This document discusses the conflicting evidence around using botulinum toxin (Botox) injections to treat depression. It summarizes that while some studies found Botox injections between the eyes reduced depressive symptoms by limiting frowning, other research found injections around crow's feet increased depression by restricting smiling. The document argues both findings support Darwin's original theory that facial expressions can influence emotions. It concludes more research is needed, but preliminary evidence suggests targeted Botox injections may be a safe and effective adjunct treatment for depression by modulating facial feedback mechanisms linked to mood.

1. opinion | xxxxxxxxx |
In 2003, Heckmann et al
published data suggesting that
treatment of the glabellar
region with botulinum toxin
could produce a change in
facial expression from angry,
sad, and fearful to happy, and
that this could impact on
emotional experience.

2. the‘botox
paradox’:
is it effective
for depression?
PatrickTreacyconsiderstheconflictingevidennceof
botulinumtoxinuseasatherapyfordepression,andproposes
thatitallcomesdowntowherethetoxinisinjected
patrick treacy is Medical
Director of Ailesbury Clinics
Ltd and Ailesbury Hair Clinics
Ltd; Chairman of the Irish
Association of Cosmetic
Doctors and Irish Regional
Representative of the British
Association of Cosmetic
Doctors; European Medical
Advisor to Network Lipolysis
and the UK’s largest cosmetic
website Consulti,ng Rooms. He
practices cosmetic medicine
in his clinics in Dublin, Cork,
London and the Middle East
email: ptreacy@gmail.com
A
recent article
byClaireColeman1
,
published in the
UK’s Daily Mail
newspaper, has led
to much confusion
with regard to the role of Botox® in
treating or causing depression. The
article was based on a study led by
Dr Michael Lewis of the School of
Psychology, Cardiff, Wales, who
followed 25 people who had
received Botox treatment for facial
lines and examined the idea of facial
feedback — where the expressions
we make with our faces affect how
we feel — and found that many
women who have the treatment for
cosmetic purposes feel depressed
because they are no longer able to
smile properly.
Previous studies, however, have
found that the treatment of frown
lines left patients feeling less
depressed. In 2006, Dr Eric Finzi and
Dr Erika Wasserman reported in
Dermatologic Surgery that treating
clinically depressed patients with
Botox on their frown lines actually
reduced patients’ feelings of
depression2
. Depression affects over
120 million people globally, making it
oneoftheleadingcausesofdisability
in the world. Although there are a
number of effective treatments,
therapeutic response remains
unsatisfactory and depression can
develop into a chronic condition in a
considerable proportion of patients.
An economic treatment option that
could provide long intervals
between treatments, and that is safe,
would be very important to doctors.
So, what is the truth? Is there an
actual physiological reason to
explain the different results?
The ‘grief’ muscles
The story begins in 1872, when
Charles Darwin recognised that
negative emotions, such as anger,
fear, and sadness — all prevalent in
depression — are associated with
hyperactivity of the corrugator and
procerus muscles in the glabellar
region of the face. Darwin called
them the ‘grief muscles’ and
formulated a new theory, known as
the ‘facial feedback hypothesis’,
which implied a mutual interaction
between emotions and facial muscle
activity. He published his new theory
in The Expression of the Emotions in
Man and Animals, which concerns
the genetically determined aspects
of behaviour.
In this book, Darwin aimed to trace
the animal origins of human
characteristics, such as the
tightening of the muscles around the
eyes in anger and efforts of memory.
Darwinevensoughtouttheopinions
of eminent British psychiatrists in
preparation of the book, which forms
Darwin’s main contribution to
psychology. His theory implied a
mutual interaction between
emotions and facial muscle activity.
Research into this stayed there
during the great upheavals of both
World Wars, until the rising
popularityofBotoxmadescientists
review his facial hypothesis.
In 2003, Heckmann et al3
published data suggesting that
treatment of the glabellar region
with botulinum toxin could produce
a change in facial expression from
angry, sad, and fearful to happy, and
that this could impact on emotional
experience. Many therapists argue
that patients who had been treated
in the glabellar area reported an
increase in emotional wellbeing and
reduced levels of fear and sadness
beyond what would be expected
from the cosmetic benefit alone.
In 1992, Larsen et al4
provided
evidence that voluntary contraction
of facial muscles could channel
emotions, which were conversely
expressed by activation of these
muscles. Hennenlotter et al5
went
one stage further and showed that
botulinum toxin treatment to the
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glabellar area stopped the activation of
limbic brain regions normally seen during
voluntary contraction of the corrugator
and procerus muscles. This indicated that
feedback from the facial musculature in
this region in some way modulated the
processing of emotions. Many other
researchers continued on this track, with
Havas et al6
noting that the processing
time for sentences with negative affective
connotation was prolonged in women
after botulinum toxin treatment to the
glabellar, and Neal and Chartrand7
speculating that the treatment interfered
with the ability to decode the facial
expression of other people. This is where
things remained, until recently, when
some authors suggested that this capacity
to counteract negative emotions could be
put to some clinical use during the
treatment of depression.
Reducing symptoms
of depression
A seminal article by Finzi and
Wasserman2
postulated that botulinum
toxin injected into the glabellar reduced
the symptoms of depression. The authors
provided data from an open case series
of 10 female patients. The article
contained a footnote from editor Alastair
Carruthers, who stated that the report
must be considered anecdotal as there
were no appropriate methods of control
used. In addition, there were other
methodological weaknesses, including
limited follow-up, lack of randomisation,
the absence of blind evaluation, and in
particular, the small number of subjects
included. Many felt that the methodology
of evaluating depression should have
been more rigorous.
At the time, I noted by letter that
patients’ self-report of depressive
symptoms by administration of the BDI-II
(Beck Depression Inventory) introduced
a significant bias. This is of more concern
because of the potential for secondary
cosmetic gain. While the BDI-II is an
accepted method of evaluating an
individual’s level of symptoms over time,
self-report in isolation was not considered
an acceptable method of diagnosing
depression. It was concluded that in
order to ensure that patients’ psychiatric
symptoms are accurately classified, a
thorough psychiatric interview must
be conducted.
In 2012, the Psychiatric University
Hospital of the University of Basel,
Switzerland, and the Medical School
Hanover, Germany, conducted a
randomised, placebo-controlled,
double‑blind trial8
. The authors
hypothesised that facial psychomotor
features associated with depression are
not just epiphenomena, but integral
components of the disorder, and may be
targeted in its therapy. To explore whether
attenuation of these features produces
alleviation in the affective symptoms,
they conducted a randomised controlled
trial of botulinum toxin injection to the
glabellar region as an adjunctive
treatment of major depression. The study
was investigator-initiated and carried out
independently of any commercial entity.
Participants in the study were recruited
from local psychiatric outpatient units
and psychiatrists in private practice. In
order to avoid attracting candidates who
were primarily motivated by receiving
this treatment for cosmetic reasons,
botulinum toxin treatment was not
explicitly mentioned. Exclusion criteria
included psychotic symptoms, suicidal
tendency, and clinical severity requiring
immediate intervention. The same
injection scheme was applied as that of
the open case series2
. At each study visit,
participants were assessed using the
Hamilton Depression Rating Scale with
Atypical Depression Supplement
(SIGH‑ADS), the BDI self-rating
questionnaire, and the Clinical Global
Impressions (CGI) Scale. To conceal
Havas et al
noted that the
processing time for
sentences with
negative affective
connotation was
prolonged in
women after
botulinum toxin
treatment to the
glabellar.

4. References
1. Coleman C. Is Maria’s story proof
Botox can make you depressed?
London, UK: Daily Mail, 2013. http://
tinyurl.com/bv2y3kr (accessed 21
May 2013)
2. Finzi E, Wasserman E. Treatment
of depression with botulinum toxin
A: a case series. Dermatol Surg
2006; 32(5): 645–9
3. Heckmann M, Teichmann B,
Schröder U, Sprengelmeyer R,
Ceballos-Baumann AO.
Pharmacologic denervation of
frown muscles enhances baseline
expression of happiness and
decreases baseline expression of
anger, sadness, and fear. J Am Acad
Dermatol 2003; 49(2): 213–6
4. Larsen RJ, Kasimatis M, Frey K.
Facilitating the furrowed brow: an
unobtrusive test of the facial
feedback hypothesis applied to
unpleasant affect. Cognition
Emotion 1992; 6: 321–38
5. Hennenlotter A, Dresel C,
Castrop F, Ceballos-Baumann AO,
Wohlschläger AM, Haslinger B. The
link between facial feedback and
neural activity within central
circuitries of emotion--new insights
from botulinum toxin-induced
denervation of frown muscles.
Cereb Cortex 2009; 19(3):537–42
6. Havas DA, Glenberg AM,
Gutowski KA, Lucarelli MJ, Davidson
RJ. Cosmetic use of botulinum
toxin-a affects processing of
emotional language. Psychol Sci
2010; 21(7): 895–900
7. Neal DT, Chartrand TL. Embodied
emotion perception: amplifying and
dampening facial feedback
modulates emotion perception
accuracy. Soc Psychol Personal Sci
2011; doi: 10.1177/1948550611406138
8. Wollmer MA, de Boer C, Kalak N
et al. Facing depression with
botulinum toxin: a randomized
controlled trial. J Psychiatr Res 2012;
46(5): 574–81
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| xxxxxx | opinion
cosmetic changes from psychometric
raters, participants wore an opaque
surgical cap, which covered the glabella
and forehead during examinations.
The study concluded — for the first
time — that a single botulinum treatment of
the glabellar region with BOTOX could
reducethesymptomsofmajordepression.
This effect developed within a few weeks
and persisted until the end of the 16-week
follow-up period. The effect sizes in the
study were large and the response and
remission rates high. It is still unknown
how botulinum toxin actually reduces
depression and it is postulated that a
number of mechanisms may be involved.
As a result of the clinical data relating to
botulinum toxin treatment on emotional
perception, it is assumed that reduced
proprioceptive feedback from the
paralysed facial muscles is a relevant
mechanism of mood improvement.
As the authors did not include patients
who were cosmetically concerned about
their frown lines, it is unreasonable to
assume that an aesthetic benefit was the
major cause of mood improvement.
There is a small possibility of either
placebo effect or central pharmacological
botulinum toxin effects, including
possible pharmacodynamics or
pharmacokinetic interactions with
concomitant antidepressant therapy.
The ‘Botox Paradox’
So, who is correct? Does Botox reduce or
augment depression? How can the
findings of Dr Lewis be in complete
contrast to those of other researchers? I
believe that both are correct, and that the
answer to tise apparent medical paradox
lies with the original theories of Darwin.
Dr Lewis and colleagues found that
people treated for another muscle
(around the crows’ feet) left patients
feeling more depressed. This does not
contravene Darwin’s original hypotheses;
in fact it supports it. The muscles around
the eye are related to happiness and
smiling, and to restrict their movement
must interfere with the facial feedback
hypotheses in a converse way to those in
the glabellar area. We can only assume
that reduced proprioceptive feedback
from these paralysed facial muscles is a
relevant mechanism of mood
deterioration, and this is why they may
increase depression. Accordingly,
happiness can make you smile and
smiling can make you happy. It is obvious
that the facial musculature not only
expresses, but also regulates, mood states.
Botulinum toxin injection interferes with
the ‘facial feedback hypothesis’ originally
postulated by Darwin. (Perhaps it was my
sixth sense, but I never felt right about
totally removing crow’s feet around a
patient’s eyes.)
Conclusions
Thereisgrowingevidencethatbotulinum
toxin injection to the glabellar region may
be an effective, safe, and sustainable
intervention in the treatment of
depression. The reason for this has not
yet been fully evaluated, but we must
consider the concept that the facial
musculature not only expresses, but also
regulates, mood states. Owing to the
longer intervals between treatments, it
may also be an economic option, and the
safety and tolerability record of
botulinum toxin injections to the
glabellar region is excellent.
However, further studies are required,
including focus on muscles in the lower
sections of the face. It is possible that
treatment of the depressor angularis oris
and the mentalis muscles, for example,
may also have mood-elevating effects,
and may enhance the clinical effect of the
glabellar injection of botulinum toxin.
Modulation of mood states with
botulinum toxin may also be effective in
the treatment of other clinical conditions
involving negative emotions, like anxiety
disorders. There have also been recent
studies investigating the possibility of
botulinum toxin for bipolar disorder and
post-traumatic stress disorder (PTSD).
It is paramount to remember that
botulinum toxin to the glabellar region
may be an effective, safe, and sustainable
intervention in the treatment of
depression. The reason for this has not yet
been fully evaluated, but we must
consider the concept as depression
affects a huge number of people, making
it one of the leading causes of disability
worldwide.