of ketamine was based on
its anesthetic properties; it is still widely used for
the treatment of chronic pain, and in critical care
and surgical settings.12
Interestingly, ketamine and esketamine also have
remarkable psychoactive effects, which might be
related to their antidepressant properties.13 The
degree of dissociation, depersonalization, and
derealization induced by ketamine also seems to
be related to the degree of response in depressed
patients.14
While the novelty of this data clearly requires
careful consideration of its implications, it sug-
gests that esketamine might be a useful tool for
the treatment of functional neurological disor-
ders. We propose the possible involvement of the
following action mechanisms that might be
involved.
First, in the case reported, the patient showed an
improvement in depressive symptoms, parallel to
the reversion of his functional motor symptoms.
While there is insufficient evidence to support a
causal correlation between psychiatric disorders
Figure 1. Evolution of the MADRS total score.
MADRS, Montgomery–Åsberg Depression Rating Scale.
Therapeutic Advances in Psychopharmacology 11
4 journals.sagepub.com/home/tpp
and functional neurological symptoms, the latter
are more prevalent in people presenting with the
former. Moreover, the presence of stressors is
known to be relevant, although not sufficient nor
necessary, for the onset of both disorders.1
In line with the theory that there is a relationship
between depression and FNDs, antidepressants
are widely used for its treatment, although there is
insufficient evidence to support this practice, and
they should only be used when there is a comor-
bid psychiatric illness.7
Regarding esketamine, some studies suggest that
it could improve brain plasticity via the stimula-
tion of BDNF production and activation of the
mammalian target of rapamycin (mTOR) path-
way. Modulation of mTOR would stimulate addi-
tional BDNF production, resulting in increased
brain plasticity (dendritic growth and improved
synaptic transmission). Esketamine could have a
more direct stimulation effect on BDNF and
mTOR than the present oral ADs. This may
explain the rapid onset of esketamine’s effect, and
also why the effects are maintained even after drug
elimination.15,16 In our case, the patient presented
a rapid improvement in depressive symptoms,
which was maintained for the following days, as
well as a rapid improvement in functional neuro-
logical symptoms, although in this case, there was
a slight loss of effect between doses. This further
reinforces the theory that the mechanisms of
action for improvement are similar in the two dis-
orders, although more frequent doses might be
needed in functional neurological disorders.
Secondly, several theories have attempted to
ascertain the neurobiological basis of FND, with
Figure 2. Symptom evolution and treatment administration through time.
J Vendrell-Serres, Ó Soto-Angona et al.
journals.sagepub.com/home/tpp 5
conflicting findings. However, emotional circuits,
(mainly limbic networks), and their influence on
the regulation ofcortico–striato–thalamo–cortical
circuits, are thought to be relevant.17 Classic
psychedelics, which act through serotoninergic
agonism, but have similar downstream effects to
esketamine via glutamatergic neurotransmission,
have recently been proposed as plausible candi-
dates to treat FND.18,19 One of the main theoreti-
cal frameworks in this regard lies in their capacity
to influence neural networks, especially the
default mode network.20
Thirdly, patient beliefs about their own symp-
toms seem to be important for prognosis of func-
tional neurological symptoms.21 It has also been
thought that FND and hypnotic states bear a
resemblance to each other, and some recent evi-
dence points in this direction, suggesting that
self-awareness and self-imagery play a central role
in this disorder.22 Suggestion techniques and
altered states of consciousness such as those pro-
vided by esketamine, would foster a change in the
patient’s prior beliefs that could influence his/her
self-imagery.23
Finally, while neither ketamine or esketamine
have, to our knowledge, been tested before for
functional neurological symptoms, ketamine has
been shown to be efficacious for treating chronic
pain,24 a condition that overlaps in several aspects
with FND, and that has been shown to respond
to similar treatments,25 which points to a possible
role of their analgesic effects. Other dissociative
anesthetics have also been tested for treatment of
FNDs, with promising results, which further rein-
forces the possible role of the proposed mecha-
nisms of action.26
Conclusion
To our knowledge, this is the first report of an
improvement in functional neurological symptom
disorder in a patient affected by a comorbid TRD
after treatment with esketamine. The novelty of
this data warrants the need for further evidence
on the use of esketamine for this indication.
However, the absence of valid treatment options
and the poor prognosis of FND should encourage
further research in this direction.
The most recent findings on the etiology of this
condition might support the efficacy of this
compound.
Conflict of interest statement
J.Vendrell-Sérres has received fees from
Lundbeck, Janssen and Angelini to act as speaker
or consultant. J.A.R.Q was on the speakers’
bureau and/or acted as consultant for Janssen-
Cilag, Novartis, Shire, Takeda, Bial, Shionogi,
Sincrolab, Novartis, BMS, Medice, Rubió,
Uriach and Raffo in the last 3 years. He also
received travel awards (air tickets + hotel) for tak-
ing part in psychiatric meetings from Janssen-
Cilag, Rubió, Shire, Takeda, Shionogi, Bial and
Medice. The Department of Psychiatry chaired
by him received unrestricted educational and
research support from the following companies in
the last 3 years: Janssen- Cilag, Shire, Oryzon,
Roche, Psious, and Rubió. O. Soto-Angona, A.
Rodríguez-Urrutia and G. Arteaga-Henríquez
report no conflict of interest.
Funding
The authors received no financial support for the
research, authorship, and/or publication of this
article.
ORCID iD
Óscar Soto-Angona https://orcid.org/0000-
0003-0234-4280
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