A Study of the Efficacy of Botox in the Treatment of Social Anxiety Disorder

The use of botulinum toxin A to correct glabellar frown lines is an effective and popular
cosmetic procedure with more than 1 million treatments per year in the United States alone
(Carruthers, A.). Botulinum toxin type A marketed commercially as BOTOX® Cosmetic (Botox), is
produced from fermentation of Hall strain Clostridium botulinum type A grown in a medium
containing casein hydrolysate, glucose, and yeast extract, intended for intramuscular use.

Botox blocks neuromuscular transmission by binding to acceptor sites on motor nerve
terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. When
injected intramuscularly at therapeutic doses, Botox produces partial chemical denervation of
the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may
atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop.
There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle
denervation produced by Botox.

Botox is indicated for the temporary improvement in the appearance of moderate to severe
glabellar lines associated with corrugator and/or procerus muscle activity in adult patients
≤ 65 years of age.

Botox is contraindicated in the presence of infection at the proposed injection site(s) and
in individuals with known hypersensitivity to any botulinum toxin preparation or to any of
the components in the formulation.

Depression

The first open label trial of Botox to the glabellar muscle complex to treat unipolar
depression was published in 2006. Since that time, three randomized double blind
placebo-controlled trials were conducted to assess the efficacy of Botox treatment of the
glabellar muscle complex in major depression. All three studies showed a response rate of 50
to 60%, and the remission rate of approximately one-third. To date, no clinical trials of
Botox have been conducted in SAD.

Social Anxiety Disorder (SAD)

Social anxiety disorder (SAD) is a common psychiatric condition marked by persistent fear and
anxiety of one or more social or performance situations. The lifetime prevalence of the
disorder is 12%, and leads to significant morbidity for those affected. The only FDA approved
treatments for SAD have response rates of 40 to 60 %, and remission rates of 20%. Therefore,
there is a real need for the development of new and effective treatments for SAD.

Patients suffering from SAD either avoid situational triggers or endure intense anxiety and
distress, leading to an impaired social life in either scenario. SAD is characterized by an
overactive anxiety pathway with a perceptual and cognitive bias towards threat.

The amygdala, a limbic region with multiple projections to cortical and subcortical regions,
is thought to be critically involved in the regulation of emotion, with a general role in
directing attention to affectively salient stimuli, recruiting and coordinating cortical
arousal for optimizing sensory and perceptual processing of ambiguous or novel stimuli.. A
tight link between fear and the amygdala has been suggested. Fear related neuronal circuits
involving the amygdala are thought to play a role in the generation of social withdrawal,
fear, and anxiety.

Recently, two studies have linked botulinum toxin A treatment of the frown with
down-regulation of amygdala activity. Patients who received botulinum toxin A injections into
their frown muscles had decreased activity in the amygdala and its coupling with brain stem
activity when mimicking angry facial expressions. Further research has confirmed that
amygdala activity in response to angry faces was decreased when the frown muscles were
paralyzed by botulinum toxin A injection. Furthermore, amygdala activity returned to its
original state after the effects of the botulinum toxin A injection had worn off, confirming
that botulinum toxin A reversibly severed afferent feedback from the corrugator muscle to the
amygdala.

Given that SAD patients show abnormal patterns of amygdalar activation after viewing
emotional faces, we believe that there is a good likelihood that some of the symptoms of SAD
will improve after botulinum toxin A treatment of the frown.

Inclusion Criteria:

- primary diagnosis of social anxiety disorder

- women of childbearing potential on an acceptable form of birth control and are not
pregnant or lactating

Exclusion Criteria:

- has ever been treated with botulinum toxin A

- has another Axis I diagnosis within in the 6-months prior to screening

- history of substance abuse within 2-months of screening

- current or recent suicidality

- scoring greater than 2 on Beck Depression Inventory (BDI) suicidality question

- psychotic or bipolar disorder

- unstable medical condition

- changes in medication or psychotherapy treatment in the month prior to screening

- significant risk of committing homicide