Toxicon xxx (2015) 1e4

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Toxicon
journal homepage: www.elsevier.com/locate/toxicon

Depression e An emerging indication for botulinum toxin treatment

Tillmann H.C. Kruger a, M.Axel Wollmer b, *
a
Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover, Germany
b
Asklepios Clinic North d Ochsenzoll, Asklepios Campus Hamburg, Medical Faculty, Semmelweis University, Germany

a r t i c l e i n f o a b s t r a c t

Article history: The treatment of glabellar frown lines with botulinum toxin injection is one of the most prevalent
Received 15 July 2015 procedures in esthetic medicine. It is possible that the popularity of this intervention is not only owing to
Received in revised form its cosmetic effect but also to modulatory effects on mood and affectivity.
10 September 2015
Recently, a series of studies including three randomized controlled trials have consistently shown that
Accepted 22 September 2015
Available online xxx
such effects can be used in the treatment of depression. Predominantly female patients suffering from
partly chronic and treatment resistant unipolar depression experienced a quick, strong and sustained
improvement in depressive symptoms after a single glabellar treatment with botulinum toxin A as a sole
Keywords:
Embodied emotions
or adjunctive therapy.
Body therapy If these findings are further corroborated in additional studies, the ever-growing spectrum of appli-
Major depressive disorder cations for botulinum toxin may spread into the field of psychiatry, showing that the superficial paralysis
of facial muscles may, probably via proprioceptive feedback mechanisms, have profound effects on the
emotional brain.
© 2015 Elsevier Ltd. All rights reserved.

1. Introduction 2009). Moreover the perception of visual emotional stimuli is

With several million applications per year injections of botuli-
num toxin as a treatment of glabellar frown lines, this is probably
the most frequent intervention in esthetic medicine (Winter and
Spiegel, 2009). Glabellar frown lines are produced by the contrac-
tion of the corrugator muscles that occurs under exposure to bright
light, during concentration and above all in order to express
negative emotions like anger, fear, or sadness. Thus, the motivation
to undergo glabellar botulinum toxin treatment and remove frown
lines may not be only the whish for a more youthful facial
appearance but also for a more relaxed and positive facial expres-
sion. Hence, it has been shown that the facial expression is shifted
away from negative towards positive emotions by glabellar botu-
linum toxin treatment (Heckmann et al., 2003). However, it is not
only emotional expression that is changed by the treatment, but
also emotional experience: This procedure may lead to an
enhancement of emotional wellbeing beyond the mere cosmetic
benefit (Sommer et al., 2003). It is also associated with reduced
levels of irritable, depressed, and anxious mood (Lewis and Bowler,
* Corresponding author. Asklepios Clinic North e Ochsenzoll, Langenhorner
Chaussee 560 22419 Hamburg, Germany.
E-mail address: m.wollmer@asklepios.com (M.Axel Wollmer).
altered and also the comprehension of sentences with negative
emotional connotations is delayed (Davis et al., 2010; Havas et al.,
2010). Accordingly, the treatment reduces the activation of the
left amygdale during imitation of an angry facial expression
(Hennenlotter et al., 2009).
2. The first case series
Physicians in esthetic medicine who treat patients with botuli-
num toxin are familiar with psychological effects of this treatment
(Sommer et al., 2003). The dermatologist and plastic surgeon Eric
Finzi was the first to specifically test the hypothesis that glabellar
injections of botulinum toxin may be useful in the treatment of
depression, a psychiatric disorder in which negative emotions
abound. In a case series Finzi and Wasserman treated ten middle-
aged women with moderate to severe partly chronic and
treatment-resistant depression with a single open label application
of botulinum toxin A (BTA) injections in the glabellar region ac-
cording to a standard protocol also used for cosmetic treatment of
frown lines (Finzi and Wasserman, 2006). As measured on the Beck
Depression Inventory (BDI) II before (mean ¼ 29) and eight weeks
after the treatment (mean ¼ 5.3) nine patients responded to the
treatment with eight of them going to remission of depression. The
only one who showed only partial response was a patient suffering

http://dx.doi.org/10.1016/j.toxicon.2015.09.035
0041-0101/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Kruger, T.H.C., Wollmer, M.A., Depression e An emerging indication for botulinum toxin treatment, Toxicon
(2015), http://dx.doi.org/10.1016/j.toxicon.2015.09.035
2 T.H.C. Kruger, M.Axel Wollmer / Toxicon xxx (2015) 1e4
from severe bipolar depression. Half of the participants received
BTA as a sole and the other half as an adjunctive treatment of
depression.
3. The first randomized controlled trial
In the first randomized controlled trial (RCT), Wollmer and
colleagues showed that a single glabellar treatment with BTA can
lead to a quick, strong and sustained improvement in the symp-
toms of depression (Wollmer et al., 2012). Their study included 30
patients, mostly women with an average age of about 50 years, who
suffered from mild to moderate, partly chronic, and treatment
resistant unipolar depression currently under stable treatment
with one or two antidepressants. These patients were able to
produce moderate to severe frown lines and where randomized to
receive blinded injection of either BTA or saline according to the
same scheme also applied in the case series by Finzi and Wasser-
man. Men received a total of 39 units onabotulinumtoxinA instead
of the 29 units applied in women to account for the higher muscle
mass. In comparison with the placebo group that remained more or
less stable throughout the study, the BTA group showed a signifi-
cant improvement in the symptoms of depression as early as two
weeks after the injection both on the Hamilton Depression Rating
Scale (HAM-D) and in the BDI. This effect was strong at the primary
end point after six weeks (47%; d ¼ 1.28) and increased further until
the end of the study after sixteen weeks (d ¼ 1.87). The improve-
ment in the depression scales was accompanied by an improve-
ment also in Clinical Global Impressions. Partial response (>25%
reduction in HAM-D score; 87%) and response (>50% reduction in
HAM-D score; 60%) rates were significantly higher in the BTA group
than in the placebo group and 33% of the BTA treated patients
attained remission. Those participants with higher levels of psy-
chomotor agitation at the baseline (HAM-D item 9 > 2) had a
particularly high probability to respond (100%, Wollmer et al.,
2014).
4. Further randomized controlled trials
In a second, larger (n ¼ 74) RCT Finzi and Rosenthal confirmed
the antidepressant effect of BTA. The participants in this trial were
slightly more depressed with otherwise similar baseline charac-
teristics compared to the study by Wollmer et al. (Finzi and
Rosenthal, 2014). According to the same protocol of the previous
trials, patients were randomized to receive either BTA (n ¼ 33) or
saline (n ¼ 41) injections and were examined after three and six
weeks using the BDI-II and Montgomery-Asberg Depresssion Rat-
ing Scale depression rating scales. Highly significant improvement
in depression occurred after three weeks and was more pro-
nounced after six weeks, which was the primary end point of the
study with similar improvement and response rates observed in
the study by Wollmer et al. (Wollmer et al., 2012). In addition Finzi
and Rosenthal also observed a significantly higher remission rate in
the BTA group compared to placebo. Of note, BTA was effective both
as a sole (remission rate 21%) and as an adjunctive (remission rate
36%) treatment and the antidepressant effect did not seem to
require the presence of glabellar frown lines at baseline (remission
in 5 of 13 participants without frown).
In a third RCT (n ¼ 30) by Magid et al. the previous findings were
further corroborated and extended (Magid et al., 2014). This study
had a crossover design, in which those patients who initially where
randomized to the BTA (n ¼ 11) arm received a second injection of
saline and those who were in the placebo arm (n ¼ 19) were
switched to BTA after 12 weeks. Since the muscle relaxing effect of
the first BTA injection had not worn off after 12 weeks and the
observed improvement in depression remained stable, the study
Please cite this article in press as: Kruger, T.H.C., Wollmer, M.A., Depression e An emerging indication for botulinum toxin treatment, Toxicon
(2015), http://dx.doi.org/10.1016/j.toxicon.2015.09.035
actually had a delayed start design, in which one group received
BTA treatment immediately and the other with a delay of 12 weeks.
With an overall follow up period of 24 week this study allowed for a
rather long-term observation of those patients who were in the BTA
first group. From the visit after 15 weeks to the final visit after 24
weeks, depression scores and frown line severity showed a diver-
gent development with further improvement in the former and a
return to baseline of the latter. Thus, the clinical improvement in
depression outlasted the cosmetic BTA effect. The group that
received BTA as the second injection after 12 weeks also showed an
improvement in depression after that second injection. Another
phase II RCT on the use of BTA as a treatment of major depression
(NCT02116361) with an estimated enrollment of 140 female pa-
tients will probably be completed early in 2016.
5. Other studies
Hexsel et al. conducted an open label study on the effects of
glabellar BTA injections on self-esteem and depression (Hexsel
et al., 2013). In a group of 25 depressed subjects the BDI score
dropped from an average of 27 to an average of 13, which corre-
sponds to the effects observed in the RCTs described above.
Recently, Boudreau et al. studied the effect of BTA on mild
depressive symptoms in patients (n ¼ 32) with chronic migraine
(Boudreau et al., 2015). BTA was applied according to the scheme
developed for the treatment of chronic migraine. The authors re-
ported improvement not only in the number of headache free days
but also in the severity of depressive symptoms as measured by the
BDI-II after 12 and 24 weeks. However, it can't be excluded the one
occurred as function of the other.
An overview of all clinical trials on the use of BTA in the treat-
ment of depression is given in Table 1.
6. Mechanism of action
Although there is consistent evidence suggestive of that
glabellar injection of BTA can reduce the symptoms of depression,
the mechanism of action by which improvement in mood is
accomplished is still unknown. There are several possibilities how
BTA alleviates depression: cosmetic effects achieved by glabellar
muscle relaxation may result in a better body image, enhanced self
esteem, and elevated mood (Molina et al., 2015). However, several
findings make it unlikely that this is the main mechanism of action:
In the first RCT the method under investigation, i.e. the injection of
BTA was not disclosed in the advertisement for the recruitment of
participants but only at screening, in order to avoid participants
that were particularly attracted by the perspective to receive a BTA
treatment with the known cosmetic effects. In the RCT treatment
outcome did not correlate with the appreciation of the cosmetic
change (Wollmer et al., 2012). Improvement in BDI scores did not
correlate with changes in self esteem scores as measured by the
Rosemberg scale (Hexsel et al., 2013) Moreover, presence of frown
lines at the baseline was not a prerequisite for response in a RCT
that did not have frown lines as an inclusion criterion (Finzi and
Rosenthal, 2014). One patient with a structurally fixed severe
frown line did not experience any cosmetic change but went into
remission. Another subject even reported that she specifically dis-
liked the cosmetic change but still attained remission of her
depression (Wollmer et al., 2012). Moreover, the antidepressant
effect outlasted the cosmetic change in a RCT with a follow-up
period of 24 weeks (Magid et al., 2014).
It is possible that a change in facial expression from the negative
emotions associated with depression towards more positive emo-
tions may confer a more positive social feedback during the inter-
action with the own mirror image or a social interaction partner.
 T.H.C. Kruger, M.Axel Wollmer / Toxicon xxx (2015) 1e4
Table 1
Trials on the use of botulinum toxin in the treatment of depression.
Yeara Studyb Authors Patients
2006 Finzi & Wasserman N ¼ 10
female
2012 RCT Wollmer et al. N ¼ 30
NCT00934687
2013 RCT Finzi & Rosenthal N ¼ 74
NCT01556971
2013 NCT01004042 Hexsel et al. N ¼ 25
2014 RCT Magid et al. N ¼ 30
NCT01392963
2015 Boudreau et al. N ¼ 32
n.a. RCT Allergan N ¼ 140
NCT02116361
a
Year of first online or print journal publication.
b
Trial number in the ClinicalTrial.gov study registry.
c
Doses separated by “/” refer to women and men, respectively.
However, both people living on their own and people living in
partnerships or families took part in the studies and the respective
social status did not predict the outcome (Wollmer et al., 2012,
2014). Therefore, it is unlikely that altered social feedback is the
main mechanism of action.
The most plausible and most probable mechanism by which BTA
may reduce the symptoms of depression is the interruption of a
feedback loop from the face to the brain that would reinforce and
maintain the negative emotions associated with depression. These
emotions are expressed by the contraction of the corrugator mus-
cles which is abolished by the BTA injection. A relative over activity
of the corrugator muscles can be recorded by electromyography in
patients suffering from depression (Schwartz et al., 1976). It may be
corrected by the paralytic effect of the injected BTA. The underlying
facial feedback hypothesis dates back to William James and Charles
Darwin in the 19th century. It means that the facial expression of an
initially faint and cool emotion generates a proprioceptive feedback
signal from the face to the brain that enhances the emotion and
allows for its powerful and warm experience (Adelmann and
Zajonc, 1989; Al Abdulmohsen and Kruger, 2011). The facial feed-
back hypothesis has been validated in classical experiments
showing that the arbitrary contraction of facial muscles can
modulate the emotional appraisal of a presented visual stimulus
(Strack et al., 1988; Larsen et al., 1992).
There is experimental evidence that a fraction of locally injected
BTA may undergo axonal and even trans-synaptic transport into the
CNS (Caleo and Schiavo, 2009). Central effects may be of clinical
relevance in humans and we can't formally exclude that they could
be involved in the mood-lifting effects of BTA observed in our
studies (Marchand-Pauvert et al., 2013).
7. Significance for the management of depression
Affecting more than 350 million people worldwide major
depression is one of the leading causes of disability in the world
(Kessler et al., 2003). There are several effective psychotherapeutic,
pharmacological and biological approaches to the treatment of
depression. However, a considerable proportion of patients do not
sufficiently respond to these existing treatment options, leaving
Please cite this article in press as: Kruger, T.H.C., Wollmer, M.A., Depression e An emerging indication for botulinum toxin treatment, Toxicon
(2015), http://dx.doi.org/10.1016/j.toxicon.2015.09.035
3
Interventionc Outcome
29 U onabotulinumtoxinA First study showing that BTA can improve
Glabella the symptoms of depression. Response or
remission was attained by almost all patients.
29/39 U onabotulinumtoxinA First RCT showing significant improvement in
or saline placebo depression and higher partial response and
Glabella response rates after adjunctive BTA injection
compared to placebo.
29/40 U onabotulinumtoxinA Significant improvement in depression, higher
or saline placebo response and also higher remission rates after
Glabella sole or adjunctive BTA injection compared to placebo.
20-40 U onabotulinumtoxinA Improvement in the symptoms of depression
after injection of BTA
29/39 U onabotulinumtoxinA Significant improvement in depression, higher
or saline placebo response and also higher remission rates after
Glabella BTA injection compared to placebo outlasting
muscular paralysis and cosmetic change.
155 U onabotulinumtoxinA Improvement in depressive symptoms associated
Head and neck with chronic migraine.
Two different doses n.a.
onabotulinumtoxinA
or saline placebo
them with chronic and treatment-resistant depression (Gilmer
et al., 2005). Thus, there is a strong medical, social and economic
need for the development of new methods to treat depression. To
use BTA in the treatment of depression is a new approach with
several favorable aspects: The long-lasting effect of a single treat-
ment may facilitate therapy adherence, which may be a critical
issue in the treatment of patients with depression (Serna et al.,
2010). If the costs are allocated per treatment day the long treat-
ment intervals render BTA an economic therapeutic option (Beer,
2010). The safety and tolerability record of BTA injections to the
glabellar region is very good (Brin et al., 2009). All these aspects
make BTA an attractive potential option in the future treatment of
depression for patients, physicians, and the public health system.
Because glabellar injection of BTA is registered for the treatment of
frown lines, depressed patients with such lines may be treated
today without going off label.
8. Open questions
Low or absent placebo effects in conjunction with difficulties to
blind patients for their treatment allocation raises the question, to
what extent the results of the RCTs may be attributed to placebo
effects. A facial injection that leads to a visible change in facial
expression certainly has a considerable suggestive power. There-
fore it is possible that the proportion of placebo effects in the
clinical improvement of depression is higher after BTA treatment
than after treatment with an oral antidepressant. Conversely it is
possible that disappointment over the obvious absence of a
cosmetic change under placebo condition may have led to nocebo
effects in this group. This may have led to an inflation of the group
differences in the randomized controlled trials and to an over-
estimation of the efficacy of BTA as a treatment of depression.
However, the RCTs patient's expectations and credibility regarding
the method did not correlate with the outcome (Wollmer et al.,
2012). Moreover, in one of the RCTs their hit rate when guessing
group allocation was scarcely above chance level and correct or
incorrect guessing was not associated with outcome either (Finzi
and Rosenthal, 2014). Importantly, in another RCT the improve-
ment in depression outlasted the cosmetic effect of the treatment
4 T.H.C. Kruger, M.Axel Wollmer / Toxicon xxx (2015) 1e4
(Magid et al., 2014).
Very few men took part in the hitherto concluded clinical trials
and an ongoing trial (NCT02116361) enrolls only women. In the first
RCT there was actually a trend towards a gender effect in favor of
women (Wollmer et al., 2012). Thus, the efficacy of BTA as a
treatment of depression in men is an open question that should be
specifically addressed in future trials. It is unclear if BTA is also
effective in severe, psychotic, or bipolar depression. A comparator
study in which BTA is tested against an established pharmacolog-
ical treatment may further clarify the true effect sizes and over-
come the problems associated with blinding. It is possible that
other facial muscles involved in the expression of sad mood, like
the mentalis muscle or the depressor anguli oris, may also be tar-
geted with BTA. Moreover it is possible that patients suffering from
other psychiatric disorders in which negative emotions are preva-
lent may benefit from BTA treatment, too. To date only onabotuli-
numtoxinA has been investigated as a treatment of depression. It is
probable, but formally remains to be established, that also other
types of botulinum toxin are effective in this new indication.
Conflicts of interest
M.A.W. received honoraria for talks from Merz, Eli Lilly, Lund-
beck, and Novartis. T.H.C.K. received honoraria for talks from Eli
Lilly, Lundbeck, Servier, and Schwabe. These activities were all
unrelated to the study. M.A.W. received a grant from the Asklepios
Hamburg GmbH Forschungsfo € rderung for related research. In April
2012, i.e. after conclusion and publication of their original study,
M.A.W. and T.H.C.K. became members of the advisory board of
Allergan. This activity ended in April 2014 for M.A.W. and in
September 2014 for T.H.C.K.
Transparency document
Transparency document related to this article can be found
online at http://dx.doi.org/10.1016/j.toxicon.2015.09.035.
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