Long-Term, Open-Label, Safety Study of LY2216684 12 to 18 mg Once Daily as Adjunctive Treatment for Patients with Major Depressive Disorder Who are Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment

Major depressive disorder (MDD) is defined in the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition Text Revision® (DSM-IV-TR) as
pervasive depressed mood or loss of interest that occurs for at least 2 weeks
along with other core symptoms of fatigue, difficulty concentrating, feelings
of worthlessness/guilt, sleep disturbance, appetite disturbance, and thoughts
of death/suicide. Current treatment recommendations for MDD focus on selective
serotonin reuptake inhibitors (SSRIs) as a first-line treatment (American
Psychiatric Association [APA] 2000). While these medications have demonstrated
efficacy, response to treatment is varied. In clinical studies, approximately
two thirds of patients meet standard criteria for treatment response (*50%
improvement in depressive symptomatology from initiation of treatment);
however, only one third of patients meet criteria for remission (resolution of
depressive symptoms) during acute treatment (8 to 12 weeks). For example, in
the Sequential Treatment Alternatives to Relieve Depression multicenter study
(STAR*D), patients were initially treated with citalopram. After 8 weeks of
treatment, response rate was 47% and remission rate was 28%.

The purpose of this study, H9P-MC-LNBO (LNBO), is to assess the long-term
safety and tolerability of LY2216684 administered QD in the adjunctive
treatment with an SSRI for up to approximately 1 year in patients with MDD who
are partial responders to their SSRI treatment. The secondary objectives of
this study will be to evaluate the long-term efficacy of LY2216684 in
adjunctive treatment with SSRIs in patients with MDD.

The primary objective of this study is to evaluate the long-term safety and
tolerability of LY2216684 administered once daily (QD) in the adjunctive
treatment with a selective serotonin reuptake inhibitor (SSRI) for up to
approximately 1 year in patients with major depressive disorder (MDD) who are
partial responders to their SSRI treatment. The safety measures include the
collection and reporting of discontinuation rates, treatment-emergent adverse
events (TEAEs), vital signs, weight, electrocardiograms (ECGs), and laboratory
analysis.

The secondary objectives of the study are:

-To evaluate the safety and tolerability of LY2216684 as an adjunctive
treatment for patients with MDD who are partial responders to their SSRI
treatment as measured by the following measures:
* Serious adverse events (SAEs)
* Discontinuation-emergent adverse events (DEAEs)
* Columbia-Suicide Severity Rating Scale (C-SSRS)
* Arizona Sexual Experiences (ASEX) scale
* Massachusetts General Hospital Cognitive and Physical Functioning
Questionnaire (CPFQ)

-To evaluate the effect of LY2216684 on depressive symptoms as an adjunctive
treatment for patients with MDD who are partial responders to their SSRI
treatment as measured by the change from baseline using the following measures:
* Montgomery-Asberg Depression Rating Scale (MADRS) total score and individual
items.
* Hospital Anxiety and Depression Scale (HADS) depression subscale
* Clinical Global Impression - Severity (CGI-S)

-To evaluate the effect of LY2216684 as an adjunctive treatment for patients
with MDD who are partial responders to their SSRI treatment in reducing fatigue
symptoms associated with depression, as measured by the change from baseline
using the following measure:
* Fatigue Associated with Depression (FAsD) average score, the fatigue
experience subscale score, and the
fatigue impact subscale score.

-To evaluate the effect of LY2216684 on depressive symptoms as an adjunctive
treatment for patients with MDD who are partial responders to their SSRI
treatment as measured by response and remission rates, as well as time to
response and remission.

-To evaluate the effect of LY2216684 as an adjunctive treatment for patients
with MDD who are partial responders to their SSRI treatment in reducing anxiety
symptoms associated with depression, as measured by the change from baseline
using the following measure:
* HADS Anxiety Subscale score.

-To evaluate the effects of LY2216684 as an adjunctive treatment for patients
with MDD who are partial responders to their SSRI treatment on quality of life
and health outcomes using the following measures:
* Sheehan Disability Scale (SDS) global functional impairment score,
work/school subscore, social life subscore,
family life/home responsibilities impairment subscores,
number of days lost, and number of days unproductive
* EuroQol Questionnaire * 5 Dimension (EQ-5D)
* Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form
(Q-LES-Q-SF)
* Resource Utilization (RU)

-To examine the influence of CYP2D6 genetic variation on LY2216684 response in
patients with MDD who are partial responders to their SSRI treatment.

-To assess the plasma concentrations of LY2216684 as adjunctive treatment with
SSRIs in patients with MDD who are partial responders to their SSRI treatment

Exploratory Objectives:
* To explore the influence of relevant drug metabolizing enzymes and/or
transporters on LY2216684 plasma
concentrations and LY2216684 response in patients with
MDD who are partial responders to their SSRI treatment.
* To examine the effect of genetic variation on response to treatment in
patients with MDD who are partial
responders to their SSRI treatment.

An open-label assessment of safety and tolerability over 1 year treatment of
LY2216684 as an adjunctive therapy in patients with MDD who are partial
responders to their SSRI treatment

Questionnaires and a patient diary will be completed

The blood samples will be collected.

A physical exam (including blood pressure, pulse rate, temperature, height and
weight) will be completed

Information on the patients caffeine, tobacco and alcohol use will be collected

A urine sample will be collected

An ECG will be completed to check the patient's overall health

The most frequently reported events (more than 10%) by healthy people who have
received one
or more than one dose of LY2216684 were feeling sleepy, upset stomach,
headache, dizziness,
hard or infrequent stools, problems beginning urination, and feeling of
irregular or forceful
beating of the heart

Please refer to Appendix 2 of the Patient Information Sheets for more
information regarding the risks and possible discomforts patients might
experience during the study procedures