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

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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.
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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
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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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... There has been renewed medical research interest in the medical use of psychoactive substances, such as psychedelics (16)(17)(18), 3,4-methylenedioxymethamphetamine (MDMA) (16), cannabis (19), and ketamine (20,21), as treatments for neuropsychiatric disorders. These treatments are often administered as single doses in medically supervised environments, thus avoiding the need to take medication regularly (16). ...
... These treatments are often administered as single doses in medically supervised environments, thus avoiding the need to take medication regularly (16). There have been specific suggestions that ketamine, MDMA, and psychedelics could be interesting research targets in the treatment of FND (21)(22)(23)(24). Ketamine is a dissociative anesthetic that has similarities to other agents used in therapeutic abreaction, and it has an emerging evidence base in trauma-related pathologies such as posttraumatic stress disorder (PTSD) (25). ...
... As with psychedelics (discussed below), the administration of a single dose of ketamine (or its S [1] enantiomer esketamine) can lead to lasting improvement in some patients with otherwise treatment-resistant depression (58); repeated doses of ketamine have also shown promise in reducing symptom severity in patients with PTSD (25). There have been two independent case reports of esketamine nasal spray used in patients with FND and refractory depression; in both cases, esketamine was prescribed for depression; however, both the mood disorder and FND improved (21,59). ...
Article
Objective: Functional neurological disorder (FND) causes a high burden of disability and distress. Although it is a common disorder, there is a pressing need for improved access to evidence-based treatments. With difficulties in finding effective treatment, some people with FND may seek alternative means of symptom relief, such as legal and illicit psychoactive substances, although the prevalence and nature of such self-management strategies are currently unclear. Additionally, psychoactive substances may represent novel treatment research opportunities, particularly for those with suboptimal improvement. The investigators examined the use of self-management techniques, as well as perspectives on novel therapies, in this patient population. Methods: An online survey was created to assess self-management strategies and views on novel treatments for FND, including psychedelic therapy. The survey was accessible for 1 month, and respondents were recruited internationally through social media and patient groups. A total of 1,048 respondents from 16 countries completed the survey. Results: Almost half (46%) of 980 respondents reported having tried legal psychoactive substances for the management of their FND symptoms and, on average, nicotine, alcohol, and cannabidiol were reported as modestly effective. Additionally, 15% of respondents reported having used illicit substances, mostly cannabis, to manage FND, with the majority reporting moderate effectiveness and experiencing no or minimal physical (90%) and psychological (95%) sequelae. Many respondents (46%) reported that they would be willing to try medically supervised psychedelic therapy (with 19% of respondents ambivalent) if it were found to be safe and effective. Conclusions: Many people with FND seek alternative means of symptom management outside usual medical care, including legal and illicit psychoactive substances. Further research exploring novel treatment options, such as psychedelics, in FND may be warranted.
... A small but growing number of studies, patient surveys, and reviews have been published exploring the role of psychedelics as a treatment for FND. These have been motivated by (i) FND's close relationship to mental health conditions such as depression, anxiety, and PTSD, (ii) the high incidence of patient-reported psychedelic self-treatment for this class of disorders, and (iii) mechanistically based arguments suggesting a match between psychedelic therapeutic effects and FND pathophysiology (Butler et al., 2020(Butler et al., , 2023Stewart et al., 2020;Vendrell-Serres et al., 2021). A systematic review of earlier research conducted in the 1950s and 1960s investigating psychedelics for treating FND (primarily with LSD) found that of the 26 patients described in the case series and reports, 69% (n = 18) experienced some improvements, with 23% (n = 6) having made complete recoveries (Butler et al., 2020). ...
... Two recent case reports signal promise. One describes the successful treatment of a patient with FNDs, characterized by sensory and motor paralysis of the left arm, using intranasal esketamine, the S-enantiomer of ketamine (Vendrell-Serres et al., 2021). The other, conducted by members of our team, describes the first case of a patient who experienced significant reductions in the severity and frequency of FS, as well as marked improvements in depressive symptoms and well-being, following sublingual and intranasal ketamine-assisted therapy (KAT) (Argento et al., 2023). ...
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Functional seizures (FS), the most common subtype of functional neurological disorder (FND), cause serious neurological disability and significantly impact quality of life. Characterized by episodic disturbances of functioning that resemble epileptic seizures, FS coincide with multiple comorbidities and are treated poorly by existing approaches. Novel treatment approaches are sorely needed. Notably, mounting evidence supports the safety and efficacy of psychedelic-assisted therapy (PAT) for several psychiatric conditions, motivating investigations into whether this efficacy also extends to neurological disorders. Here, we synthesize past empirical findings and frameworks to construct a biopsychosocial mechanistic argument for the potential of PAT as a treatment for FS. In doing so, we highlight FS as a well-defined cohort to further understand the large-scale neural mechanisms underpinning PAT. Our synthesis is guided by a complexity science perspective which we contend can afford unique mechanistic insight into both FS and PAT, as well as help bridge these two domains. We also leverage this perspective to propose a novel analytic roadmap to identify markers of FS diagnostic specificity and treatment success. This endeavor continues the effort to bridge clinical neurology with psychedelic medicine and helps pave the way for a new field of psychedelic neurology.
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Background Functional neurological disorder (FND) is a common cause of neurological symptoms including paralysis, seizures, and movement disorders. It is often debilitating, is associated with high health and social care costs, and can have a poor prognosis. Functional magnetic resonance imaging (fMRI) has suggested FND is a multi-network disorder; the default mode network (DMN) may be specifically implicated. Converging evidence suggests that other variable mechanisms including dissociation, interoception, and motor agency may be differentially abnormal in people with FND. Psychedelics are currently under investigation for numerous neuropsychiatric disorders and have been shown to disrupt functional networks such as the DMN. Administering psychedelics to people with FND will help us to probe mechanistic theories of the disorder. Protocol In this open-label neuroimaging study, we will administer 25mg oral psilocybin with psychological support to people with chronic FND (target n = 24). Participants will undergo resting-state and task-based (Libet’s clock, a measure of motor agency) fMRI sequences which will be compared in a pre-post manner. Additional mechanistic outcomes including measures of interoception (heartbeat tracking task), somatisation, illness perceptions, imaginative suggestibility, and dissociation will be collected. Data on expectancy, preparedness, and subjective experience of the psychedelic experience will also be gathered. Participants will be followed up for three months following psilocybin administration. fMRI changes in networks such as the DMN will be analysed using seed-based approaches, and additional exploratory analysis of resting-state imaging will take place. Discussion The study will help us to probe the mechanisms thought to potentially underpin FND. As the first modern study of psychedelics in FND, it will also help us to understand whether psychedelic administration alongside psychological support might be safe and feasible in this patient population.
Chapter
This chapter gives an overview and update on functional neurological disorder (FND), also known as dissociative neurological symptom disorder and previously known as conversion disorder. FND is the presence of neurological symptoms that are not explained or explainable by a neurological disorder. FND has been assumed to be a purely stress-related psychiatric disorder, but over the recent decades, this simplistic conception has been supplanted by more nuanced models of symptom generation. FND is no longer a diagnosis of exclusion. Instead, wherever possible, it is ruled-in by distinct features of history and examination, the latter known as positive clinical signs. There have been concurrent advances in the biological understanding of FND, exemplified by functional neuroimaging studies that have indicated that FND can be distinguished from, for example, feigned symptoms mimicking the disorder. FND encompasses multiple subtypes, from seizures to motor disorders to sensory abnormalities. Symptoms often co-occur, sometimes in a striking fashion. Current treatment options for FND are limited, and many patients have severe long-term symptoms despite best-available treatment including psychological therapies and medication. Nevertheless, there are simple, and sometimes effective, steps that clinicians can take to manage and treat patients.
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Functional seizures, a primary subtype of functional neurological disorder (FND), are a known cause of serious neurological disability with an increasing awareness of their impact amongst the neuroscience community. Situated at the intersection of neurology and psychiatry, FND is characterized by a range of alterations in motor, sensory or cognitive performance, such as abnormal movements, limb weakness, and dissociative, seizure-like episodes. Functional seizures are known, in part, to have psychological underpinnings; however, the lack of effective and consistent treatment options requires research and novel approaches to better understand the etiology, diagnosis and what constitutes a successful intervention. Ketamine, a selective blocker of the N-methyl-D-aspartate receptor, has a well-established safety and efficacy profile. In recent years, ketamine-assisted therapy has shown increasing potential for treating a broad range of psychiatric conditions, building on its demonstrated rapid-acting antidepressant effects. Here we present a 51-year-old female with refractory daily functional seizures leading to significant disability and a medical history significant for major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). After unsuccessful treatment attempts, the patient underwent a novel protocol with ketamine-assisted therapy. After 3 weeks of ketamine-assisted therapy followed by 20 weeks of intermittent ketamine treatment and ongoing integrative psychotherapy, the patient’s seizures were significantly reduced in frequency and severity. She experienced significant improvements in depressive symptoms and functional ability scores. To our knowledge, this is the first reported case describing improvement in functional seizures following ketamine-assisted therapy. While rigorous studies are needed, this case report encourages further investigation of ketamine-assisted therapy for functional seizures and other functional neurological symptoms.
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Functional neurological disorders (FNDs), which are sometimes also referred to as psychogenic neurological disorders or conversion disorder, are common disabling neuropsychiatric disorders with limited treatment options. FNDs can present with sensory and/or motor symptoms, and, though they may mimic other neurological conditions, they are thought to occur via mechanisms other than those related to identifiable structural neuropathology and, in many cases, appear to be triggered and sustained by recognizable psychological factors. There is intriguing preliminary evidence to support the use of psychedelic-assisted therapy in a growing number of psychiatric illnesses, including FNDs. We review the theoretical arguments for and against exploring psychedelic-assisted therapy as a treatment for FNDs. We also provide an in-depth discussion of prior published cases detailing the use of psychedelics for psychosomatic conditions, analyzing therapeutic outcomes from a contemporary neuroscientific vantage as informed by several recent neuroimaging studies on psychedelics and FNDs. © 2020 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd
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Functional neurological disorder (FND), formerly known as conversion disorder, causes a high burden of disability and distress, and is amongst the most commonly encountered conditions in neurology clinics and neuropsychiatric services, yet the therapeutic evidence base is somewhat limited. There has been recent interest in the therapeutic potential of psychedelics such as psilocybin and lysergic acid diethylamide (LSD), and in recent studies psychedelics have shown promise in treating a range of neuropsychiatric conditions. Modification of neural circuits associated with self-representation is thought to underlie some of this effect, and as some contemporary theories of FND focus on aberrant somatic self-representation, psychedelics may therefore represent an unexplored treatment option for FND. We systematically reviewed studies involving the use of psychedelics in FND. Nine studies published between 1954 and 1967, with a total of 26 patients, were identified. Due to restriction of licencing of psychedelic drugs since this period, no modern studies were identified. In most cases, patients received a course of psychotherapy with variable adjunctive administration of psychedelics (in a combination known as ‘psycholytic therapy’), with protocols varying between studies. Of those treated, 69% (n = 18) were found to have made at least some recovery on heterogeneous and subjective clinician-rated criteria. Adverse events were mostly mild and transient; however, at least one patient terminated the study due to distressing effects. All included studies were of low quality, often lacking control groups and valid outcome measures. Although no conclusions on efficacy may be drawn from these data, further research may help to determine whether psychedelics offer a feasible, safe and effective treatment for FND.
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Objective: The relationship between ketamine's hallucinogenic- and dissociative-type effects and antidepressant mechanism of action is poorly understood. This paper reviewed the correlation between subjective effects defined by various psychometric scales and observed clinical outcomes in the treatment of patients with Major Depressive Disorder (MDD). Methods: Based on PRISMA guidelines, we reviewed the dissociative and psychotomimetic mental state induced with ketamine during MDD treatment. Our selected studies correlated depression rating with validated scales collected at regular intervals throughout the study period such as the Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). We excluded studies with bipolar depression or with repeated dosing and no single-dose phase. We included 8 of 556 screened reports. Results: Two of five CADSS studies found significant negative correlations between increases in CADSS scores and depression scores. One of six BPRS studies demonstrated correlations between BPRS scores and depression scores. The 5D-ASC's one study found no correlation with the MADRS. Conclusions: Ketamine's dissociative and psychotomimetic effects were correlated with depression changes in 37.5% of studies, but most studies did not examine this relationship and future studies should consider this association since it appears important for MDMA and psilocybin therapies.
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This paper formulates the action of psychedelics by integrating the free-energy principle and entropic brain hypothesis. We call this formulation relaxed beliefs under psychedelics (REBUS) and the anarchic brain, founded on the principle that—via their entropic effect on spontaneous cortical activity—psychedelics work to relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system. We assemble evidence for this model and show how it can explain a broad range of phenomena associated with the psychedelic experience. With regard to their potential therapeutic use, we propose that psychedelics work to relax the precision weighting of pathologically overweighted priors underpinning various expressions of mental illness. We propose that this process entails an increased sensitization of high-level priors to bottom-up signaling (stemming from intrinsic sources), and that this heightened sensitivity enables the potential revision and deweighting of overweighted priors. We end by discussing further implications of the model, such as that psychedelics can bring about the revision of other heavily weighted high-level priors, not directly related to mental health, such as those underlying partisan and/or overly-confident political, religious, and/or philosophical perspectives. Significance Statement Psychedelics are capturing interest, with efforts underway to bring psilocybin therapy to marketing authorisation and legal access within a decade, spearheaded by the findings of a series of phase 2 trials. In this climate, a compelling unified model of how psychedelics alter brain function to alter consciousness would have appeal. Towards this end, we have sought to integrate a leading model of global brain function, hierarchical predictive coding, with an often-cited model of the acute action of psychedelics, the entropic brain hypothesis. The resulting synthesis states that psychedelics work to relax high-level priors, sensitising them to liberated bottom-up information flow, which, with the right intention, care provision and context, can help guide and cultivate the revision of entrenched pathological priors.
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This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of non-pharmacological interventions for somatoform disorders (specifically somatisation disorder, undifferentiated somatoform disorder, somatoform disorders unspecified, somatoform autonomic dysfunction, pain disorder and alternative somatoform diagnoses proposed in literature) and MUPS in adults in comparison with treatment as usual, waiting list controls, attention placebo, psychological placebo and other psychological or physical therapies.
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Background: Over the past 2 decades, the use of intravenous ketamine infusions as a treatment for chronic pain has increased dramatically, with wide variation in patient selection, dosing, and monitoring. This has led to a chorus of calls from various sources for the development of consensus guidelines. Methods: In November 2016, the charge for developing consensus guidelines was approved by the boards of directors of the American Society of Regional Anesthesia and Pain Medicine and, shortly thereafter, the American Academy of Pain Medicine. In late 2017, the completed document was sent to the American Society of Anesthesiologists' Committees on Pain Medicine and Standards and Practice Parameters, after which additional modifications were made. Panel members were selected by the committee chair and both boards of directors based on their expertise in evaluating clinical trials, past research experience, and clinical experience in developing protocols and treating patients with ketamine. Questions were developed and refined by the committee, and the groups responsible for addressing each question consisted of modules composed of 3 to 5 panel members in addition to the committee chair. Once a preliminary consensus was achieved, sections were sent to the entire panel, and further revisions were made. In addition to consensus guidelines, a comprehensive narrative review was performed, which formed part of the basis for guidelines. Results: Guidelines were prepared for the following areas: indications; contraindications; whether there was evidence for a dose-response relationship, or a minimum or therapeutic dose range; whether oral ketamine or another N-methyl-D-aspartate receptor antagonist was a reasonable treatment option as a follow-up to infusions; preinfusion testing requirements; settings and personnel necessary to administer and monitor treatment; the use of preemptive and rescue medications to address adverse effects; and what constitutes a positive treatment response. The group was able to reach consensus on all questions. Conclusions: Evidence supports the use of ketamine for chronic pain, but the level of evidence varies by condition and dose range. Most studies evaluating the efficacy of ketamine were small and uncontrolled and were either unblinded or ineffectively blinded. Adverse effects were few and the rate of serious adverse effects was similar to placebo in most studies, with higher dosages and more frequent infusions associated with greater risks. Larger studies, evaluating a wider variety of conditions, are needed to better quantify efficacy, improve patient selection, refine the therapeutic dose range, determine the effectiveness of nonintravenous ketamine alternatives, and develop a greater understanding of the long-term risks of repeated treatments.
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Importance Functional neurological disorders (FND) are common sources of disability in medicine. Patients have often been misdiagnosed, correctly diagnosed after lengthy delays, and/or subjected to poorly delivered diagnoses that prevent diagnostic understanding and lead to inappropriate treatments, iatrogenic harm, unnecessary and costly evaluations, and poor outcomes. Observations Functional Neurological Symptom Disorder/Conversion Disorder was adopted by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, replacing the term psychogenic with functional and removing the criterion of psychological stress as a prerequisite for FND. A diagnosis can now be made in an inclusionary manner by identifying neurological signs that are specific to FNDs without reliance on presence or absence of psychological stressors or suggestive historical clues. The new model highlights a wider range of past sensitizing events, such as physical trauma, medical illness, or physiological/psychophysiological events. In this model, strong ideas and expectations about these events correlate with abnormal predictions of sensory data and body-focused attention. Neurobiological abnormalities include hypoactivation of the supplementary motor area and relative disconnection with areas that select or inhibit movements and are associated with a sense of agency. Promising evidence has accumulated for the benefit of specific physical rehabilitation and psychological interventions alone or in combination, but clinical trial evidence remains limited. Conclusions and Relevance Functional neurological disorders are a neglected but potentially reversible source of disability. Further research is needed to determine the dose and duration of various interventions, the value of combination treatments and multidisciplinary therapy, and the therapeutic modality best suited for each patient.
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Purpose of review: This article provides a broad overview of conversion disorder, encompassing diagnostic criteria, epidemiology, etiologic theories, functional neuroimaging findings, outcome data, prognostic indicators, and treatment. Recent findings: Two important changes have been made to the recent Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria: the criteria that conversion symptoms must be shown to be involuntary and occurring as the consequence of a recent stressor have been dropped. Outcome studies show that the rate of misdiagnosis has declined precipitously since the 1970s and is now around 4%. Functional neuroimaging has revealed a fairly consistent pattern of hypoactivation in brain regions linked to the specific conversion symptom, accompanied by ancillary activations in limbic, paralimbic, and basal ganglia structures. Cognitive-behavioral therapy looks promising as the psychological treatment of choice, although more definitive data are still awaited, while preliminary evidence indicates that repetitive transcranial magnetic stimulation could prove beneficial as well. Summary: Symptoms of conversion are common in neurologic and psychiatric settings, affecting up to 20% of patients. The full syndrome of conversion disorder, while less prevalent, is associated with a guarded prognosis and a troubled psychosocial outcome. Much remains uncertain with respect to etiology, although advances in neuroscience and technology are providing reproducible findings and new insights. Given the confidence with which the diagnosis can be made, treatment should not be delayed, as symptom longevity can influence outcome.