The Relationship Among Changes in Brain Network Activation in Adult Outpatients With Major Depressive Disorder

Vortioxetine is a novel antidepressant with hypothetical multimodal mechanism of action. It
is thought to work through a combination of multiple pharmacological modes of action: 5-HT
(hydroxytryptamine, or serotonin) reuptake inhibition, 5-HT3 (hydroxytryptamine, or
serotonin) and 5-HT7 (hydroxytryptamine, or serotonin) receptor antagonism, 5-HT1A
(hydroxytryptamine, or serotonin) receptor agonism, and 5-HT1B (hydroxytryptamine, or
serotonin) receptor partial agonism. In vivo nonclinical studies have demonstrated that
vortioxetine enhances levels of the neurotransmitters 5-HT (hydroxytryptamine, or serotonin),
norepinephrine (NE), dopamine (DA), acetylcholine and histamine in specific areas of the
brain. These affinities are all considered to be of clinical relevance and involved in the
mechanism of action at therapeutic doses.

Vortioxetine has been shown to improve core depressive symptoms and improve cognitive
function in adult outpatients with MDD and subjective complaints of cognitive function. This
pilot study is intended to evaluate the extent to which BNA technology can provide clinically
valuable information and provide information toward designing a subsequent confirmatory study
that will further elucidate the effect of vortioxetine on MDD and cognitive function in this
population. This exploratory study will ascertain the acute changes in core depression
symptoms, cognitive function, tolerability, and safety using flexible-dose vortioxetine in
adult outpatients with MDD with subjective complaints of cognitive functioning, as measured
by BNA changes and standard outcome measures for depression and cognition.

The study consists of 8 weeks of open-label treatment for MDD with response to treatment
measured by standard research depression scales and BNA electroencephalogram (EEG) readings
taken at certain points during the trial. An important aim in this study is to explore what
correlations may exist between changes in measured brainwave patterns and reported change in
depressive symptoms

Inclusion Criteria:

- The subject has single episode or recurrent MDD (acute onset of recurrence of
recurrent MDD with poor inter-episode recovery) (inter-episode periods cannot meet
full MDD criteria) as the primary diagnosis according to DSM-IV-TR criteria. The
current major depressive episode (MDE) will be confirmed using the Mini International
Neuropsychiatric Interview (MINI V6.0.0).

- The subject has a MADRS total score ≥26.

- Subject reports subjective cognitive dysfunction (such as difficulty concentrating,
slow thinking, and difficulty in learning new things or remembering things).

- The reported duration of the current MDE is at least 3 months and no longer than 24
months.

- The subject is a man or woman between 18 and 65 years old, inclusive.

- Right-handed, normal (corrected) vision, and normal hearing.

Exclusion Criteria:

- The subject has a score of ≥70 on the Digit Symbol Substitution Test (DSST) at the
Baseline Visit.

- Failure to respond to or inability to tolerate an adequate trial of vortioxetine in
the past.

- Exposure to an investigational compound 30 days prior to enrollment

- Exposure to any psychoactive or otherwise excluded medication within five half-lives
of the baseline visit or during the study. Excluded medications include:
antidepressants, anxiolytics, anticonvulsants, barbiturates, chloral hydrate, lithium,
antipsychotics, benzodiazepines, hypnotics, monoamine oxidase inhibitors (MAOIs),
muscle relaxers, triptans, centrally-acting antihistamines, central alpha-2 agonists,
decongestants, psychostimulants, dopamine agonists, opioid pain medications, oral
corticosteroids, L-methylfolate, S-adenosyl methionine (SAMe), 5-HTP
(hydroxytryptophan), St. John's Wort,

- The subject has 1 or more of the following:

- Primary psychiatric disorder other than MDD as defined in the Diagnostic and
Statistical Manual of Mental Disorders 4 Text Revision (DSM-IV-TR) (as assessed
by the MINI, Version 6.0.0).

- Current or history of attention deficit hyperactivity disorder (ADHD), pervasive
developmental disorder, manic or hypomanic episode, schizophrenia, or any other
psychotic disorder, including major depression with psychotic features, mental
retardation, organic mental disorders, or mental disorders due to a general
medical condition as defined in the DSM-IV-TR.

- Current diagnosis of alcohol or other substance abuse or dependence (excluding
nicotine or caffeine) as defined in the DSM-IV-TR that has not been in sustained
full remission for at least 6 months (for abuse) and 12 months (for dependence)
prior to Screening.

- Positive urine drug screen prior to Baseline.

- Presence or history of a clinically significant neurological disorder (including
epilepsy).

- Neurodegenerative disorder (Alzheimer Disease, Parkinson Disease, multiple
sclerosis, Huntington Disease, etc).

- Any unstable medical condition as determined by the principal investigator (PI).

- Any DSM-IV Axis II disorder that might compromise the study as determined by the
PI.

- The subject has any other disorder for which the treatment takes priority over
treatment of MDD or is likely to interfere with study treatment or impair treatment
compliance.

- The subject has physical, cognitive, or language impairment of such severity as to
adversely affect the validity of the data derived from the neuropsychological tests.

- The subject has a significant risk of suicide according to the PI's clinical judgment.

- The subject, in the opinion of the PI, poses a risk of harm to others.

- The subject has initiated formal cognitive or behavioral therapy, systemic
psychotherapy within less than 6 months of study screening, or has plans to initiate
such therapy during the study.

- The subject has received electroconvulsive therapy, vagus nerve stimulation, or
repetitive transcranial magnetic stimulation within 12 months prior to Screening.

- The current MDE is considered by the PI to have been resistant to 2 adequate
antidepressant treatments of at least 6 weeks duration each at the recommended dose.

- The subject is pregnant or breastfeeding, or is intending to become pregnant before,
during, or within 30 days after participating in this study.